Patient Symptomatology in Anal Dysplasia

Research

Original Investigation Patient Symptomatology in Anal Dysplasia

Caitlin W. Hicks, MD, MS; Elizabeth C. Wick, MD; Ira L. Leeds, MD; Jonathan E. Efron, MD; Susan L. Gearhart, MD; Bashar Safar, MBBS; Sandy H. Fang, MD

Invited Commentary IMPORTANCE High-resolution anoscopy (HRA) is becoming increasingly advocated as a page 569 method of screening for anal dysplasia in high-risk patients.

OBJECTIVE To describe, through HRA findings, the association between patient symptomatology and anal dysplasia among patients at high risk for anal dysplasia.

DESIGN, SETTING, AND PARTICIPANTS Univariable and multivariable analyses were conducted of data from a prospectively maintained HRA database on all patients undergoing HRA with biopsy from November 1, 2011, to March 13, 2014, at a tertiary care HRA clinic. Data included demographics, medical history and comorbidities, HIV status and related measures (CD4 cell counts, HIV viral load, and use of highly active antiretroviral therapy), sexual orientation (when available), patient symptoms at initial presentation, physical examination findings, anal Papanicolaou (Pap) smear findings.

MAIN OUTCOMES AND MEASURES High-resolution anoscopy diagnosis of high- vs low-grade dysplasia or no dysplasia.

RESULTS One hundred sixty-one HRA biopsy specimens (mean [SEM], 1.77 [0.11] biopsy specimens per patient) were obtained from 91 patients (mean [SEM] age, 45.7 [1.2] years; 61 men [67%]; 47 black patients [52%]; and 70 human immunodeficiency virus–positive patients [77%]). Twenty-seven patients (30%) had high-grade dysplasia, 26 had low-grade dysplasia (29%), and 38 had no dysplasia (42%). The majority of patients (63 [69%]) were asymptomatic (anal pain, 11 [12%]; bleeding, 14 [15%]; and pruritus, 10 [11%]). Forty-one patients (45%) presented with anal pain (odds ratio, 5.25; 95% CI, 1.44-21.82; P = .02), and patients with either high- or low-grade dysplasia were more likely to present with anal lesions on physical examination compared with patients without dysplasia (odds ratio, 4.34; 95% CI, 1.78-11.20; P = .002). Multivariable analysis suggested that anal pain was independently associated with high-grade dysplasia (odds ratio, 6.42; 95% CI, 1.18-43.3; P = .03).

CONCLUSIONS AND RELEVANCE Anal dysplasia is a silent disease that is frequently asymptomatic. However, patients with anal pain, anal lesions, and other high-risk factors are at increased risk of having high-grade anal dysplasia. These patients may benefit from routine screening with HRA.

Author Affiliations: Division of Colorectal Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland. Corresponding Author: Sandy H. Fang, MD, Division of Colorectal Surgery, Department of Surgery, Johns Hopkins Hospital, 600 N Wolfe JAMA Surg. 2015;150(6):563-569. doi:10.1001/jamasurg.2015.28 St, Blalock 618, Baltimore, MD 21287 Published online April 15, 2015. ([email protected]).

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he prevalence of anal cancer has been increasing dur- Anal Pap Smear and HRA ing the past few decades, especially among the Anal Pap smears and HRAs were performed in our weekly HRA T human immunodeficiency virus (HIV)–positive clinic. Patients were referred to the clinic from their primary population.1 It is estimated that anal cancer affects approxi- care physician or our institution’s HIV clinic and/or if they had mately 46 in 100 000 HIV-positive men and 10 in 100 000 a history of abnormal Pap smear results. After written in- HIV-positive women compared with 2 in 100 000 HIV- formed consent was obtained, the patient was positioned in negative men and negligible rates for HIV-negative women.2 the left lateral decubitus position and an anal Pap smear was The incidence of anal cancer is even higher in HIV-positive performed. The perianal skin was inspected on gross exami- men who have sex with men (MSM) (approximately 131 in nation and with the colposcope. Lidocaine cream, 4%, was 100 000).1 placed at the anal verge and within the anal canal during the There is well-established evidence that anal intraepithe- digital anorectal examination. Gauze soaked in acetic acid, 5%, lial neoplasia (AIN) progresses to cancer with time, particu- was then placed within the anal canal for 3 minutes. After the larly within the immunosuppressed population.3 For gauze was removed, the dentate line was identified and visu- HIV-positive MSM with high-grade AIN, progression to anal alized with the colposcope. Lugol iodine solution was ap- cancer has been reported to occur in 10% to 50% of cases plied. Cold forceps were used to obtain biopsy specimens of within 2 years.4-6 Although no formal screening guidelines areas of acetowhitening and Lugol negativity, in addition to vas- currently exist, health care professionals experienced in the cular abnormalities or findings consistent with dysplasia. Anal care of high-risk populations have therefore started screen- Pap smear and all HRA biopsy specimens were submitted to ing their patients for anal dysplasia.7 In 2012, the American the pathology department for further analysis. Society of Colon and Rectal Surgeons published recom- Cytologic findings on the anal Pap smear were catego- mended practice parameters for anal squamous neoplasms, rized as no dysplasia, atypical squamous cells of undeter- including surveillance examinations at 4- to 6-month inter- mined significance, low-grade dysplasia (low-grade squa- vals for both high-risk individuals and as surveillance after mous intraepithelial lesions and AIN grade 1), or high-grade treatment of AIN.3 However, to our knowledge, the associa- dysplasia (high-grade squamous intraepithelial lesions [HSIL], tion between patient symptomatology and anal dysplasia AIN grade 2, AIN grade 3, low-grade squamous intraepithelial findings has never been reported, so the utility of clinical lesions suspicious for HSIL, and atypical squamous cells sus- presentation findings as an indication of anal cancer risk in picious for HSIL). Patients were classified as having high- high-risk patients is unknown. The objective of the current grade anal dysplasia based on HRA pathologic findings of AIN study was to describe the association between patient grade 2 or 3, low-grade anal dysplasia based on HRA patho- symptomatology and high-resolution anoscopy (HRA) find- logic findings of AIN grade 1, or no dysplasia based on HRA ings by analyzing the breakdown of symptoms in all patients pathologic findings of no dysplasia. at high risk for anal dyplasia who present for HRA, as well as symptoms in patients grouped by HRA findings of Statistical Analysis high-grade (AIN grades 2 and 3) vs low-grade (AIN grade 1) Baseline and descriptive statistics were summarized as mean dysplasia. (SEM) or number (percentage), as appropriate. Descriptive statistics and univariable analyses, including t tests (continuous variables) or Pearson χ2 tests or Fisher exact tests (categorical Methods variables), were used to describe the breakdown of symptoms in all patients presenting for HRA and in patients grouped Design by findings of high-grade (AIN grades 2 and 3) vs low-grade (AIN Data were obtained from our prospectively maintained insti- grade 1) dysplasia. Multivariable logistic regression was per- tutional review board–approved HRA database. The study was formed to determine independent predictors of high-grade dys- conducted according to accepted ethical standards for hu- plasia. Model covariates were chosen based on factors found man investigation and had approval from the Johns Hopkins to be significant on univariable analysis (age, sex, anal pain, Hospital Institutional Review Board prior to its initiation. All anal lesions on examination, HIV viral load >20 copies/mL, and medical records of patients 18 years or older undergoing HRA high-grade dysplasia on anal Pap smear). with biopsy between November 1, 2011, and March 13, 2014, Two-tailed tests were used for all analyses, and P ≤ .05 was were reviewed for inclusion in the study. Patients who under- considered significant. Statistical analyses were performed went HRA without biopsies, did not have biopsy results avail- using JMP, version 9.0 (SAS Institute). able in the records, or were undergoing repeat HRA were ex- cluded (n = 94). Data on demographics, medical history and comorbidi- Results ties, HIV status and related measures (CD4 cell counts, HIV viral load, and use of highly active antiretroviral therapy), sexual Overall Findings orientation (when available), patient symptoms at initial pre- A total of 161 HRA biopsies (mean [SEM], 1.77 [0.11] biopsies sentation, physical examination findings, anal Papanicolaou per patient) were obtained from 91 patients (mean [SEM] (Pap) smear findings, and HRA findings were analyzed for all age, 45.7 [1.2] years; 61 men [67%]; 47 black patients [52%]; eligible patients. and 70 HIV-positive patients [77%]) during the 2½-year

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study period. A summary of the demographic characteristics Table 1. Demographic and Clinical Characteristics of Patients of included patients is in Table 1. Of those who were asked, Undergoing High-Resolution Anoscopy 73% of patients (22 of 30) were MSM and 78% of patients (14 Characteristic Valuea of 18) practiced anoreceptive sex. A history of anal condy- Age, mean (SEM), y [range] 45.7 (1.2) [23-79] loma was common (30 [33%]), and more than half of the patients (46 [51%]) had previously had some form of anorec- Male sex 61 (67) tal surgical intervention. Race The majority of patients (63 [69%]) were asymptomatic White 37 (41) at the time of screening. Among those presenting with Black 47 (52) symptoms, bleeding was most common (14 [15%]), followed Other 7 (8) by anal pain (11 [12%]) and pruritus (10 [11%]). Forty-one BMI, mean (SEM) [range] 26.4 (1.2) [18.1-50] patients (45%) had anal lesions on physical examination. HIV positive 70 (77) Anal Pap smear cytologic results demonstrated no dysplasia CD4 cell count, mean (SEM), cells/μL [range] 552 (41) [50-1600] in 19 patients (22%), atypical cells of uncertain significance CD4 cell count, <200 cells/μL 10/70 (14) in 23 (27%), low-grade dysplasia in 19 (22%), and high-grade HIV viral load >20 copies/mL 21/70 (30) dysplasia in 25 (29%) (Table 1). Pathologic results found on HAART 68/70 (97) HRA demonstrated the presence of high-grade (AIN grades 2 and 3) dysplasia in 27 patients (30%), low-grade (AIN grade 1) Previous anorectal surgical intervention 46 (51) dysplasia in 26 (29%), and no dysplasia in 38 (42%). The anal Anal condyloma history 30 (33) Pap smear and pathologic findings on HRA were consistent Previous anal excision 32 (35) in 60 patients (66%). Previous medical treatment 7 (8) Anal Papanicolaou smear findings High-Grade vs Low-Grade vs No Dysplasia No dysplasia 19/86 (22) To determine the association between patient symptomatol- ASCUS 23/86 (27) ogy and HRA dysplasia findings, presenting anal symptoms Low-grade dysplasia 19/86 (22) and other clinical factors were analyzed for patients with High-grade dysplasia 25/86 (29) high-grade vs low-grade vs no dysplasia. Patients with high- Cervical dysplasia 15 (16) and low-grade dysplasia were younger (P = .04) and more frequently male (P = .01) compared with those with no dys- Comorbidities plasia (Table 2). Race, sexual orientation (when available), Hepatitis C 20 (22) HIV status, comorbidities, and smoking status were not sta- Other STDs 15 (16) tistically different between groups. There was a trend for Immunosuppression 2 (2) more patients with high- and low-grade dysplasia to have Inflammatory bowel disease 1 (1) HIV viral loads greater than 20 copies/mL compared with Transplant 1 (1) those with no dysplasia, but this trend was not statistically Diabetes mellitus 1 (1) significant (P = .07) (Table 2). Patients with high-grade dys- Hypertension 21 (2) plasia on HRA had a higher incidence of high-grade dyspla- CAD 4 (4) sia on anal Pap smear (54%) than patients with low-grade CKD 4 (4) (19%) or no dysplasia (18%) (P = .02). COPD 6 (7) Patients with high-grade dysplasia presented with anal pain more frequently than did patients with low-grade or no dys- Smoking 37 (41) plasia (odds ratio, 5.25; 95% CI, 1.44-21.82), and patients with Abbreviations: ASCUS, atypical squamous cells of undetermined significance; either high- or low-grade dysplasia were more likely to pre- BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CAD, coronary artery disease; CKD, chronic kidney disease; sent with anal lesions on physical examination compared with COPD, chronic obstructive pulmonary disease; HAART, highly active patients with no dysplasia (odds ratio, 4.34; 95% CI, 1.78- antiretroviral therapy; HIV, human immunodeficiency virus; STD, sexually 11.20). There were no significant differences when compar- transmitted disease. ing anal bleeding, pruritus, or overall symptomatology be- a Data are presented as number (percentage) unless otherwise noted. tween groups (Figure, A). In contrast, symptomatology stratified by findings on anal Pap smears showed no signifi- gested that anal pain (P = .03), younger patient age (P = .04), cant trends: patients with high-grade dysplasia on anal Pap and high-grade dysplasia (P = .05) on anal Pap smears were smears reported similar frequencies of anal pain, bleeding, pru- each independently associated with the presence of high- ritus, overall symptomatology, and anal lesions compared with grade dysplasia on HRA (Table 3). Male sex (P = .13) and the those with low-grade dysplasia, atypical squamous cells of un- presence of anal lesions on physical examination (P = .15) determined significance, or no dysplasia (Figure, B). showed a trend toward increasing risk of high-grade dysplasia on HRA, but this trend was not statistically significant. Multivariable Analysis An HIV viral load greater than 20 copies/mL was also not sig- Multivariable logistic regression analysis accounting for vari- nificantly associated with high-grade dysplasia after risk ables found to be significant on univariable analysis sug- adjustment (Table 3).

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Table 2. Demographic and Clinical Characteristics of Patients With High-Resolution Anoscopy Findings of High-Grade vs Low-Grade vs No Dysplasia

No. (%) High-Grade Dysplasia Low-Grade Dysplasia No Dysplasia Characteristic (n = 27) (n = 26) (n = 38) P Value Age, mean (SEM) [range], y 43.2 (2.6) 43.0 (2.6) 49.3 (1.9) .04 Male sex 22 (81) 20 (77) 19 (50) .01 Race White 10 (37) 11 (42) 16 (42) .43 Black 14 (52) 14 (54) 19 (50) BMI, mean (SEM) [range] 27.2 (2.1) 25.3 (2.0) 26.8 (2.6) .81 HIV positive 22 (81) 21 (81) 27 (71) .53 CD4 count, mean (SEM), 500 (75) 520 (72) 618 (65) .43 cells/μL [range] CD4 count <200 cells/μL 5/22 (22.7) 3/21 (13.6) 2/27 (7.41) .27 HIV viral load >20 copies/mL 8/22 (36.3) 9/21 (42.9) 4/27 (14.8) .07 HAART 19/22 (86) 21/21 (100) 27/27 (100) .16 Sexual orientation MSM 10/11 (91) 5/7 (71) 7/12 (58) .35 Anoreceptive sex 4/5 (80) 3/6 (50) 7/7 (100) .24 Previous anorectal surgical intervention 15 (56) 15 (58) 18 (50) .62 Anal condyloma history 8 (30) 12 (46) 10 (26) .25 Previous excision 10 (37) 12 (46) 10 (26) .25 Medical treatment 3 (11) 2 (8) 2 (5) .65 Anal Papanicolaou smear findings No dysplasia 4/26 (15) 2 (8) 13/34 (38) ASCUS 4/26 (15) 9 (35) 10/34 (29) .02 Low-grade dysplasia 4/26 (15) 10 (39) 5/34 (15) High-grade dysplasia 14/26 (54) 5 (19) 6/34 (18) Cervical dysplasia 1 (4) 5 (19) 9 (24) .46 Comorbidities Hepatitis C 8 (30) 4 (15) 8 (21) .40 Other STDs 6 (22) 4 (15) 5 (13) .59 Abbreviations: ASCUS, atypical Immunosuppression 0 1 (4) 1 (3) .62 squamous cells of undetermined Inflammatory bowel disease 1 (4) 0 0 .31 significance; BMI, body mass index (calculated as weight in kilograms Transplant 0 1 (4) 0 .28 divided by height in meters squared); Diabetes mellitus 0 0 1 (3) .49 CAD, coronary artery disease; Hypertension 8 (30) 5 (19) 8 (21) .62 CKD, chronic kidney disease; COPD, chronic obstructive pulmonary CAD 1 (4) 1 (4) 2 (5) .94 disease; HAART, highly active CKD 0 1 (4) 3 (8) .31 antiretroviral therapy; HIV, human COPD 0 1 (4) 5 (13) .09 immunodeficiency virus; MSM, men who have sex with men; STD, sexually Smoking 13 (48) 12 (46) 12 (32) .29 transmitted disease.

in the United States when routine cytologic screening by Pap Discussion smear was introduced in the late 1940s.10 Given that anal cancer is now more prominent in certain populations than cervi- Anal cancer is an increasingly prevalent disease that affects cal cancer was at that time, there is significant debate regard- nearly 8000 people per year in the United States.8 Although ing the appropriateness of introducing routine screening patients who are HIV positive and those who are immunosup- guidelines for anal cancer as well. pressed (ie, after a transplant) have the highest incidence of Despite substantial discussion on the topic, there are still disease, rates of invasive anal cancer are increasing among all no official recommendations for the screening and surveil- men and women at an estimated rate of 2.0% to 5.1% per year.1,8 lance of anal cancer to date. Risk factors for HSILs of the As a result, routine screening surveillance protocols for anal anus have previously been studied, but there is a paucity of dysplasia that are similar to those for cervical dysplasia have data regarding the association between patient symptoms been a topic of discussion since 1997.9 The peak incidence of and anal pathologic findings. In the current study, we cervical cancer was estimated to be 115 per 100 000 women describe the distribution of symptoms, both overall and

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Figure. Patient Symptoms by High-Resolution Anoscopy Table 3. Multivariable Logistic Regression Analysis of Factors and Anal Papanicolaou Smear Dysplasia Grade Associated With High-Grade Anal Dysplasia Risk of High-Grade vs Low-Grade A High-resolution anoscopy vs No Dysplasia Covariate Estimate (SEM) P Value 70 P =.007 Anal dysplasia Age, y −0.057 (0.03) .04 High-grade Low-grade None 60 Male sex 0.49 (0.32) .13 Anal pain 0.90 (0.41) .03 50 P =.21 HIV viral load >20 copies/mL 0.08 (0.28) .78 40 Lesions on examination 0.37 (0.26) .15 P =.02 Anal Papanicolaou smear 0.58 (0.29) .05 30 P =.43

Patients, % high-grade dysplasia P =.33 20 Abbreviation: HIV, human immunodeficiency virus.

10 grade AIN. These findings are consistent with our results dem-

0 onstrating that patients with high-grade dysplasia on HRA had Any Symptom Anal Pain Bleeding Pruritus Anal Lesion a higher incidence of high-grade dysplasia on anal Pap smear than did patients with low-grade or no dysplasia. Human im- B Anal Papanicolaou smear munodeficiency virus status was not an independent predictor of dysplasia in our study, likely because many patients who 70 P =.32 Anal dysplasia were referred to our clinic were HIV positive (70 [77%]). In ad- High-grade Low-grade ASCUS None 60 dition, we did not assess human papillomavirus status as a predictor because we do not routinely screen for human papillo- 50 mavirus status in presenting patients based on its high 12 40 P =.99 sensitivity (90%) but low specificity (40%) for HSIL. Other P =.28 P =.12 studies have reported time from HIV diagnosis, use of highly 30 Patients, % active antiretroviral therapy, CD4 cell count, sexual practices P =.52 20 (anoreceptive sex or MSM), and smoking as potential predictors of high-grade dysplasia.11,13,14 However, these factors 10 have not been routinely supported by larger, more recent 11,15-20 0 series, and were also not found to be predictive of high- Any Symptom Anal Pain Bleeding Pruritus Anal Lesion grade dysplasia in our study. Of note, male sex and anal lesions on physical examina- A, Patients with high-grade dysplasia on high-resolution anoscopy presented with anal pain more frequently than did patients with low-grade or no dysplasia, tion were significantly associated with high-grade dysplasia and patients with either high- or low-grade dysplasia on high-resolution on univariable analysis in our study, although they were not anoscopy were more likely to present with anal lesions on physical examination statistically significant in our multivariable model. The inci- compared with patients with no dysplasia. B, Symptoms stratified by anal Papanicolaou smear findings showed no significant trends: patients with dence of anal cancer is known to be more than 4 times higher high-grade dysplasia on anal Papanicolaou smear reported anal pain, bleeding, in men compared with women.2 Similarly, suspicious lesions pruritus, overall symptoms, and anal lesions with similar frequency as those on physical examination are a well-recognized risk factor for with low-grade dysplasia, atypical squamous cells of undetermined significance anal cancer.14 As a result, digital anorectal examinations are a (ASCUS), or no dysplasia. ubiquitous aspect of the recommended annual physical examination for HIV-positive patients.15 In our study, less than based on HRA pathologic findings, among a group of half of all patients with anal dysplasia had anal lesions and the patients who were deemed to be high-risk for anal dysplasia presence of an anal lesion showed a nonsignificant associa- by their primary care physician. We demonstrate that tion with high-grade dysplasia, indicating that the sensitivity although symptoms are reported infrequently among of this clinical predictor is likely low. Therefore, although ini- patients presenting for HRA screening, anal pain is an inde- tial screening for patients considered at high risk for anal dys- pendent predictor of high-grade dysplasia. Anal lesions also plasia should include a digital rectal examination, the lack of appear to be precursors for more advanced disease, although a palpable or visible lesion should not preclude a patient from the presence of an anal lesion was not significantly associ- undergoing more extensive screening. ated with high-grade dysplasia after risk adjustment. One of the largest concerns regarding the implementa- Given the rapid increase in anal cancer rates that has been tion of a standardized screening algorithm for patients who observed during the past 2 decades,1,8 several studies have re- are at risk for having anal dysplasia relates to the cost- ported on risk factors that are thought to be predictive of anal effectiveness of this practice. High-grade dysplasia is a recog- cancer and its precursor—HSIL. In a study of more than 1000 nized risk for the development of anal cancer.21 However, the histologic specimens by Swedish et al,11 the authors found that progression of anal dysplasia to invasive anal cancer is thought HIV status, human papillomavirus infection, and abnormal anal to be slower than the progression of similar dysplastic cervi- cytologic results were independently predictive of high- cal lesions,1,22 and the long-term effect of routine screening on

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survival and other outcomes is unknown. Several screening data represent a biased population of patients; that is, pa- algorithms for anal dysplasia have been proposed based on the tients who were seen in the HRA clinic had already been pre- above-mentioned published risk factor data.19,23-27 Most of screened as being at high risk because the majority were re- these algorithms use HIV status and findings on anal Pap smear ferred by our institution’s HIV care center. As such, our findings as criteria for proceeding to HRA. However, there is currently are not applicable to large populations but should be consid- no comprehensive approach that incorporates both symp- ered a preliminary description of clinical and symptomatic risk toms and clinical data to aid in the identification of which in- that could potentially be applied in appropriate settings such dividuals may be at the highest risk for dysplasia. This is the as HIV clinics. The benefit of this design is that it captures first study, to our knowledge, that attempts to link HRA find- symptom and clinical data on all patients referred to a ter- ings with patient symptomatology, and our findings high- tiary center HRA clinic, which allows us to present a compre- light the importance of maintaining a high index of suspicion hensive overview of the clinical presentation of a high-risk for dysplasia among high-risk patients regardless of their clini- population that has been lacking from prior studies. cal presentation and frequent lack of symptoms. Future studies investigating the utility of clinical risk calculators for anal dysplasia may be useful in identifying patients who would ben- Conclusions efit from HRA screening. Our study contains some limitations. The number of pa- The development of targeted screening guidelines for anal dys- tients with available data on sexual practices was limited, which plasia is becoming increasingly relevant. To date, clinical prac- may have underpowered our study to identify a potential sig- tice is guided by data from small cohort and retrospective stud- nificant effect of MSM or anoreceptive sex on dysplasia risk. ies, which has resulted in a range of potential risk factors However, of the patients for whom we had data on this sub- associated with an increased risk of high-grade anal dyspla- ject, nearly three-quarters practiced high-risk sexual behav- sia. Abnormal anal Pap smear findings, HIV status, and male iors. The high prevalence of MSM and anoreceptive sex in our sex are commonly identified risk factors. We present data from patient population makes the likelihood that we would have a prospective high-risk HRA clinic suggesting that anal dys- detected a significant association between sexual practices and plasia is frequently asymptomatic, but that patients with anal anal dysplasia relatively low, similar to the phenomenon that pain, anal lesions, and other high-risk factors are at increased we observed with HIV status. Our sample size of 91 patients risk of having high-grade anal dysplasia. These patients may was relatively low in this preliminary study. In addition, our benefit from routine screening with HRA.

ARTICLE INFORMATION REFERENCES relationship to histopathology. Dis Colon Rectum. Accepted for Publication: November 25, 2014. 1. Machalek DA, Poynten M, Jin F, et al. Anal human 1997;40(8):919-928. Published Online: April 15, 2015. papillomavirus infection and associated neoplastic 10. Gustafsson L, Pontén J, Bergström R, Adami doi:10.1001/jamasurg.2015.28. lesions in men who have sex with men: a systematic HO. International incidence rates of invasive review and meta-analysis. Lancet Oncol. 2012;13(5): cervical cancer before cytological screening. Int J Author Contributions: Dr Fang had full access to all 487-500. Cancer. 1997;71(2):159-165. the data in the study and takes responsibility for the integrity of the data and the accuracy of the data 2. Silverberg MJ, Lau B, Justice AC, et al. Risk of 11. Swedish KA, Lee EQ, Goldstone SE. The analysis. anal cancer in HIV-infected and HIV-uninfected changing picture of high-grade anal intraepithelial Study concept and design: Hicks, Efron, Gearhart, individuals in North America. Clin Infect Dis.2012; neoplasia in men who have sex with men: the Safar, Fang. 54(7):1026-1034. effects of 10 years of experience performing Acquisition, analysis, or interpretation of data: 3. Steele SR, Varma MG, Melton GB, et al. Practice high-resolution anoscopy. Dis Colon Rectum. 2011; Hicks, Wick, Leeds, Fang. parameters for anal squamous neoplasms. Dis 54(8):1003-1007. Drafting of the manuscript: Hicks, Gearhart, Fang. Colon Rectum. 2012;55(7):735-749. 12. Goldstone SE, Lowe B, Rothmann T, Nazarenko I. Critical revision of the manuscript for important 4. Devaraj B, Cosman BC. Expectant management Evaluation of the hybrid capture 2 assay for intellectual content: Hicks, Wick, Leeds, Efron, Safar, of anal squamous dysplasia in patients with HIV. Dis detecting anal high-grade dysplasia. Int J Cancer. Fang. Colon Rectum. 2006;49(1):36-40. 2012;131(7):1641-1648. Statistical analysis: Hicks. 5. Scholefield JH, Castle MT, Watson NF. Malignant 13. Ciobotaru B, Leiman G, St John T, Hyman N, Obtained funding: Fang. Ramundo M, Grace C. Prevalence and risk factors Administrative, technical, or material support: Hicks, transformation of high-grade anal intraepithelial neoplasia. Br J Surg. 2005;92(9):1133-1136. for anal cytologic abnormalities and human Wick, Efron, Fang. papillomavirus infection in a rural population of Study supervision: Fang. 6. Watson AJ, Smith BB, Whitehead MR, Sykes PH, HIV-infected males. Dis Colon Rectum. 2007;50(7): Conflict of Interest Disclosures: None reported. Frizelle FA. Malignant progression of anal 1011-1016. intra-epithelial neoplasia. ANZ J Surg. 2006;76(8): Funding/Support: This project was completed 715-717. 14. Fox P. Anal cancer screening in men who have with funding from the State of Maryland, sex with men. Curr Opin HIV AIDS. 2009;4(1):64-67. 7. Fleshner PR, Chalasani S, Chang GJ, Levien DH, Department of Health and Mental Hygiene, 15. Sendagorta E, Herranz P, Guadalajara H, et al. Cigarette Restitution Fund Cancer Research Grant. Hyman NH, Buie WD; Standards Practice Task Force, American Society of Colon and Rectal Prevalence of abnormal anal cytology and Role of the Funder/Sponsor: The funding source Surgeons. Practice parameters for anal squamous high-grade squamous intraepithelial lesions among had no role in the design and conduct of the study; neoplasms. Dis Colon Rectum. 2008;51(1):2-9. a cohort of HIV-infected men who have sex with collection, management, analysis, and men. Dis Colon Rectum. 2014;57(4):475-481. interpretation of the data; preparation, review, or 8. American Cancer Society. Cancer Facts & Figures 2013. Atlanta, GA: American Cancer Society; 2013. 16. Richel O, De Vries HJ, Dijkgraaf MG, Van Noesel approval of the manuscript; and decision to submit CJ, Prins JM. Risk factors for the presence of anal the manuscript for publication. 9. Jay N, Berry JM, Hogeboom CJ, Holly EA, intraepithelial neoplasia in HIV+ men who have sex Darragh TM, Palefsky JM. Colposcopic appearance with men [published online December 18, 2013]. of anal squamous intraepithelial lesions:

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Invited Commentary Considering Standards of Care for Anal Cancer James Fleshman, MD

High-resolution anoscopy (HRA) has become a term that in- The study reported by Hicks et al1 in this issue emphasizes duces fear and trepidation in the hearts of most colorectal sur- some of the controversies surrounding the overall problem of geons. There is a certain sinking feeling when one considers HSIL. As usual, there are more questions than answers. Can the the time and effort that will be authors tell us how many patients without symptoms, never expended, with little return, having HRA but observed closely, will develop anal squamous Related article page 563 when the standard of care be- cell cancer? Is there a reliable correlation between the pres- comes the routine use of HRA ence of an anal lesion and anal pain and HSIL? Can routine fol- for all human immunodeficiency virus–positive patients. This low-up with anoscopy and destruction of obvious anal lesions time and effort are for a 0.131% risk of anal cancer in the highest- have the same protective effect as HRA on anal cancer? Can risk group—men having sex with men who have human im- asymptomatic high-risk individuals be observed until they de- munodeficiency virus. In fact, colorectal surgeons observe velop one of the symptoms associated with HSIL? What are the most of these individuals on a regular basis in the office if they “findings consistent with dysplasia,” as mentioned by the au- have condyloma or symptoms of anal disease. Anoscopy with- thors? Only 29% of the patients referred had cytologic findings out high resolution actually reveals most anal lesions that cause on anal Papanicolaou tests showing high-grade dysplasia. How symptoms. The time spent performing HRA compared with helpful is the Papanicolaou test, if the test and HRA were con- routine anoscopy may discourage most health care profes- sistent in only 66% of cases? Finally, if only 30% of the group sionals from using HRA, except those focused on high-grade referred by primary care physicians for rising concern about anal squamous intraepithelial lesions (HSIL) and human immuno- cancer had HSIL and none had anal cancer, why not start with deficiency as a specialty. follow-up routine regular anoscopy instead of HRA?

ARTICLE INFORMATION Corresponding Author: James Fleshman, MD, Conflict of Interest Disclosures: None reported. Author Affiliations: Department of Surgery, Baylor Department of Surgery, Baylor University Medical University Medical Center, Dallas, Texas; Center, 3500 Gaston Ave, First Floor Roberts, REFERENCE Department of Surgery, Texas A&M Health Sciences Dallas, TX 75246 (james.fleshman@baylorhealth 1. Hicks CW, Wick EC, Leeds IL, et al. Patient College of Medicine, Dallas. .edu). symptomatology in anal dysplasia [published online Published Online: April 15, 2015. April 15, 2015]. JAMA Surg. doi:10.1001/jamasurg doi:10.1001/jamasurg.2015.48. .2015.28.

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