Marks, Douglas K. BS; Goldstone, Stephen E. MD
Over the last 15 years, there has been an increase in the incidence of anal squamous cell carcinoma (ASCC), most dramatically in men who have sex with men (MSM).1 According to a recent multicenter cohort study, the incidence rate in HIV-positive MSM is 69 per 100,000, nearly 5 times the rate observed in HIV-negative MSM.2 Current evidence indicates that ASCC incidence is unlikely to decline in the absence of novel treatment options.3
High-grade anal intraepithelial neoplasia (HGAIN) is believed to be the ASCC precursor.4–6 The exact rate of progression of HGAIN to ASCC is not known but is estimated to be 8.5%–13%.5–7 Both anal and cervical cancers develop as a result of infection with oncogenic strains of human papilloma virus (HPV), most commonly HPV 16 and 18.7,8 To prevent progression to invasive cancer, cervical dysplasia is excised with the surrounding squamous-columnar junction (SCJ), with conization or loop electrosurgical excision9–11 achieving cure rates of greater than 95% in HIV-negative females.11 Aggressive screening and treatment of cervical dysplasia has even resulted in a decline in HIV-positive women progressing to invasive cancer.12 Anal dysplasia, like cervical dysplasia, is most frequently located at the SCJ, but resection of the anal SCJ results in undo morbidity including stricture, anal spasm, and dyschezia.13,14 As a result, targeted ablation of individual lesions has become the most common management approach. Multiple techniques including laser, electrocautery ablation (ECA), infrared coagulation (IRC), cryotherapy, or topical agents (imiquimod, tricholoracetic acid, and 5% 5-Fluoro-uracil cream)13,15–23 have been employed.
We previously showed that IRC was an effective in-office treatment in both HIV-negative and HIV-positive patients with individual lesion cure rates after the first ablation of 81% and 72%, respectively.20,24 We now endeavored to determine if in-office ECA of intra-anal HGAIN was as safe and effective as IRC ablation in MSM.20,24,25
MATERIALS AND METHODS
Identification of Subjects
With Institutional Review Board approval from Mount Sinai Medical Center, Investigational Review Board and in accordance with health insurance portability and accountability act regulations, we performed a retrospective chart review on all MSM patients who underwent ECA of intra-anal HGAIN from January 2006 to April 2010 at a surgical practice (S.E.G.) specializing in treatment of anorectal HPV-related disease. It was at this time that we began to use ECA almost exclusively for treatment of HGAIN. For inclusion, subjects were required to have a history of biopsy confirmed HGAIN treated with ECA during the study period and at least 5 months follow-up after ECA. Patients were excluded if they had ever received IRC treatment or participated in vaccine trials. MSM who had prior HGAIN treatment by laser ablation in the operating room were eligible for inclusion if recurrent disease was treated in-office with ECA. Lesion size was not measured, and lesions could be confluent. Only lesions within the anal canal, proximal to the anal verge, were included in the analysis. Circumferential disease was not treated in office but instead ablated in the operating room as were patients with extensive condyloma. As previously described, evaluation included anal cytology followed by digital rectal examination and standard anoscopy.26 Cytology was obtained with a wetted Dacron swab and reported as squamous cells within normal limits (benign), atypical squamous cells of undetermined significance, atypical cells cannot rule out high-grade dysplasia, low-grade squamous intraepithelial lesion, and high-grade squamous intraepithelial lesion. Patients with abnormal cytology, and/or visible lesions on standard anoscopy, underwent high-resolution anoscopy (HRA) in accordance with the technique of Jay et al.27 Lesions suspicious for HGAIN were biopsied and fixed in 10% formalin and processed for histology diagnosis with results reported in accordance with the Bethesda classification of normal or benign, low-grade anal intraepithelial neoplasia, HGAIN, and ASCC.28
Patients with HGAIN amenable to in-office treatment were most often treated at a subsequent visit after biopsy confirmation of disease. Lesions were re-identified during HRA and infiltrated with either 0.5% bupivicaine or 1% lidocaine with epinephrine to achieve local anesthesia. The anesthetic was infiltrated just distal to the lesion, and minimal amounts were used to avoid lesion distortion. Later in the series, patients with larger volume disease were offered in-office monitored sedation delivered by an anesthesiologist to alleviate discomfort from multiple injections of local anesthetic. Approximately 50% of patients chose monitored sedation.
The lesion was ablated with The Hyfrecator 2000 (ConMed Corporation, Utica, NY) on 13–15 watts. A 6 ultraclean blade with extended insulation (ConMed Corporation) was passed down the anoscope to make contact with the lesion. Using a gentle brushing technique, the lesion was ablated by moving the blade lightly across the surface like a gentle paint brush. The char was swept away with the blade or removed with blunt dissection utilizing the end of the anoscope. Thick lesions were debrided with a Baby Tischler Biopsy Punch (CooperSurgical, Inc, Trumbull, CT) to the level of submucosal vessels. Hemostasis was achieved with the hyfrecator. The hyfrecator smoke plume was removed with a Porta PlumeSafe 604 smoke evacuator (Buffalo Filter, Lancaster, NY) held in place by an assistant. All procedures were performed by S.E.G. It is not our practice to ablate flat low-grade anal intraepithelial neoplasia, but we routinely ablate condyloma, and these lesions are not included in the analysis.
Follow-up consisted of regular 3–6 month evaluations including a history of postsurgical complications and digital rectal exam. At 3 months postablation, patients would also have standard anoscopy to access healing and gross recurrence. Given the high recurrence rates with IRC, at 6 months, patients would have cytology and simultaneous HRA to rule out recurrence. If no lesion was found, then the patient would be evaluated at 12 months with cytology and standard anoscopy. Patients with an observed lesion on standard anoscopy or abnormal cytology were always referred for HRA. Patients with HGAIN on biopsy were classified as having recurrent disease and offered repeat ablation. Patients with benign cytology or without HGAIN on HRA maintained regular follow-up. The screening and treatment algorithm is depicted in Figure 1.
Treatment success after ECA was defined as no evidence of HGAIN on HRA or benign cytology if a follow-up HRA was not performed. Recurrence was defined as either cytologic or biopsy-proven HGAIN after treatment. Overall recurrence was defined as identification of HGAIN at any point during follow-up, in either the treated location or at a new site. Persistence is recurrence of disease at the treatment site. A metachronous recurrence is HGAIN found at a site not previously treated. Time to recurrence was measured from ECA to the date recurrent HGAIN was diagnosed.
Statistical analyses were performed with SAS (SAS Institute Inc, Cary, NC). The χ2 tests were used to compare proportions and Student t tests to compare means, as appropriate. The Cox proportional hazards model was used to compute risk ratios (equivalent of odds ratios) and confidence intervals after adjusting for other covariates. Recurrence rates were estimated using Kaplan–Meier product limit method with comparison between the HIV-positive and HIV-negative groups evaluated with log-rank statistic.
A total of 100 HIV-negative and 132 HIV-positive MSM met enrollment criteria, with a median age of 42 (range: 21–70) years and 49 (range: 27–74) years, respectively (P < 0.0001). Mean length of follow-up was 21.1 (range 6.1–43.9) months and 20.0 (range 5.4–46.0) months for HIV-negative and HIV-positive MSM (P = 0.40). HIV-positive MSM had significantly more lesions treated at their first ablation than HIV-negative MSM; in total, 375 lesions were treated at first treatment in the HIV-positive MSM versus 226 in the HIV-negative MSM (P = 0.006). After HGAIN diagnosis, 90% of patients had ECA by 1.5 months for HIV-negative versus 1.8 months in the HIV-positive patients.
HGAIN Recurrence After ECA
Table 1 details the overall recurrence rates observed for HIV-negative and HIV-positive MSM. In both the HIV-positive and HIV-negative groups, more patients recurred after first electrocautery than remained disease free. In the HIV-negative group, 53 (53%) patients recurred after first ablation with a mean of 1.6 lesions over a median of 7.0 months, whereas 47 (47%) patients did not recur over a median of 17.3 months. For HIV-positive patients, 80 (61%) recurred after first ablation with a mean of 1.9 lesions over a median of 6.8 months, whereas 52 (39%) did not recur over a median of 13 months. Mean number of recurrent lesions for both HIV-positive and HIV-negative MSM was never greater than 2. In both the HIV-negative and HIV-positive patients, there was no statistically significant decrease in overall recurrence rates with continued ECA. Lesion burden was observed to affect recurrence rates only in the HIV-positive patients. Patients with 1 HGAIN on first ECA were 55% (P = 0.008) and 73% (P < 0.0001) less likely to have recurrence than patients with 2 or 3 lesions, respectively.
Table 2 depicts HGAIN persistence after treatment in HIV-positive and HIV-negative MSM. After ablation, persistent HGAIN was identified in 27 (27%) of HIV-negative MSM, but 226 lesions were treated once, and 35 persisted yielding an individual lesion cure rate of 85%. In the HIV-positive patients, 55 (42%) had persistent HGAIN after their first ablation, but 375 lesions were treated once, and 93 persisted yielding an individual lesion cure rate of 75%. In the HIV-negative patients, the persistence rate after ECA of refractory HGAIN was 3.03 [(1.32, 6.93); P = 0.009] times greater than the persistence rate after initial electrocautery of index lesions. Similarly, in the HIV-positive patients, the persistence rate for lesions after third ECA was 3.08 [(1.58, 5.99); P = 0.0009] and 2.98 [(1.34, 6.65); P = 0.008] times greater than after first and second electrocautery, respectively. Increased persistence between first and second ECAs was observed but not statistically significant.
Comparison of HGAIN Recurrence Between HIV-Positive and HIV-Negative MSM
Our data demonstrates that HGAIN recurrence was greater among HIV-positive patients than HIV-negative patients (Fig. 2). After first ECA, HIV-positive MSM were 1.28 times [(0.91, 1.82); P = 0.1578] more likely to recur than HIV-negative MSM and 2.34 [(1.24, 4.43); P = 0.009] times more likely to recur after second ECA. Similarly, the persistence rate after first ECA in HIV-positive patients was double that of the HIV-negative patients (P = 0.003).
Of note, at last visit, 83% of HIV-negative and 69% of HIV-positive patients were HGAIN free.
One HIV-positive patient (0.4%) progressed to ASCC despite multiple ECAs. Initially, the patient presented with circumferential intra-anal HGAIN and was treated with laser ablation in the operating room. At that time, no biopsies indicated ASCC. He developed 4 localized HGAIN recurrent lesions 21 months after surgery and was treated in office with ECA. Five months later, he developed a single recurrence retreated with ECA. Six months later, multiple recurrent HGAINs developed, and 1 lesion that had persisted throughout now seemed raised. Despite the fact that the biopsy was only HGAIN, the lesion was excised instead of ablated and found to have ASCC deep to the HGAIN.
No patients developed other serious adverse events after ECA, including anal stenosis, persistent bleeding, hemorrhage, failure to heal, or infection necessitating antibiotic therapy. Most often pain was the only postprocedure complaint and was adequately controlled by over the counter medication or mild narcotic analgesia, however, no postprocedure diaries were utilized.
This study represents the largest efficacy analysis of ECA to date. The only other major study published by Chang et al21 in 2002 examines ECA for extensive HGAIN disease in the operating room setting. The study reported recurrence rates of 79% in HIV-positive group and 0% in HIV-negative group but was limited by small size (n = 37) and fairly short follow-up.21 In the extended and much larger follow-up series that included these patients, the 0% recurrence did not hold.22 Our results confirm that ECA is an effective treatment for HGAIN and can be used safely in-office.
In both HIV-positive and HIV-negative patients, lesions that failed initial ECA were less likely to be successfully ablated on subsequent treatment. This observation has both positive and negative implications. As might be predicted, there does not seem to be any lasting tissue effect after ECA such as scarring or destruction of the transformation zone that could diminish recurrence. Development of persistent lesions may be secondary to inadequate initial lesion ablation or “oncogenic” virus present in adjacent cells that activates during wound healing causing a new HGAIN to develop. At this point, there is no way of knowing if the persistent lesion actually resulted from remaining disease left behind or if it developed from a new cell line. The greater difficulty in preventing persistence of a recurrent lesion with successive ablations, however, seems to support the possibility that the lesion was caused by a more oncogenic virus (perhaps HPV 16).
Similarly, HIV-positive patients with less extensive HGAIN, defined by fewer lesions at presentation, had lower recurrence rates than those presenting with multiple lesions. Patients with only 1 lesion at first ablation were 55% less likely to recur than those with 2 lesions (P = 0.008) and 73% less likely than patients with 3 lesions (P < 0.0001). Extensive dysplastic tissue may indicate either infection with a more oncogenic virus or a more immune compromised host. Interestingly, we did not see a statistically significant association between disease burden and risk of recurrence in HIV-negative patients. This could result from the fact the HIV-negative patients had fewer lesions and likely a more robust immune response reducing recurrence. If we had more HIV-negative patients with extensive disease, we might have seen a difference.
Comparing overall recurrence rates to persistence rates clearly demonstrates that recurrence in nontreated areas (metachronous recurrence) is the major factor preventing patients from achieving disease free status. Although our study demonstrates that ECA effectively ablates dysplastic lesions, it also suggests that even with successive treatments recurrence over time remains a problem. Clearly, ablation destroys dysplastic cells but does not eradicate the HPV infection from other cells or prevent re-infection leaving the patient at risk for new foci of dysplasia. It remains to be seen with long-term follow-up for patients in monogamous relationships if risk of recurrence decreases.
Despite the fact that patients required multiple treatments to ablate HGAIN and recurrence remained high, morbidity was minimal. The mean time to recurrence in both groups approached a year. Moreover, the mean number of recurrent lesions did not exceed 2, so repeat ablations were localized and not extensive. This could translate into less pain with more rapid healing.
Comparison of ECA to Other Treatments
We previously reported IRC as an effective in-office treatment modality for HGAIN with individual lesion cure rates after the first IRC of 81% in HIV-negative and 72%, in HIV-positive patients20,24 and are not significantly different than what we now report for ECA. Moreover, there was no difference in overall recurrence or metachronous lesion recurrence between patients treated with IRC versus ECA20,24 (Table 3). Of note, in the IRC study, both the HIV-negative and HIV-positive groups were younger with mean age of 38 and 41 years as compared with 42 and 49 years, respectively (P < 0.0001, P = 0.02) in this EC study. In addition, in the IRC study, the mean number of lesions at first treatment in HIV-positive patients was 1.6 versus 2.2 lesions in this study (P = 0.0005). In light of previously described relationship between disease burden and recurrence in the HIV-positive patients, we might expect that these differences would cause increased recurrence in the current EC trial, but this was not the case. The IRC data we reported is also consistent with 2 other studies of HIV-positive MSM who reported individual lesion cure rates of approximately 65%.14,23 Therefore, given that IRC and ECA have similar outcomes when treating HGAIN, the choice of modality should be based on clinician comfort and preference. ECA does require smoke evacuation that is best handled with an assistant although IRC does not. It is, however, our belief that whether these minor surgical procedures are performed with IRC or ECA, an assistant shouldbe present, as a problem could arise even in the best of circumstances. Although not measured, in our hands, the overall impression was that EC seemed faster, more hemostatic, and allowed more extensive disease to be treated in office than the IRC.
Topical agents for treating HGAIN have also been studied. Imiquimod was recently evaluated in a double-blind randomized controlled trial.19 In the treatment group of 28 patients, imiquimod demonstrated a 61% cure rate over 36 months. Although imiquimod could be a promising nonsurgical treatment, it required 3 times weekly application for 4 months. That withstanding the treatment was tolerable with only a few patients discontinuing treatment. Tricholoracetic acid has also been used for topical ablation in patients with limited disease, with 73% and 71% individual lesion cure rates for AIN1 and AIN2-3, respectively.18 Limited follow-up and disease burden make direct comparison with ECA difficult.
Some clinicians advocate a more conservative approach monitoring HGAIN closely and only treating if early ASCC develops or if lesions become palpable or grossly visible.29 Their rational is that many patients with HGAIN will not progress to cancer and those who do will be caught early when lesions can be cured by excision. However, recent studies by Ortholan et al30 looked at recurrence rates after treatment of T1 or T1S anal cancer and found that excision alone for T1S had a 33% local recurrence rate requiring radiation therapy. Patients with invasion into the submucosa (T1), who failed local treatment, required abdominoperineal resection. These outcomes are associated with significant morbidity and decreased quality of life. Treatment of HGAIN aims to reduce incidence of anal cancer and requirements for large surgical resection or radiation and chemotherapy. Although unfortunate, 1 patient developed ASCC although managed with ECA. To date, HGAIN treatment series document a 0%–1.2% progression to ASCC, which is far lower than retrospective studies which report an 8.5% to 13% progression without intervention.5,6,13,20,22,24 Based on these estimates, the incidence of anal cancer would be predicted to be much higher in our cohort had HGAIN not been ablated.
There are several limitations to this study besides the fact that it is retrospective with a relatively short follow-up. Although HRA is the gold standard in detection of HGAIN, it requires human interpretation, which allows for the possibility that lesions can be missed and recurrence underdiagnosed. In addition, patients with benign cytology and negative standard anoscopy were considered nonrecurrent which might further underestimate recurrence rates. The study was performed only on males, which could limit applicability to women. Moreover, patients were excluded from in-office management if their disease was judged too extensive, and these results may not be generalizable to patients with large volume HGAIN. In addition posttreatment diaries were not performed, which would have provided data quantifying postprocedural pain. It remains to be seen if identical results would be achieved in a larger and longer prospective trial with men and women. Moreover, all procedures were performed by a single clinician (S.E.G.) very experienced in identification and treatment of HGAIN. It remains to be seen if similar results are reported by others.
ECA of HGAIN is a safe and effective office based procedure comparable with other available treatments. Cure rates of individual lesions are excellent, but patients continue to develop metachronous recurrence making continued follow-up important. Although we documented a single progression to ASCC (0.4%), rates are far lower than series advocating a “watch and wait” approach.
We would like to express our appreciation to the pathologists at Enzo (Farmingdale, NY) and Quest Laboratories (Teterboro, NJ) for their guidance with anatomic pathology and cytology. We also would like to thank Erin Moshier for her assistance with statistical analysis.
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