Electrocautery Ablation of High-Grade Anal Squamous Intraepithelial Lesions in HIV-Negative and HIV-Positive Men who have sex with Men
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ECA (treated with electrocautery ablation) of HGAIN is a safe and effective office based procedure comparable to other available treatments. Cure rates of individual lesions are excellent but patients continue to develop metachronous recurrence making continued follow-up important. While we documented a single progression to ASCC (0.4%), rates are far lower than series advocating a "watch and wait" approach."
Marks, Douglas K. B.S.; Goldstone, Stephen E. M.D.
JAIDS Journal of Acquired Immune Deficiency Syndromes:
POST ACCEPTANCE, 30 November 2011
Background: Anal squamous cell carcinoma (ASCC) incidence has been rising over the past decade, most dramatically in HIV-positive men who have sex with men (MSM). We aimed to identify a novel in-office approach for ablating high-grade anal intraepithelial neoplasia (HGAIN), the believed precursor lesion to ASCC.
Materials & Methods: We performed a retrospective analysis of medical records from a NYC surgical practice, identifying patients with HGAIN treated with electrocautery ablation (ECA) and followed for at least five months with high resolution anoscopy, biopsies and/or cytology. We sought to determine HGAIN recurrence, as well as progression to ASCC after ECA.
Results: 232 MSM, 132 HIV-positive and 100 HIV-negative, with median follow up of 19.0 and 17.5 months respectively met inclusion criterion.
In HIV-negative and HIV-positive MSM the probability of curing a lesion after first ECA was 85% and 75% respectively. Over follow up, 53% of HIV-negative and 61% of HIV-positive patients recurred. After first and second ECA HIV-positive MSM were 1.28 times (p=0.16) and 2.34 times (p=0.009) more likely to recur than HIV-negative MSM. The majority of recurrence was due to development of additional lesions at untreated sites (metachronous recurrence). One patient (0.4%) developed ASCC. At last visit, 83% of HIV-negative and 69% of HIV-positive patients were HGAIN free.
Conclusion: ECA is an effective treatment for HGAIN, with fewer patients progressing to ASCC than predicted with expectant management. HIV-positive patients are significantly more likely to recur than HIV-negative patients.
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 five times the rate observed in HIV-negative MSM2. Current evidence indicates that ASCC incidence is unlikely to decline in the absence of novel treatment options3.
High-grade anal intraepithelial neoplasia (HGAIN) is believed to be the ASCC precursor4-6. 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 188,9 . To prevent progression to invasive cancer, cervical dysplasia is excised with the surrounding squamous-columnar junction (SCJ), with conization or loop electrosurgical excision (LEEP)10-12 achieving cure rates of greater than 95% in HIV-negative females12. Aggressive screening and treatment of cervical dysplasia has even resulted in a decline in HIV-positive women progressing to invasive cancer13. 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 dyschezia7, 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 (TCA) and 5% 5-Fluoro-uracil cream)7, 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%, respectively20, 24. We now endeavored to determine if in-office ECA of intra anal HGAIN was as safe and effective as IRC ablation in MSM20, 24, 25.
A total of 100 HIV-negative and 132 HIV-positive MSM met enrollment criteria, with a median age of 49 (range 27-74) years and 42 (range 21-70) years respectively (p<0.0001). Mean length of followup 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 vs.226 in the HIV-negative MSM (p=0.006). Following HGAIN diagnosis, 90 percent of patients had ECA by 1.5 months for HIV-negative vs. 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 mean of 8.2 months, whereas, 47 (47%) patients did not recur over a mean of 18.1 months. For HIV-positive patients, 80 (61%) recurred after first ablation with a mean of 1.9 lesions over a mean of 9.1 months, whereas 52 (39%) did not recur over a mean of 16.0 months. Mean number of recurrent lesions for both HIV-positive and HIV-negative MSM was never greater than two. 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 one HGAIN on first ECA were 55% (p=0.008) and 73% (p<0.0001) less likely to have recurrence than patients with two or three lesions, respectively.
Table 2 depicts HGAIN persistence after treatment in HIV-positive and HIV-negative MSM. Following 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 following initial electrocautery of index lesions. Similarly, in the HIV-positive patients, the persistence rate for lesions following 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 following 1st and 2nd electrocautery respectively. Increased persistence between 1st and 2nd ECA's 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 (Figure 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 ECA's. 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 HGAIN's developed, and one
lesion that had persisted throughout now appeared 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 following ECA, including anal stenosis, persistent bleeding, hemorrhage, failure to heal, or infection necessitating antibiotic therapy. Most often pain was the only post-procedure complaint and was adequately controlled by over the counter medication or mild narcotic analgesia, however no post procedure diaries were utilized.
This study represents the largest efficacy analysis of ECA to date. The only other major study published by Chang et al. 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 up21. In the extended and much larger followup series that included these patients, the 0% recurrence did not hold22. 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 appear to be any lasting tissue effect following 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 activates during wound healing causing a new HGAIN to develop. At this point there is noway 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 one lesion at first ablation were 55% less likely to recur than those with two lesions (p=0.008) and 73% less likely than patients with three 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 non-treated areas (metachronous recurrence) is the major factor preventing patients from achieving disease free status. While 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 two 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 & 41 years as compared to 42 and 49 years respectively (p<.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 that 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 while IRC does not. It is, however, our belief that whether these minor surgical procedures are performed with IRC or ECA, an assistant should [be present] 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 trial19. In the treatment group of 28 patients, Imiquimod demonstrated a 61% cure rate over 36 months. While Imiquimod could be a promising non-surgical treatment, it required three times weekly application for four months. That withstanding the treatment was tolerable with only a few patients discontinuing treatment. TCA 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, respectively18. 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 visible29. Their rational is that many patients with HGAIN will not progress to cancer and those that do will be caught early when lesions can be cured by excision. However, recent studies by Ortholan et al. 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 therapy30. 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, one patient developed ASCC while 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 intervention5-7, 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. While 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 under-diagnosed. In addition, patients with benign cytology and negative standard anoscopy were considered non-recurrent 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 post-treatment 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 (SG) 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 to other available treatments. Cure rates of individual lesions are excellent but patients continue to develop metachronous recurrence making continued follow-up important. While we documented a single progression to ASCC (0.4%), rates are far lower than series advocating a "watch and wait" approach.