Anal Pap smears and anal cancer: What dermatologists should know Walter Liszewski, BA,a Amy T. Ananth, MD,b Lauren E. Ploch, MD,b,c and Nicole E. Rogers, MDb New Orleans, Louisiana Squamous epithelial cells are susceptible to infection by the human papillomavirus. Infection of squamous epithelium with oncogenic human papillomavirus types is associated with development of dysplasia and potential malignant transformation. Historically, cervical cancer has been the most prevalent human papillomaviruseinduced squamous neoplasia. However, because of widespread screening via Pap smear testing, rates of cervical cancer in the United States have decreased dramatically during the past 50 years. Rates of anal cancer, in contrast, have doubled during the past 30 years. The groups at highest risk for development of anal cancer are men who have sex with men, HIV-positive patients, and patients immunosuppressed as a result of solid-organ transplantation. By detecting dysplasia before it develops into invasive cancer, anal Pap smears may be a potentially useful screening tool for anal cancer, particularly in individuals known to be at increased risk. However, at this time, sufficient data supporting the benefit of anal Pap smear screening are lacking. With insufficient evidence, no national health care organizations currently recommend the use of anal Pap smears as a routine screening test, even among high-risk groups. ( J Am Acad Dermatol 2014;71:985-92.) Key words: anal cancer; anal dysplasia; anal Pap smear; human papillomavirus; squamous cell carcinoma of the anus.
T
he Papanicolaou test, or Pap smear, is used to screen for cervical cancer by identifying dysplastic squamous cells in the cervical mucosa. Like the cervix, the anus is lined by stratified squamous epithelium, which can undergo malignant transformation when infected by specific types of human papillomavirus (HPV). Although all HPV types can promote cancer, the risk is greater with ‘‘high-risk’’ types than with ‘‘low-risk’’ types. Approximately 84% to 90% of all cases of anal cancer are caused by HPV infection. Among HPV-related cancers, high-risk types 16 and 18 are responsible for 70% of all cervical cancers and 93% of all anal cancers.1-4 Just as Pap smears have led to a dramatic decrease in the incidence of cervical cancer in the United States, they may potentially be used to decrease the incidence of anal cancer, although large, well-controlled trials have yet to validate this. Two vaccines against HPV have been developed, namely Cervarix, which targets high-risk HPV types 16 and 18, and Gardasil, which targets From Tulane University School of Medicinea; and Department of Dermatologyb and Ochsner Clinic Foundation,c Tulane University. Funding sources: None. Conflicts of interest: None declared. Accepted for publication June 28, 2014. Reprint requests: Nicole E. Rogers, MD, Department of Dermatology, Tulane University, 701 Metairie Rd, Metairie, LA 70005. E-mail: [email protected].
Abbreviations used: AIN: CDC: HPV: HRA: ICER: MSM: SCCA:
anal intraepithelial neoplasia Centers for Disease Control and Prevention human papillomavirus high-resolution anoscopy incremental cost-effectiveness ratio men who have sex with men squamous cell carcinoma of the anus
low-risk HPV types 6 and 11 in addition to types 16 and 18.5 The Centers for Disease Control and Prevention (CDC) recommends HPV vaccination for girls and boys ages 11 to 12 years and for men who have sex with men (MSM) and HIV-positive patients up to age 26. Computer modeling has predicted that HPV vaccination will result in lower rates of anal cancer. In clinical trials high rates of seroconversion and decreased rates of anal dysplasia have been observed in HIV-positive and -negative MSM after vaccination.6-10 Published online July 31, 2014. 0190-9622/$36.00 Ó 2014 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2014.06.045
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anal Pap smears are performed with a polyester swab. Anal cancer, like cervical cancer, tends to Between 1975 and 2010, according to the National occur at the squamous-glandular transformation Cancer Institute’s Surveillance Epidemiology and zone, so the swab is inserted 3 to 5 cm past the End Results data, the delayed-adjusted incidence of external anal sphincter to obtain cells from the cervical cancer in the United States decreased from rectoanal transformation zone.30,32 Once fully in14.8 to 6.7 cases per 100,000 women (Fig 1). During serted, the swab is rotated, then continually rotated the same period, rates of squamous cell carcinoma of as it is slowly removed. The the anus (SCCA) increased sample from the swab can be from 0.95 to 1.82 cases per CAPSULE SUMMARY mounted and fixed to a slide 100,000 women (Fig 2) and or it can be placed into a from 0.66 to 1.42 cases per In the United States, rates of anal cancer liquid cytology solution.32,33 100,000 men (Fig 3).11 In have increased during the past 3 After the Pap smear is men, the increase in SCCA decades. completed, a digital rectal can largely be attributed to Almost all cases of anal cancer are examination should be perHIV/AIDS. In women, the caused by human papillomavirus formed, followed by a visual increase appears to be a infection. inspection of the anus and result of changes in sexual palpation of the inguinal practices, specifically inWe review the epidemiology of anal lymph nodes.32 creased number of lifetime cancer and the data supporting the use The Bethesda System, the sexual partners and recepof anal Pap smears to screen for anal cytologic classification systive anal intercourse.12 dysplasia. tem initially developed for Factors associated with an cervical Pap smears, has increased risk of SCCA been translated for classification of anal Pap include history of cervical or vulvar dysplasia, smoksmears.34 Table I outlines this grading system. ing, and receptive anal sex (in males or females).13-22 Any patient with an abnormal smear result, ie, In particular, patients who are immunocompromised atypical squamous cell of undetermined significance as a result of solid-organ transplantation or HIV are at and above, should subsequently undergo highparticularly elevated risk.22 Compared with the genresolution anoscopy (HRA).35 eral population, the risk of SCCA is 24 times higher in During HRA, an anoscope is inserted into the anal HIV-positive women, 32 times higher in HIV-positive canal, and the epithelium is inspected (Fig 4). men overall, and 52 times higher in HIV-positive Subsequently, 3% acetic acid, followed by Lugol’s MSM.23-25 The rate of anal cancer in HIV-positive iodine, is applied to the squamocolumnar junction. MSM is approximately twice that of HIV-negative When treated with this solution, dysplastic lesions MSM.26 Interestingly, HIV-positive men without a may turn white or appear to have abnormal vasculahistory of receptive anal intercourse are still at an ture, ulceration, or discoloration.36,37 However, inelevated risk for SCCA.27 Since the adoption of highly flamed epithelium, such as caused by lichen sclerosus active antiretroviral therapy, rates of certain AIDSor lichen planus, may also turn white.38 Areas with defining malignancies, specifically Kaposi sarcoma atypical appearance are biopsied and sent for histoand non-Hodgkin lymphoma, have sharply declined pathologic examination.36,37 It is essential that HRA whereas cases of SCCA have continued to in28-30 only be performed by physicians who have been crease. Highly active antiretroviral therapy had adequately trained in the procedure because mucous, previously not been shown to reduce the incidence fecal material, and folds in the mucosa make it difficult of anal dysplasia,22,29 however, recent data suggest to adequately visualize the entire anal mucosa.37 persistent undetectable viral loads decrease the risk 31 Dysplasia noted on biopsy specimens is termed of developing SCCA. Among patients with a history ‘‘anal intraepithelial neoplasia’’ (AIN) and is classiof solid-organ transplantation, the risk of anal fied according to depth of involvement of the dysplasia and SCCA is estimated to be 10 to 100 epithelium (Table II).34 Although the classification times higher than in the general population.22 of anal dysplasia seems straightforward, a lack of interobserver agreement among pathologists evaluating anal biopsy specimens has been noted.39-41 ANAL PAP SMEARS There is disagreement whether HRA should be Collection and interpretation performed directly after an anal Pap smear, or Anal Pap smears can be easily collected in the whether HRA should only be performed if anal outpatient setting. Although cervical Pap smears are cytology is abnormal.42-44 When compared with performed with both a spatula and pointed brush, d
d
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Fig 1. Annual age-adjusted incidence of cervical cancer per 100,000 women of all races in the United States.
Fig 2. Annual age-adjusted incidence of anal cancer per 100,000 women of all races in the United States.
Fig 3. Annual age-adjusted incidence of anal cancer per 100,000 men of all races in the United States.
biopsy specimens obtained during HRA, anal Pap smears have a sensitivity of 61% to 93% and a specificity of 32% to 67%.42,45-48 The sensitivity of anal Pap smears has been shown to be higher in HIVpositive patients, especially those with CD4 counts below 400, larger areas of involvement, and AIN 2 or 3.46 However, the sensitivity of anal Pap smears is lower than the sensitivity of cervical Pap smears.49 In 1 study in which HRA was performed directly after anal Pap smear, 53% of patients who had normal anal cytology were found to have abnormal pathology on biopsy specimens obtained during HRA, with 23% having high-grade squamous intraepithelial lesion.44 In another study, 45% of HIV-positive and 23% of HIV-negative MSM who had negative cytology had AIN on HRA.50 Anal cytology has a low sensitivity, but it is less invasive and uncomfortable for the patient than HRA. In addition, HRA requires technical proficiency, and there is a shortage of
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physicians who have been adequately trained. Although cytology and subsequent HRA may be ideal, it is currently more practical to reserve HRA for cases of abnormal anal cytology.37,50 The role of testing anal Pap smear specimens for HPV is also controversial. There is disagreement whether all samples, no samples, or only samples with abnormal cytology (reflex testing) should be tested for HPV.43,51-54 A recent meta-analysis showed that 92.6% of all HIV-positive MSM had at least 1 HPV type on anal cytology, 73.5% had at least 1 oncogenic type of HPV, and 35.4% had type 16 specifically. Similarly, 62.9% of HIV-negative MSM had at least 1 type of HPV, 37.2% had at least 1 oncogenic type of HPV, and 12.5% had type 16.55 Because HPV infection is extremely common, HPV testing may not be useful in guiding clinical treatment of patients. The natural progression of anal dysplasia and potential transformation into invasive carcinoma is not well understood. In a study of MSM, 63% of HIVpositive men with low-grade squamous intraepithelial lesion progressed to high-grade squamous intraepithelial lesion within 2 years, compared with 36% of HIV-negative MSM.56 Interestingly, among HIVpositive patients on highly active antiretroviral therapy, AIN 2/3 is less likely to regress if the patient’s CD4 nadir was below 200.57 In pooled, retrospective studies of immunocompetent patients, solid-organ transplant recipients, and HIV-positive patients, 9% to 13% of all patients with AIN 3 progressed to SCCA.58 Ultimately, more data on the progression and regression of anal dysplasia are greatly needed. Treatment and follow-up There is disagreement whether AIN 2 and 3 should be treated or observed, although most physicians advocate observation for AIN 1.58-64 Current treatment options include carbon-dioxide laser ablation, cryosurgery, topical 5-fluorouracil, and topical imiquimod. With the exception of transient pain and irritation, these treatments are generally well tolerated.21,59,63 A 2012 Cochrane review, however, concluded that there is currently insufficient evidence to determine whether AIN should or should not be treated.64 Even when anal dysplasia is treated, it often reoccurs, particularly in HIV-positive patients.61 There is also no current evidence to suggest that treating AIN increases survival. However, regardless of the grade of dysplasia, patients with symptoms secondary to their dysplasia, such as pruritus or dyschezia, should be considered for treatment.59 Historically, invasive SCCA was treated by surgical removal of the anus and adjacent perineum. Not surprisingly, larger excisions were associated with
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Table I. Bethesda grading system for anal cytology Dysplasia classification
Normal ASC-US
ASC-H LSIL HSIL
Description
No dysplastic squamous cells observed Because of inflammation, squamous cells may appear atypical, however, the irregularity of the cells is likely a result of current, nonspecific inflammation of the mucosa and not HPV infection; were it not for the current inflammation, the cells would likely appear to be normal Similar to ASC-US, ASC-H cells appear atypical, however, they have some, but not all, characteristics of the dysplastic cells seen in HSIL Mild dysplasia of squamous cells is observed, usually as a result of HPV Moderate to severe dysplasia of squamous cells is observed, usually as a result of HPV
ASC-H, Atypical squamous cellsecannot exclude HSIL; ASC-US, atypical squamous cells of undetermined significance; HPV, human papillomavirus; HSIL, high-grade squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion.
Evidence and recommendations for anal Pap smears Currently, no national bodies, such as the US Preventive Services Task Force, have established recommendations for anal Pap smears. However, the CDC, American Society of Colon and Rectal Surgeons, and the United Kingdom’s National Screening Committee have acknowledged that anal Pap smears may be practical in high-risk populations, such as HIV-positive patients or those with solid-organ transplantation, although the dearth of results from large-scale studies prevents a formal recommendation.68-70
Fig 4. Evidence of anal dysplasia on high-resolution anoscopy. A, Dysplastic lesion (arrowheads) with punctations at the squamocolumnar junction. B and C, Positive acetowhite staining (arrows) of the anal mucosa in the superior field of the anoscope. Used with permission courtesy of Dr Olivier Richel (A) Dr Michael Hagensee (B and C).
the risk of anal stenosis, abscess formation, dyschezia, and anal spasms.58 The current standard of care is the Nigro protocol, which uses a combination of radiation therapy, 5-fluorouracil, and mitomycin.65,66 The 5-year survival for SCCA is approximately 75%, and recurrence rates range from 20% to 37%.21 After treatment, patients should receive a digital rectal examination and palpation of the inguinal nodes every 3 to 6 months for the first 2 years, followed by a digital rectal examination and inguinal node palpation every 6 to 12 months for the next 3 years.67
Cost-effectiveness of anal Pap smears Three models have shown that anal Pap smear screening may be cost-effective for certain patient populations in the United States. These models use an incremental cost-effectiveness ratio (ICER), which is a ratio of the cost of a procedure relative to the number of quality-adjusted life years gained. In general, an ICER of less than $30,000 to $50,000 is considered to be cost-effective.30 In HIV-positive men, the ICER of annual Pap smears is estimated to be $16,600, whereas performing anal Pap smears every 3 years in HIV-negative MSM would be $7800.71,72 In HIV-positive women with a CD4 count of less than 200, annual and biennial anal Pap smears have an estimated ICER of $112,026 and $35,805, respectively.73 For comparison, the ICER of skin examinations in Americans with an average risk of melanoma after the age of 50 years is $10,100 if performed once and $586,800 if performed annually.74 Ultimately, these models suggest that routine anal Pap smears may be cost-effective in HIV-positive men and women and in HIV-negative MSM.
THE ROLE OF THE DERMATOLOGIST With limited data and no national recommendations, do anal Pap smears have a place in dermatology?
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Table II. Classification of dysplasia in anal epithelial biopsies Dysplasia classification
AIN1 AIN2 AIN3
Description
Anal cytology equivalent
From the basal layer, dysplasia is present in the lower third of the epithelium From the basal layer, dysplasia is present in the lower one third to two thirds of the epithelium From the basal layer, dysplasia is present in the lower two thirds of to entire epithelium
LSIL HSIL HSIL
AIN, Anal intraepithelial neoplasia; HSIL, high-grade squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion.
Table III. International Classification of Diseases, Ninth Revision and Current Procedural Terminology codes relating to anal Pap smears and anoscopy ICD-9 codes 796.7 796.71 796.72 796.73 796.74 796.75 796.76 796.77 796.78 CPT codes 46600
46606
Abnormal glandular Papanicolaou smear of anus Papanicolaou smear of anus with ASC-US Papanicolaou smear of anus with ASC-H Papanicolaou smear of anus with LSIL Papanicolaou smear of anus with HSIL Anal high-risk HPV DNA test positive Papanicolaou smear of anus with cytologic evidence of malignancy Satisfactory anal smear but lacking transformation zone Unsatisfactory anal cytology smear Anoscopy; diagnostic, with or without collection of specimen(s) by brushing or washing Anoscopy; with biopsy, single or multiple
ASC-H, Atypical squamous cellsecannot exclude HSIL; ASC-US, atypical squamous cells of undetermined significance; CPT, Current Procedural Terminology; HSIL, high-grade squamous intraepithelial lesion; ICD-9, International Classification of Diseases, Ninth Revision; LSIL, low-grade squamous intraepithelial lesion; HPV, human papillomavirus.
Many dermatologists frequently see patients who are at an increased risk for development of SCCA, such as MSM and those with HIV. What role do dermatologists play in treating these patients? Unfortunately, it is not clear. Although we know MSM, HIV-positive individuals, and immunosuppressed organ transplant recipients are at an increased risk of developing SCCA, there are no national recommendations to screen these patients with anal Pap smears. At this point in time, the best screening test in this population is a thorough history and physical.75 Dermatologists should ask about a history of cervical or vulvar dysplasia, HIV status, smoking, immunosuppression, and sexual practices, specifically receptive anal intercourse. Review of systems should include symptoms of SCCA, such as anal fissures, pruritus, discharge,
Fig 5. Decision tree concerning when to consider anal Pap smear or high-resolution anoscopy (HRA) in patients at high risk for anal cancer. ROS, Review of systems; SCCA, squamous cell carcinoma of the anus.
bleeding, or pain.76 The dermatologist should also perform a physical examination to look for discoloration, growths, or ulcers of the anus and palpate the inguinal lymph nodes.30 Billing for anal Pap smears can be complicated. There is no Current Procedural Terminology code for collection of an anal Pap smear. Instead, a physician must bill for a general visit and perform the collection as part of the visit. There are laboratory International Classification of Diseases, Ninth Revision codes that a pathologist can use for reading anal cytology, and there are Current Procedural Terminology codes for HRA (Table III). In the authors’ experience, insurance companies may not pay for anal Pap smear testing, however, if the results are abnormal, they will cover the cost of HRA with biopsies.
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In summary, anal Pap smear may be considered as a screening tool for patients at high risk for development of SCCA (HIV-positive patients, MSM, and organ transplant patients), although this is not currently the standard of care and is not covered by medical insurance policies. For patients at high risk with signs or symptoms of SCCA that persist despite conservative medical management, HRA with biopsy is warranted (Fig 5). Before an anal Pap smear is performed, the dermatologist should discuss the diagnostic limitations of the test, the uncertainty of how to manage AIN if it is detected, the lack of national recommendations for the test, and the likelihood that it will not be covered by insurance. If the patient decides to have an anal Pap smear, the test should be performed by a physician who has experience performing and counseling patients about anal Pap smears and anal cancer. The physician must also be able to perform HRA or to easily refer the patient to a physician who can in the event that the anal cytology is abnormal. In addition, the cytology should be read by a pathologist who has experience reading anal Pap smears. Ultimately, if invasive SCCA is found, the patient must be referred to a medical oncologist or colorectal surgeon. Conclusion Over the past 3 decades, the incidence of SCCA in the United States has doubled. MSM, HIV-positive patients, and solid-organ transplant recipients are known to be at an increased risk of developing SCCA. Because of insufficient evidence on the benefits and harms of screening for SCCA and AIN with anal Pap smears, there are no national recommendations advocating their use as a routine screening tool, however, anal Pap smears may be useful in this select group of patients. Ultimately, large, long-term studies on the progression of AIN and the benefits and risks of treating AIN are needed. REFERENCES 1. Chaturvedi AK. Beyond cervical cancer: burden of other HPV-related cancers among men and women. J Adolesc Health 2010;46:S20-6. 2. DeVuyst H, Clifford GM, Nascimento MC, Madeleine MM, Franceschi S. Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis. Int J Cancer 2009;124:1626-36. 3. Gillison ML, Chaturvedi AK, Lowy DR. HPV prophylactic vaccines and the potential prevention of noncervical cancers in both men and women. Cancer 2008;113:3036-46. 4. Parkin DM. The global health burden of infectionassociated cancers in the year 2002. Int J Cancer 2006; 118:3030-44.
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42. Nahas CS, da Silva Filho EV, Segurado AA, Genevcius RF, Gerhard R, Gutierrez EB, et al. Screening anal dysplasia in HIV-infected patients: is there an agreement between anal Pap smear and high-resolution anoscopy-guided biopsy? Dis Colon Rectum 2009;52:1854-60. 43. Machalek DA, Grulich AE, Hillman RJ, Jin F, Templeton DJ, Tabrizi SN, et al. The Study of the Prevention of Anal Cancer (SPANC): design and methods of a three-year prospective cohort study. BMC Public Health 2013;13:946. 44. Lee EQ, Goldstone SE. Predictors of anal dysplasia in men who have sex with men with benign cytology. Dis Colon Rectum 2011;54:347-51. 45. Arain S, Walts AE, Thoman P, Bose S. The anal Pap smear: cytomorphology of squamous intraepithelial lesions. Cytojournal 2005;2:4. 46. Nathan M, Singh N, Garrett N, Hickey N, Prevost T, Sheaff M. Performance of anal cytology in a clinical setting when measured against histology and high-resolution anoscopy findings. AIDS 2010;24:373-9. 47. Fox PA, Seet JE, Stebbing J, Francis N, Barton SE, Strauss S, et al. The value of anal cytology and human papillomavirus typing in the detection of anal intraepithelial neoplasia: a review of cases from an anoscopy clinic. Sex Transm Infect 2005;81:142-6. 48. Palefsky JM, Holly EA, Hogeboom CJ, Berry JM, Jay N, Darragh TM. Anal cytology as a screening tool for anal squamous intraepithelial lesions. J Acquir Immune Defic Syndr Hum Retrovirol 1997;14:415-22. 49. Chiao EY, Giordano TP, Palefsky JM, Tyring S, El Serag H. Screening HIV infected individuals for anal cancer precursor lesions: a systematic review. Clin Infect Dis 2006; 43:223-33. 50. Chin-Hong PV, Berry JM, Cheng SC, Catania JA, Da Costa M, Darragh TM, et al. Comparison of patient- and cliniciancollected anal cytology samples to screen for human papillomaviruseassociated anal intraepithelial neoplasia in men who have sex with men. Ann Intern Med 2008;149: 300-6. 51. Walts AE, Thomas P, Bose S. Anal cytology: is there a role for reflex HPV DNA testing? Diagn Cytopathol 2005;33:152-6. 52. Bean SM, Chhieng DC. Anal-rectal cytology: a review. Diagn Cytopathol 2010;38:538-46. 53. Darragh TM, Winkler B. Anal cancer and cervical cancer screening: key differences. Cancer Cytopathol 2011;119:5-19. 54. Ortoski RA, Kell CS. Anal cancer and screening guidelines for human papillomavirus in men. J Am Osteopath Assoc 2011; 111:S35-43. 55. Machalek DA, Poynten M, Jin F, Fairley CK, Farnsworth A, Garland SM, et al. Anal human papillomavirus infection and associated neoplastic lesions in men who have sex with men: a systematic review and meta-analysis. Lancet Oncol 2012;13: 487-500. 56. Palefsky JM, Holly EA, Hogeboom CJ, Ralston ML, DaCosta MM, Botts R, et al. Virologic, immunologic, and clinical parameters in the incidence and progression of anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual men. J Acquir Immune Defic Syndr Hum Retrovirol 1998;17: 314-9. 57. Wong WWY, Jin F, McHugh LC, Maher T, Sinclarie B, Frulich AE, et al. Progression to and spontaneous regression of high-grade anal squamous intraepithelial lesions in HIV-infected and uninfected men. AIDS 2013;27:2233-43. 58. Scholefield JH, Harris D, Radcliffe A. Guidelines for management of anal intraepithelial neoplasia. Colorectal Dis 2011;13(Suppl):3-10.
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59. Weis SE. Current treatment options for management of anal intraepithelial neoplasia. Onco Targets Ther 2013;6: 651-65. 60. Cleary RK, Schaldenbrand JD, Fowler JJ, Schuler JM, Lampman RM. Treatment options for perianal Bowen’s disease: survey of American Society of Colon and Rectal Surgeons members. Am Surg 2000;66:686-8. 61. Deveraj B, Cosman BC. Expectant management of anal squamous dysplasia in patients with HIV. Dis Colon Rectum 2006;49:36-40. 62. Goldstone SE, Kawalek AZ, Huyett JW. Infrared coagulator: a useful tool for treating anal squamous intraepithelial lesions. Dis Colon Rectum 2005;48:1042-5. 63. US Department of Veterans Affairs, Office of Clinical Public Health Programs for the Public Health Strategic Health Care Group. Primary care of veterans with HIV. 1st ed. Department of Veteran Affairs; 2009. 64. Macaya A, Mu~ noz-Santos C, Balaguer A, Barbera MJ. Interventions for anal canal intraepithelial neoplasia. Cochrane Database Syst Rev 2012;12:CD009244. 65. Czito BG, Willett CG. Current management of anal canal cancer. Curr Oncol Rep 2009;11:186-92. 66. Sato H, Koh PK, Bartolo DC. Management of anal canal cancer. Dis Colon Rectum 2005;48:1301-15. 67. Glynne-Jones R, Northover JMA, Cervantes A, EMSO Guidelines Working Group. Anal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21:v87-92. 68. Fleshner PR, Chalasani S, Chang GJ, Levien DH, Hyman NH, Buie WD. Practice parameters for anal squamous neoplasms. Dis Colon Rectum 2008;51:2-9.
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69. Centers for Disease Control and Prevention. Guidelines for preventing opportunistic infections among HIV-infected personse2002. MMWR Morb Mortal Wkly Rep 2002;51:1-46. 70. Hocking A, Fisher A, Bell L. Screening for anal cancer: external review against program appraisal criteria for the UK National Screening Committee. Version one. Plymouth, United Kingdom: UK National Screening Committee; October 2012. 71. Goldie SJ, Kuntz KM, Weinstein MC, Freedberg KA, Palefsky JM. Cost-effectiveness of screening for anal squamous intraepithelial lesions and anal cancer in human immunodeficiency virusenegative homosexual and bisexual men. Am J Med 2000;108:634-41. 72. Goldie SJ, Kuntz KM, Weinstein MC, Freedberg KA, Welton ML, Palefsky JM. The clinical effectiveness and cost-effectiveness of screening for anal squamous intraepithelial lesions in homosexual and bisexual HIVpositive men. JAMA 1999;281:1822-9. 73. Lazenby GB, Unal ER, Andrews AL, Simpson K. A costeffectiveness analysis of anal cancer screening in HIV-positive women. J Low Genit Tract Dis 2012;16:275-80. 74. Losina E, Walensky RP, Geller A, Beddingfield FC III, Wolf LL, Gilchrest BA, et al. Visual screening for malignant melanoma: a cost-effectiveness analysis. Arch Dermatol 2007;143:21-8. 75. US Department of Health and Human Services Health Resources and Services Administration HIV/AIDS Bureau. Guide for HIV/AIDS clinical care [section 6, anal dysplasia]. Rockville (MD): US Department of Health and Human Services; 2011. 76. Simpson JA, Scholefield JH. Diagnosis and management of anal intraepithelial neoplasia and anal cancer. BMJ 2011;343: d6818.
T
he Papanicolaou test, or Pap smear, is used to screen for cervical cancer by identifying dysplastic squamous cells in the cervical mucosa. Like the cervix, the anus is lined by stratified squamous epithelium, which can undergo malignant transformation when infected by specific types of human papillomavirus (HPV). Although all HPV types can promote cancer, the risk is greater with ‘‘high-risk’’ types than with ‘‘low-risk’’ types. Approximately 84% to 90% of all cases of anal cancer are caused by HPV infection. Among HPV-related cancers, high-risk types 16 and 18 are responsible for 70% of all cervical cancers and 93% of all anal cancers.1-4 Just as Pap smears have led to a dramatic decrease in the incidence of cervical cancer in the United States, they may potentially be used to decrease the incidence of anal cancer, although large, well-controlled trials have yet to validate this. Two vaccines against HPV have been developed, namely Cervarix, which targets high-risk HPV types 16 and 18, and Gardasil, which targets From Tulane University School of Medicinea; and Department of Dermatologyb and Ochsner Clinic Foundation,c Tulane University. Funding sources: None. Conflicts of interest: None declared. Accepted for publication June 28, 2014. Reprint requests: Nicole E. Rogers, MD, Department of Dermatology, Tulane University, 701 Metairie Rd, Metairie, LA 70005. E-mail: [email protected].
Abbreviations used: AIN: CDC: HPV: HRA: ICER: MSM: SCCA:
anal intraepithelial neoplasia Centers for Disease Control and Prevention human papillomavirus high-resolution anoscopy incremental cost-effectiveness ratio men who have sex with men squamous cell carcinoma of the anus
low-risk HPV types 6 and 11 in addition to types 16 and 18.5 The Centers for Disease Control and Prevention (CDC) recommends HPV vaccination for girls and boys ages 11 to 12 years and for men who have sex with men (MSM) and HIV-positive patients up to age 26. Computer modeling has predicted that HPV vaccination will result in lower rates of anal cancer. In clinical trials high rates of seroconversion and decreased rates of anal dysplasia have been observed in HIV-positive and -negative MSM after vaccination.6-10 Published online July 31, 2014. 0190-9622/$36.00 Ó 2014 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2014.06.045
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anal Pap smears are performed with a polyester swab. Anal cancer, like cervical cancer, tends to Between 1975 and 2010, according to the National occur at the squamous-glandular transformation Cancer Institute’s Surveillance Epidemiology and zone, so the swab is inserted 3 to 5 cm past the End Results data, the delayed-adjusted incidence of external anal sphincter to obtain cells from the cervical cancer in the United States decreased from rectoanal transformation zone.30,32 Once fully in14.8 to 6.7 cases per 100,000 women (Fig 1). During serted, the swab is rotated, then continually rotated the same period, rates of squamous cell carcinoma of as it is slowly removed. The the anus (SCCA) increased sample from the swab can be from 0.95 to 1.82 cases per CAPSULE SUMMARY mounted and fixed to a slide 100,000 women (Fig 2) and or it can be placed into a from 0.66 to 1.42 cases per In the United States, rates of anal cancer liquid cytology solution.32,33 100,000 men (Fig 3).11 In have increased during the past 3 After the Pap smear is men, the increase in SCCA decades. completed, a digital rectal can largely be attributed to Almost all cases of anal cancer are examination should be perHIV/AIDS. In women, the caused by human papillomavirus formed, followed by a visual increase appears to be a infection. inspection of the anus and result of changes in sexual palpation of the inguinal practices, specifically inWe review the epidemiology of anal lymph nodes.32 creased number of lifetime cancer and the data supporting the use The Bethesda System, the sexual partners and recepof anal Pap smears to screen for anal cytologic classification systive anal intercourse.12 dysplasia. tem initially developed for Factors associated with an cervical Pap smears, has increased risk of SCCA been translated for classification of anal Pap include history of cervical or vulvar dysplasia, smoksmears.34 Table I outlines this grading system. ing, and receptive anal sex (in males or females).13-22 Any patient with an abnormal smear result, ie, In particular, patients who are immunocompromised atypical squamous cell of undetermined significance as a result of solid-organ transplantation or HIV are at and above, should subsequently undergo highparticularly elevated risk.22 Compared with the genresolution anoscopy (HRA).35 eral population, the risk of SCCA is 24 times higher in During HRA, an anoscope is inserted into the anal HIV-positive women, 32 times higher in HIV-positive canal, and the epithelium is inspected (Fig 4). men overall, and 52 times higher in HIV-positive Subsequently, 3% acetic acid, followed by Lugol’s MSM.23-25 The rate of anal cancer in HIV-positive iodine, is applied to the squamocolumnar junction. MSM is approximately twice that of HIV-negative When treated with this solution, dysplastic lesions MSM.26 Interestingly, HIV-positive men without a may turn white or appear to have abnormal vasculahistory of receptive anal intercourse are still at an ture, ulceration, or discoloration.36,37 However, inelevated risk for SCCA.27 Since the adoption of highly flamed epithelium, such as caused by lichen sclerosus active antiretroviral therapy, rates of certain AIDSor lichen planus, may also turn white.38 Areas with defining malignancies, specifically Kaposi sarcoma atypical appearance are biopsied and sent for histoand non-Hodgkin lymphoma, have sharply declined pathologic examination.36,37 It is essential that HRA whereas cases of SCCA have continued to in28-30 only be performed by physicians who have been crease. Highly active antiretroviral therapy had adequately trained in the procedure because mucous, previously not been shown to reduce the incidence fecal material, and folds in the mucosa make it difficult of anal dysplasia,22,29 however, recent data suggest to adequately visualize the entire anal mucosa.37 persistent undetectable viral loads decrease the risk 31 Dysplasia noted on biopsy specimens is termed of developing SCCA. Among patients with a history ‘‘anal intraepithelial neoplasia’’ (AIN) and is classiof solid-organ transplantation, the risk of anal fied according to depth of involvement of the dysplasia and SCCA is estimated to be 10 to 100 epithelium (Table II).34 Although the classification times higher than in the general population.22 of anal dysplasia seems straightforward, a lack of interobserver agreement among pathologists evaluating anal biopsy specimens has been noted.39-41 ANAL PAP SMEARS There is disagreement whether HRA should be Collection and interpretation performed directly after an anal Pap smear, or Anal Pap smears can be easily collected in the whether HRA should only be performed if anal outpatient setting. Although cervical Pap smears are cytology is abnormal.42-44 When compared with performed with both a spatula and pointed brush, d
d
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Fig 1. Annual age-adjusted incidence of cervical cancer per 100,000 women of all races in the United States.
Fig 2. Annual age-adjusted incidence of anal cancer per 100,000 women of all races in the United States.
Fig 3. Annual age-adjusted incidence of anal cancer per 100,000 men of all races in the United States.
biopsy specimens obtained during HRA, anal Pap smears have a sensitivity of 61% to 93% and a specificity of 32% to 67%.42,45-48 The sensitivity of anal Pap smears has been shown to be higher in HIVpositive patients, especially those with CD4 counts below 400, larger areas of involvement, and AIN 2 or 3.46 However, the sensitivity of anal Pap smears is lower than the sensitivity of cervical Pap smears.49 In 1 study in which HRA was performed directly after anal Pap smear, 53% of patients who had normal anal cytology were found to have abnormal pathology on biopsy specimens obtained during HRA, with 23% having high-grade squamous intraepithelial lesion.44 In another study, 45% of HIV-positive and 23% of HIV-negative MSM who had negative cytology had AIN on HRA.50 Anal cytology has a low sensitivity, but it is less invasive and uncomfortable for the patient than HRA. In addition, HRA requires technical proficiency, and there is a shortage of
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physicians who have been adequately trained. Although cytology and subsequent HRA may be ideal, it is currently more practical to reserve HRA for cases of abnormal anal cytology.37,50 The role of testing anal Pap smear specimens for HPV is also controversial. There is disagreement whether all samples, no samples, or only samples with abnormal cytology (reflex testing) should be tested for HPV.43,51-54 A recent meta-analysis showed that 92.6% of all HIV-positive MSM had at least 1 HPV type on anal cytology, 73.5% had at least 1 oncogenic type of HPV, and 35.4% had type 16 specifically. Similarly, 62.9% of HIV-negative MSM had at least 1 type of HPV, 37.2% had at least 1 oncogenic type of HPV, and 12.5% had type 16.55 Because HPV infection is extremely common, HPV testing may not be useful in guiding clinical treatment of patients. The natural progression of anal dysplasia and potential transformation into invasive carcinoma is not well understood. In a study of MSM, 63% of HIVpositive men with low-grade squamous intraepithelial lesion progressed to high-grade squamous intraepithelial lesion within 2 years, compared with 36% of HIV-negative MSM.56 Interestingly, among HIVpositive patients on highly active antiretroviral therapy, AIN 2/3 is less likely to regress if the patient’s CD4 nadir was below 200.57 In pooled, retrospective studies of immunocompetent patients, solid-organ transplant recipients, and HIV-positive patients, 9% to 13% of all patients with AIN 3 progressed to SCCA.58 Ultimately, more data on the progression and regression of anal dysplasia are greatly needed. Treatment and follow-up There is disagreement whether AIN 2 and 3 should be treated or observed, although most physicians advocate observation for AIN 1.58-64 Current treatment options include carbon-dioxide laser ablation, cryosurgery, topical 5-fluorouracil, and topical imiquimod. With the exception of transient pain and irritation, these treatments are generally well tolerated.21,59,63 A 2012 Cochrane review, however, concluded that there is currently insufficient evidence to determine whether AIN should or should not be treated.64 Even when anal dysplasia is treated, it often reoccurs, particularly in HIV-positive patients.61 There is also no current evidence to suggest that treating AIN increases survival. However, regardless of the grade of dysplasia, patients with symptoms secondary to their dysplasia, such as pruritus or dyschezia, should be considered for treatment.59 Historically, invasive SCCA was treated by surgical removal of the anus and adjacent perineum. Not surprisingly, larger excisions were associated with
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Table I. Bethesda grading system for anal cytology Dysplasia classification
Normal ASC-US
ASC-H LSIL HSIL
Description
No dysplastic squamous cells observed Because of inflammation, squamous cells may appear atypical, however, the irregularity of the cells is likely a result of current, nonspecific inflammation of the mucosa and not HPV infection; were it not for the current inflammation, the cells would likely appear to be normal Similar to ASC-US, ASC-H cells appear atypical, however, they have some, but not all, characteristics of the dysplastic cells seen in HSIL Mild dysplasia of squamous cells is observed, usually as a result of HPV Moderate to severe dysplasia of squamous cells is observed, usually as a result of HPV
ASC-H, Atypical squamous cellsecannot exclude HSIL; ASC-US, atypical squamous cells of undetermined significance; HPV, human papillomavirus; HSIL, high-grade squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion.
Evidence and recommendations for anal Pap smears Currently, no national bodies, such as the US Preventive Services Task Force, have established recommendations for anal Pap smears. However, the CDC, American Society of Colon and Rectal Surgeons, and the United Kingdom’s National Screening Committee have acknowledged that anal Pap smears may be practical in high-risk populations, such as HIV-positive patients or those with solid-organ transplantation, although the dearth of results from large-scale studies prevents a formal recommendation.68-70
Fig 4. Evidence of anal dysplasia on high-resolution anoscopy. A, Dysplastic lesion (arrowheads) with punctations at the squamocolumnar junction. B and C, Positive acetowhite staining (arrows) of the anal mucosa in the superior field of the anoscope. Used with permission courtesy of Dr Olivier Richel (A) Dr Michael Hagensee (B and C).
the risk of anal stenosis, abscess formation, dyschezia, and anal spasms.58 The current standard of care is the Nigro protocol, which uses a combination of radiation therapy, 5-fluorouracil, and mitomycin.65,66 The 5-year survival for SCCA is approximately 75%, and recurrence rates range from 20% to 37%.21 After treatment, patients should receive a digital rectal examination and palpation of the inguinal nodes every 3 to 6 months for the first 2 years, followed by a digital rectal examination and inguinal node palpation every 6 to 12 months for the next 3 years.67
Cost-effectiveness of anal Pap smears Three models have shown that anal Pap smear screening may be cost-effective for certain patient populations in the United States. These models use an incremental cost-effectiveness ratio (ICER), which is a ratio of the cost of a procedure relative to the number of quality-adjusted life years gained. In general, an ICER of less than $30,000 to $50,000 is considered to be cost-effective.30 In HIV-positive men, the ICER of annual Pap smears is estimated to be $16,600, whereas performing anal Pap smears every 3 years in HIV-negative MSM would be $7800.71,72 In HIV-positive women with a CD4 count of less than 200, annual and biennial anal Pap smears have an estimated ICER of $112,026 and $35,805, respectively.73 For comparison, the ICER of skin examinations in Americans with an average risk of melanoma after the age of 50 years is $10,100 if performed once and $586,800 if performed annually.74 Ultimately, these models suggest that routine anal Pap smears may be cost-effective in HIV-positive men and women and in HIV-negative MSM.
THE ROLE OF THE DERMATOLOGIST With limited data and no national recommendations, do anal Pap smears have a place in dermatology?
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Table II. Classification of dysplasia in anal epithelial biopsies Dysplasia classification
AIN1 AIN2 AIN3
Description
Anal cytology equivalent
From the basal layer, dysplasia is present in the lower third of the epithelium From the basal layer, dysplasia is present in the lower one third to two thirds of the epithelium From the basal layer, dysplasia is present in the lower two thirds of to entire epithelium
LSIL HSIL HSIL
AIN, Anal intraepithelial neoplasia; HSIL, high-grade squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion.
Table III. International Classification of Diseases, Ninth Revision and Current Procedural Terminology codes relating to anal Pap smears and anoscopy ICD-9 codes 796.7 796.71 796.72 796.73 796.74 796.75 796.76 796.77 796.78 CPT codes 46600
46606
Abnormal glandular Papanicolaou smear of anus Papanicolaou smear of anus with ASC-US Papanicolaou smear of anus with ASC-H Papanicolaou smear of anus with LSIL Papanicolaou smear of anus with HSIL Anal high-risk HPV DNA test positive Papanicolaou smear of anus with cytologic evidence of malignancy Satisfactory anal smear but lacking transformation zone Unsatisfactory anal cytology smear Anoscopy; diagnostic, with or without collection of specimen(s) by brushing or washing Anoscopy; with biopsy, single or multiple
ASC-H, Atypical squamous cellsecannot exclude HSIL; ASC-US, atypical squamous cells of undetermined significance; CPT, Current Procedural Terminology; HSIL, high-grade squamous intraepithelial lesion; ICD-9, International Classification of Diseases, Ninth Revision; LSIL, low-grade squamous intraepithelial lesion; HPV, human papillomavirus.
Many dermatologists frequently see patients who are at an increased risk for development of SCCA, such as MSM and those with HIV. What role do dermatologists play in treating these patients? Unfortunately, it is not clear. Although we know MSM, HIV-positive individuals, and immunosuppressed organ transplant recipients are at an increased risk of developing SCCA, there are no national recommendations to screen these patients with anal Pap smears. At this point in time, the best screening test in this population is a thorough history and physical.75 Dermatologists should ask about a history of cervical or vulvar dysplasia, HIV status, smoking, immunosuppression, and sexual practices, specifically receptive anal intercourse. Review of systems should include symptoms of SCCA, such as anal fissures, pruritus, discharge,
Fig 5. Decision tree concerning when to consider anal Pap smear or high-resolution anoscopy (HRA) in patients at high risk for anal cancer. ROS, Review of systems; SCCA, squamous cell carcinoma of the anus.
bleeding, or pain.76 The dermatologist should also perform a physical examination to look for discoloration, growths, or ulcers of the anus and palpate the inguinal lymph nodes.30 Billing for anal Pap smears can be complicated. There is no Current Procedural Terminology code for collection of an anal Pap smear. Instead, a physician must bill for a general visit and perform the collection as part of the visit. There are laboratory International Classification of Diseases, Ninth Revision codes that a pathologist can use for reading anal cytology, and there are Current Procedural Terminology codes for HRA (Table III). In the authors’ experience, insurance companies may not pay for anal Pap smear testing, however, if the results are abnormal, they will cover the cost of HRA with biopsies.
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In summary, anal Pap smear may be considered as a screening tool for patients at high risk for development of SCCA (HIV-positive patients, MSM, and organ transplant patients), although this is not currently the standard of care and is not covered by medical insurance policies. For patients at high risk with signs or symptoms of SCCA that persist despite conservative medical management, HRA with biopsy is warranted (Fig 5). Before an anal Pap smear is performed, the dermatologist should discuss the diagnostic limitations of the test, the uncertainty of how to manage AIN if it is detected, the lack of national recommendations for the test, and the likelihood that it will not be covered by insurance. If the patient decides to have an anal Pap smear, the test should be performed by a physician who has experience performing and counseling patients about anal Pap smears and anal cancer. The physician must also be able to perform HRA or to easily refer the patient to a physician who can in the event that the anal cytology is abnormal. In addition, the cytology should be read by a pathologist who has experience reading anal Pap smears. Ultimately, if invasive SCCA is found, the patient must be referred to a medical oncologist or colorectal surgeon. Conclusion Over the past 3 decades, the incidence of SCCA in the United States has doubled. MSM, HIV-positive patients, and solid-organ transplant recipients are known to be at an increased risk of developing SCCA. Because of insufficient evidence on the benefits and harms of screening for SCCA and AIN with anal Pap smears, there are no national recommendations advocating their use as a routine screening tool, however, anal Pap smears may be useful in this select group of patients. Ultimately, large, long-term studies on the progression of AIN and the benefits and risks of treating AIN are needed. REFERENCES 1. Chaturvedi AK. Beyond cervical cancer: burden of other HPV-related cancers among men and women. J Adolesc Health 2010;46:S20-6. 2. DeVuyst H, Clifford GM, Nascimento MC, Madeleine MM, Franceschi S. Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis. Int J Cancer 2009;124:1626-36. 3. Gillison ML, Chaturvedi AK, Lowy DR. HPV prophylactic vaccines and the potential prevention of noncervical cancers in both men and women. Cancer 2008;113:3036-46. 4. Parkin DM. The global health burden of infectionassociated cancers in the year 2002. Int J Cancer 2006; 118:3030-44.
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