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Random Biopsy During High-Resolution Anoscopy Increases Diagnosis of Anal High-Grade Squamous Intraepithelial Lesions

Silvera, Richard MPH; Gaisa, Michael M. MD, PhD; Goldstone, Stephen E. MD

JAIDS Journal of Acquired Immune Deficiency Syndromes: January 1st, 2014 - Volume 65 - Issue 1 - p 65–71
doi: 10.1097/QAI.0b013e3182a9b3d3
Clinical Science

Objective: Random biopsy (RB) of normal appearing cervix during colposcopy increases high-grade dysplasia (HSIL) diagnosis but has not been studied in high-resolution anoscopy (HRA), that is, colposcopy transferred to the anal canal. We investigated the utility of RB during HRA.

Design: At HRA, the anal canal was divided into 4 quadrants. Areas suspicious for HSIL had standard biopsy (SB); random biopsies were taken from quadrants without apparent HSIL. Inclusion required ≥1 RB. Two providers performed all procedures (S.E.G., >10 years experience; M.M.G. 3 years experience)[LINE SEPARATOR]

Results: Overall, 391 participants enrolled (mean age, 44.7 years); most were male (87.2%), non-Hispanic (69.8%), white (62.7%), and HIV positive (72.9%). Of 1761 biopsies, 883 were RBs (mean, 2.26/participant). HSIL was identified in 252 lesions, and in 132 participants (33.8%). Thirty-two HSILs (12.7%) and 13 participants (9.8%) were diagnosed by RB. RB increased total HSILs identified per participant (mean, 0.65 vs. 0.56; P < 0.001) and participants with HSIL (P < 0.001). Histologically, HSIL diagnoses via SB were no more dysplastic than random biopsies (relative risk, 0.82; range, 0.37–1.8). In multivariable analysis, factors affecting adjusted relative risk (ARR) of HSIL with any biopsy were provider [S.E.G vs. M.M.G.; ARR, 5.9; 95% confidence interval (CI), 1.3 to 25.8] and oncogenic human papillomaviral infection (ARR, 24.3; 95% CI, 2.8 to 213.3). Risk of HSIL on RB alone in multivariate analysis was associated with HSIL via SB (ARR, 3.4; 95% CI, 1.6 to 7.1 or ARR, 1.4; 95% CI, 1.1 to 1.9 per standard HSIL). Provider, HIV status, detectable viral load, age, or prior screening for or treatment of HSIL did not affect the utility of RB.

Conclusions: Addition of RB to HRA significantly increased both the number of HSILs and participants with HSIL identified.

Icahn School of Medicine at Mount Sinai, New York, NY.

Correspondence to: Stephen E. Goldstone, MD, 420 West 23rd Street, New York, NY 10011 (e-mail:

R.S. was funded by the Icahn School of Medicine at Mount Sinai Summer Scholars Program.

Presented orally at the Conference on Retroviruses and Opportunistic Infections Q-111/Paper #142, March 3–6, 2013 Atlanta GA.

The authors have no conflicts of interest to disclose.

R.S. aided in the design of the trial, collected and analyzed the data, wrote a draft of the article, and approved the article. M.M.G. aided in the design of the trial, performed the procedure, edited, and approved the article. S.E.G. designed the trial, performed the procedures, wrote a draft of the article, and approved the article.

Received May 30, 2013

Accepted August 19, 2013

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Anal squamous cell carcinoma (ASCC) is an uncommon malignancy, with an estimated 6230 cases identified in the United States in 2012 and an age-adjusted incidence of 1.7 per 100,000.1 Men who have sex with men (MSM), HIV-infected individuals, and transplant patients are at an increased risk as are women with a history of lower genital tract neoplasia.1–4 Cervical and anal cancers are both caused by infection with oncogenic human papillomavirus (HPV) strains. Oncogenes promote mutations and unregulated cell division, which can progress to low-grade dysplasia (LSIL) and high-grade dysplasia (HSIL). HSIL is the presumed cancer precursor in both the cervix and anus. Cervical cancer rates have been dramatically decreased through cytology screening. Women with abnormal cells are referred for colposcopy where HSIL and cancer are recognized by abnormal vascular patterns, friability, and mass effect. Abnormalities are biopsied, and if HSIL is present, the patient is generally treated with the loop electrocautery excision procedure to remove precancerous lesions, the entire squamocolumnar junction (SCJ), and any occult lesions.

To stem the rising tide of ASCC, clinicians adapted cervical cancer screening techniques to the anal canal.5 Jay et al6 first described high-resolution anoscopy (HRA), essentially, colposcopy transferred to the anal canal. The anal canal is stained with acetic acid and the squamocolumnar transformation zone and anal canal are examined with magnification. Many clinicians also apply Lugol's iodine to better distinguish LSIL from HSIL. HSIL and ASCC are typified by acetowhite, Lugol-negative epithelium with vascular abnormalities (mosaicism, punctuation, atypical vessels), abnormal glands, friability, ulceration, and mass effect. Suspicious lesions are biopsied for histology. Although HSIL progression to ASCC has not been definitively proven by a randomized prospective trial, many clinicians advocate ablating HSIL to prevent cancer.7,8 To date, minimal progression to cancer has been achieved through ablation of HSIL by either electrocautery or infrared coagulation when compared with observation.7–13

HRA and colposcopy are difficult procedures, and experience increases the ability to identify HSIL.10,14–17 Most clinicians only biopsy areas suspicious for HSIL. However, in the cervix, some advocate taking random biopsies of normal appearing tissue after sampling abnormal areas to detect occult HSIL. Including random biopsy (RB) in cervical screening increased the prevalence of HSIL from 3.2% to 4.2%.18 Among women with HSIL found on targeted biopsy, 17.6% of RBs were HSIL.19 Utility of random cervical biopsy can vary between clinicians with 6 of 7 physicians in 1 cervical screening study identifying significantly more HSIL when adding RB.16 Despite these findings, random cervical biopsy remains controversial and not routine for many clinicians.20 To date, the utility of random biopsies during HRA screening has not been well studied. Nahas et al21 reported that 10% of random biopsies collected during HRA were LSIL. We endeavored to determine whether RB during HRA would identify significantly more patients with HSIL and more lesions.

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This was a prospective study of participants presenting for HRA at 2 sites in New York City specialized in the diagnosis and treatment of anal dysplasia. One site is a publicly funded, hospital-based clinic (M.M.G.) and the other is a private surgical practice (S.E.G.). S. E. Goldstone is a surgeon with more than 15 years experience performing HRA, whereas M. M. G is an infectious disease specialist with 3 years HRA experience. The Program for Protection of Human Subjects of the Icahn School of Medicine at Mount Sinai approved this study. All participants were aged 18 years or older presenting for HRA between April and October 2012 because they were determined to be at high risk for HSIL due to abnormal anal cytology within 90 days of examination, an abnormal digital anorectal examination, or a visible anal lesion thought to be HPV-related. Individuals with a history of ASCC, circumferential intra-anal condyloma without skip areas, those receiving anticoagulant therapy, with history of a bleeding disorder, and women in their third trimester of pregnancy were excluded.

Clinicians recorded basic demographics, HIV status and treatment history, sexual history, history of screening and treatment for HSIL and condyloma, and any sexually transmitted infections. Participants whose insurance would allow underwent testing for 13 high and intermediate risk HPV types by Hybrid Capture 2 (HC2; Qiagen, Corp, Gaithersburg, MD). Two of the authors (M.M.G. and S.E.G.) performed HRA after applying acetic acid to the anal canal for approximately 1 minute followed by insertion of a lubricated, clear anoscope. Microscopic examination of the anal canal was performed using a colposcope. After identifying areas suspicious for HSIL, Lugol's solution was applied under direct visualization. Acetowhite, Lugol-negative lesions suspicious for HSIL were biopsied first and immediately fixed in 10% formalin for histological examination. The anal canal was divided into 4 quadrants along the 12- to 6-, and 3- to 9-o’clock axes. Any quadrant(s) with flat mucosa at the SCJ (exophytic condyloma were excluded) that were thought to be free of HSIL and were not considered for routine biopsy were then randomly biopsied at the SCJ. Choosing a site for a RB was based on objective measures of visual appearance including vascular patterns, acetowhitening, and Lugol's staining. Squamous metaplasia is a normal finding at the transformation zone and is not routinely biopsied unless the lesion appears equivocal for HSIL. If there was any suspicion that a biopsied area of probable metaplasia or flat LSIL could be possible HSIL, it was not deemed random. When choosing a site for RB at the SCJ, clinicians preferentially sampled areas that could harbor HSIL even though that possibility was deemed remote. Thus, when present, areas of normal appearing metaplasia or flat LSIL without suspicion of HSIL were preferentially sampled over nonacetowhite, Lugol-positive epithelium (Fig. 1). Quadrants with multiple lesions suspicious for HSIL received multiple biopsies to sample all abnormalities. Lesions that spanned multiple quadrants were only biopsied in each quadrant when morphology differed.



Clinicians recorded their presumptive diagnosis of all biopsies. When performing standard biopsies, clinicians sample many areas where lesion features are not pathognomonic of HSIL. They are biopsied because there is some suspicion that the lesion could be HSIL, although the clinician may believe that a different diagnosis, such as LSIL or metaplasia, is more likely. Thus, areas undergoing standard biopsy (SB) may not have a presumptive diagnosis of HSIL. Patients requiring 4 quadrant biopsies because of suspected HSIL were discontinued from the study, as were those with circumferential condylomata without skip areas. Perianal and/or anal verge biopsies were not included in this analysis and not considered when determining whether a RB was indicated. All participants received at least 4 intra-anal biopsies. Histological evaluation was performed by a commercial laboratory or hospital-based pathologists. A single expert pathologist subsequently reviewed HSILs only identified via RB, but there was no adjudication of discrepant results. Participants with HSIL by either SB or RB were offered treatment outside the study.

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Statistical Analysis

Statistical analyses were performed using PASW Statistic 20 (Release Version 20, 2011; SPSS, Inc, Chicago, IL; The data were analyzed using χ2 tests, Fisher exact test, McNemar test, Student t tests, Mann–Whitney U tests, and paired samples t tests. Multivariate binary logistic regression analyses were constructed by the inclusion of all significant bivariates. Significance was defined as P ≤ 0.05 or a confidence interval that did not include 1. The review of the random biopsies yielded some discrepancies with the local laboratories, so all analyses were calculated in 2 ways based on the local laboratory and then the expert pathologist diagnoses. The significance of all results was not affected, so we report herein based on the local laboratory findings because that standard guides clinical practice.

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A total of 541 patients were approached about the study, 48 (9%) declined, 102 (19%) were ineligible, leaving 391 (73%) participants (Fig. 2). Mean participant age was 44.7 years (range, 20–77 years; SD, 11.58) (Table 1). Most were male at birth (87.2%), non-Hispanic (69.8%), and white (62.7%). The majority were HIV positive (72.9%) and receiving highly active antiretroviral therapy (HAART) (95.8% of HIV positive). The mean time since HIV diagnosis was 13.8 years (range, 0–32 years; SD, 8.4), median CD4+ T-cell count was 578 cells per cubic millimeter (range, 7–1632 cells/mm3), and most had undetectable HIV-1 plasma viral load (73.1%). Most males had sex with men (MSM) (93.5%), but 5.0% reported sex with both males and females. Most participants who were identified as female at birth reported sex exclusively with males (92.0%). There was no significant difference between patients enrolled in the study and those who either refused or were ineligible with respect to age, race, ethnicity, sex, HIV status, or gender of sexual partners (data not shown).



Table 1

Table 1

Only 174 (44.5%) participants received HC2 HPV testing, and 133 (76.4%) had oncogenic HPV detected. Participants who received HPV testing were more likely to have been seen at the surgical practice (S.E.G.), be older, not identify as Hispanic or Latino, identify as white, be HIV negative, report never smoking tobacco, report a history of screening or treatment for HSIL, and report a history of diagnosis or treatment for anogenital condyloma (data not shown). History of anogenital condyloma was reported by 219 (56.0%), although 138 (35.3%) had a history of prior treatment for HSIL.

Overall biopsy proven HSIL was found in 132 participants (33.8%), with 100 participants (75.8%) having the diagnosis made solely via SB and in 13 participants (9.8%) solely via RB. Inclusion of RB significantly increased total participants with HSIL (132) compared with those found solely using SB (119) (McNemar' test, P < 0.001). Of 878 SBs (mean, 2.25 per participant), 220 (25.1%) were HSIL. Of 883 RBs (mean, 2.26 per participant), 32 (3.6%) were HSIL. Overall, participants had 252 individual HSILs (mean of 0.64 per participant; range: 0–6; SD, 1.09). Comparing HSIL lesions found per participant using only SB to total lesions found using both SB and RB found a significant increase in HSIL identified per participant when RB was added (mean 0.65 vs. 0.56; P < 0.001). Thirty-two HSILs (12.7%) and 13 participants (9.8%) were diagnosed solely via RB. Of 61 participants (15.6%) with normal HRA examinations who received 4 random biopsies, 5 (8.2%) had HSIL. Histologically, HSIL found via SBs were not more likely to be AIN3 compared with HSIL found via RBs [relative risk (RR), 0.82; range, 0.37–1.8; P = 0.70].

Nine participants had HSIL cytology. Six had corresponding HSIL histology on HRA; of those, 1 participant had HSIL identified only through RB. Three did not have HSIL found either with RB or SB (all were evaluated by M.M.G.).

Expert review of the 32 HSILs found via RB downgraded 6 lesions (4 to LSIL, 1 to atypical cells, and 1 unsatisfactory for diagnosis), leaving 11 participants with HSIL diagnosed solely via RB. Overall, local and expert pathology had excellent agreement, with a Cronbach alpha of 0.93 [95% confidence interval (CI), 0.92 to 0.94].

Clinicians' presumptive diagnosis based upon HRA findings for both SB and RB are shown in Table 2. Overall, agreement between presumptive and pathology diagnoses was fair, with a Cronbach alpha of 0.60 (95% CI, 0.56 to 0.64) but differed significantly between clinicians (S.E.G.: Cronbach alpha, 0.74; 95% CI, 0.70 to 0.77; M.M.G.: Cronbach alpha, 0.46; 95% CI, 0.38 to 0.53). The major difference between providers was that one (M.M.G.) was more likely to over-predict HSIL and less likely to predict benign tissue. The presumptive diagnoses of the 32 RBs that were HSIL were normal (59.4%), squamous metaplasia (25%), hyperkeratosis (12.5%), and LSIL (3.1%).

Table 2

Table 2

Table 3 reports on bivariate and multivariate binary logistic regression associations between participant characteristics and having HSIL via SB and RB. Overall, HSIL increased if participants were screened at the surgical practice (RR, 2.6; 95% CI, 1.7 to 4.0), were HIV positive and not receiving HAART (RR, 3.8; 95% CI, 1.1 to 13.0), reported their race as white (RR, 1.8; 95% CI, 1.1 to 2.8), and had prior HSIL treatment (RR, 1.9; 95% CI, 1.2 to 2.9). For those who were tested, having oncogenic HPV via HC2 had an increased risk of HSIL (RR, 7.9; 95% CI, 2.9 to 21.4). Sexual orientation, gender of sexual partners, HIV status, race, ethnicity, monogamy, history of smoking, prior screening for or treatment of anogenital warts, prior screening for HSIL, receptive anal sex, unprotected receptive anal sex, or anal sexually transmitted infection were not significantly associated with HSIL by SB or RB (data not shown). In multivariate binary logistic analysis, only oncogenic HPV infection [adjusted relative risk (ARR), 24.3; 95% CI, 2.8 to 213.3] and screening at the surgical practice (S.E.G.) (ARR, 5.9; 95% CI, 1.3 to 25.8) increased the risk of HSIL.

Table 3

Table 3

Table 4 presents bivariate and multivariate binary logistic regression associations with HSIL via RB alone. The only factors significantly increasing HSIL were venue (surgical practice) (RR, 2.4; 95% CI, 1.1 to 5.3) and having at least 1 HSIL via SB (RR, 3.8; 95% CI, 1.8 to 8.0). In multivariate binary logistic regression, only having at least 1 HSIL via SB was significant with an ARR of 3.4 (95% CI, 1.6 to 7.1) or an ARR of 1.4 (95% CI, 1.1 to 1.9) per standard HSIL.

Table 4

Table 4

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RB significantly increased both the number of HSILs identified per participant and the number of participants with HSIL. Without RB, 12.7% of HSILs (n = 33) and 9.8% of participants with HSIL (n = 13) would have gone unidentified. This suggests that current clinical practices may miss lesions and patients with potentially precancerous lesions. However, RB did not have a high yield as only 3.6% of collected RBs had HSIL pathology. Agreement between clinician assessment and histological diagnoses was fair (Cronbach alpha, 0.60) and echoes the point that visual appearance and clinician interpretation inadequately identifies HSIL. This finding was even more striking for physician assessment of random biopsies where only 3% of lesions that were histologically HSIL were considered to have HPV-related dysplasia based on HRA appearance.

HSIL diagnosis via SB or RB was strongly associated with oncogenic HPV (ARR, 22.1) and venue of participation (surgical practice; ARR, 7.1) in multivariate analysis. Thus, HC2 testing to identify patients with oncogenic HPV might be a useful addition to clinical practice to alert clinicians of HSIL risk and heighten scrutiny during HRA. However, the patients who were tested differed significantly from those who were not, so a larger study where all patients are tested for oncogenic HPV is necessary to determine if this finding holds. Although we cannot say with certainty why screening at the surgical site increased the risk of HSIL, it could be related to the clinician's (S.E.G.) considerable experience in HRA, as evidenced by the fact that all 3 participants without HSIL histology, despite having HSIL cytology, were evaluated by the clinician with only 3 years of experience. It could also be a function of different patient populations seen at the 2 venues with those with more extensive disease, and probably a greater likelihood of HSIL, seeking out a surgeon. The surgical practice also enrolled a higher percentage of participants who were MSM (P < 0.001), HIV positive for a longer duration (15.5 years vs. 12.7 years; P = 0.007), or more likely to have been treated for HSIL in the past (P< 0.001), characteristics that may increase HSIL. Conversely, participants enrolled from the public clinic had a higher percentage of women (P < 0.001) and had abnormal cytology rather than grossly visible lesions as their reason for HRA (P < 0.001). These factors could contribute to lower rates of HSIL in this population. In multivariate binary logistic regression, considering traits associated with HSIL via only RB, venue was not significant, suggesting that RB was useful in varied patient populations.

The only trait that remained associated with HSIL via RB was having HSIL on SB (ARR 3.4). This coupled with the fact that the more HSILs a patient had on SB, the greater the likelihood of HSIL via RB could be extremely useful in formulating clinical guidelines. If a clinician is fairly confident that the patient has an HSIL, then a strong argument can be made to collect additional random biopsies in quadrants that seem disease free. Interestingly, age, oncogenic HPV by HC2, prior HSIL, or detectable HIV viral load were not associated with HSIL detection via RBs and may not be useful in determining which patients could benefit from additional biopsies. Clearly, this is preliminary data and given that <4% of total RBs were HSIL, further study could help determine which patients warrant additional biopsies to allow for a higher yield.

RB is still controversial in the cervix where additional benefit derived by discovering additional HSIL at the transformation zone may not be as clinically significant when the transformation zone is routinely removed during loop electrocautery excision treatment. Occult lesions would thus be treated by excision in the specimen. In the anus, targeted ablation is the only treatment readily available, and an undiagnosed lesion is an untreated lesion. Untreated lesions do have the potential to progress to cancer. Ablating lesions found by RB that appeared to be completely normal mucosa was greatly aided by photographic documentation of the biopsy site. The clinician could then use the photograph taken during the primary HRA to guide the areas requiring treatment. A larger treatment area may however be required to ensure that the occult lesion was destroyed.

We cannot tell from this study why some lesions on HRA may appear less like HSIL (or even normal) than others. The fact that these lesions were no more likely to be AIN2 than AIN3 does not help in determining whether they could represent regressing or evolving dysplasia that has not yet developed morphological abnormalities, characteristic of HSIL at HRA. If they are regressing, then finding them is of little clinical significance. Evolving lesions may become obvious at a subsequent HRA and could explain why metachronous recurrence (a new HSIL at a previously untreated location) after HSIL ablation remains high at 23%–62%, necessitating repeated ablations to clear disease.8,9 Unfortunately, a high lost to follow-up rate after ablation is common, so untreated, missed lesions could translate into a higher risk of cancer.8,9,13,22 If we make every effort to diagnose all HSILs at each HRA by including RB, we can hopefully not only decrease the chance a lost to follow-up patient will develop cancer but also decrease the number of treatments a patient needs to clear their disease. Further study must investigate possible pathophysiological difference between lesions discovered through SB and RB.

It does not seem from these data that RB is more important for less experienced clinicians as one of the authors (M.M.G.) (although he found less HSIL than S.E.G.) with only 3 years of experience did not have a significantly greater rate of HSIL with RB. It is possible that 3-year experience places the specialist (M.M.G.) at a level of excellence above a threshold where RB is helpful and could be more advantageous to clinicians just beginning HRA. It does seem that having considerable experience does increase the clinician's ability to better predict the histological diagnosis from HRA findings, as evidenced by the significantly higher agreement with histological diagnosis (Crohnbach's alpha: S.E.G., 0.74 vs. M.M.G., 0.46).

This study had several limitations. Participants were primarily male, MSM, white, non-Hispanic, and HIV positive receiving HAART. Therefore, the findings may not be generalizable to other populations. Those tested for oncogenic HPV differed significantly from those not tested. There is also a possible clinician bias in determining what was considered a SB or RB. Clinicians might have been more likely to biopsy a lesion as a possible HSIL during the study, which they might not have biopsied in standard clinical practice. Even so, we still report significantly more HSIL through RB. The expert reference pathologist only reviewed samples of HSIL identified via RB, and it is possible that SB samples might have been reclassified, potentially affecting the proportion of HSIL identified by RB. Moreover, the SCJ is not removed during treatment, so we cannot say definitively that RB, as we described it, found all HSILs. We did not record specific HRA findings of individual lesions (punctuation, mosaicism, etc) that led to biopsy, so we cannot determine which appearances were more predictive of HSIL than others. Finally, out of approximately 1000 RBs, only 3.6% were HSIL and cost:benefit analysis is necessary to determine financial utility of the procedure.

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RB of normal appearing quadrants during HRA significantly increased both the number of HSILs identified per person and the number of persons with HSIL. Although clinician experience did not alter the utility of RB, those with obvious HSIL at HRA were more likely to benefit from RB. RB may be clinically more important in the anus, rather than the cervix, where targeted HSIL ablation is the only widely used treatment and an undiagnosed lesion is more likely to go untreated.

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The authors thank T.D., MD, for her generous offer of her time and expertise in reviewing the pathology slides for the random biopsies that resulted in HSIL diagnosis. They also thank the pathologists at Quest Diagnostics (Teterboro, NJ), Enzo Clinical Labs, Inc (Farmingdale, NY), and Mount Sinai Medical Center (New York, NY) for interpreting the cytology and histology samples.

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high-resolution anoscopy; anal dysplasia; anal cancer; HPV; anal intraepithelial neoplasia

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