Response factors associated with electrocautery treatment of intra-anal high-grade squamous intraepithelial lesions in a population of HIV-positive men who have sex with men

Abstract

Background: Ablative treatment of anal high-grade squamous intraepithelial lesions (HSIL) reduces the risk of progression to anal squamous cell carcinoma. Objectives: To identify factors that influence the response to treatment of anal HSIL by electrocautery ablation (ECA) in a population of HIV-positive men who have sex with men (MSM). Design: Retrospective study of ECA treatment response in a prospectively followed anal dysplasia cohort. HIV-positive MSM diagnosed with anal HSIL were included. Demographic and HIV data were recorded. Response to treatment was assessed by biopsy after at least 18 months of follow-up. Results: One hundred and twenty-eight HSILs in 91 men were included in this study. The overall response rate at 18 months was 70.3%. The number of electrocautery sessions required (2 ECA sessions vs 1: adjusted odds ratio [aOR] = 0.36 (95%CI 0.13-1.01); >=3 sessions vs 1: aOR = 0.10 (95%CI 0.04-0.29); p < 0.001]) and the history of previous HPV-related anal pathology (previous anal lesions vs no previous lesions AOR = 2.83 (95%CI 1.14-7.02), p = 0.024) were independently associated with response at 18 months. No serious adverse events were reported. Conclusions: Consideration should be given to alternative therapies in patients with unresolved HSIL after 1 ECA treatment.

Keywords

Anal high-grade squamous intraepithelial lesions high-resolution anoscopy electrocautery human immunodeficiency virus human papillomavirus

Background

The incidence of anal squamous cell carcinoma (ASCC) in the general population has increased steadily since the 1960s and is currently 0.5 to 1.5/100.000 people/year with a female predominance.^1,2 In HIV-positive men who have sex with men (MSM), the rates of SCCA are between 70 and 128 cases per 100.000 person/years^3,4 and represent the fourth most common cancer in this population.^5,6

There is increasing evidence that untreated high-risk human papillomavirus (HR-HPV)–associated anal high-grade squamous intraepithelial lesions (HSILs) can progress to invasive cancer.^7–11 Several studies have also shown that ablative treatment of anal HSIL decreases the risk of progression to SCCA in populations at high-risk of this neoplasia.^12–14 Recently, a large retrospective analysis of the Surveillance, Epidemiology, and End Results database including men and women regardless of HIV status with anal intraepithelial neoplasia (AIN) grade III showed that approximately 10% of these patients progressed to SCCA within 5 years, while ablative procedures were associated with a statistically significant decreased risk of progression.¹² Despite this, there are no national or international guidelines for the optimal management of anal HSIL. Most clinicians treat anal HSIL when it is diagnosed despite high rates of both regression (25–30%)^13,15 and recurrence following treatment.^16–18 These treatment techniques include electrocautery ablation (ECA), infrared coagulation (IRC), CO2 laser, or application of trichloroacetic acid (TCA).^16–21 Self-applied topical agents such as imiquimod or 5-fluorouracil can be also used under medical supervision.^20,22,23 The choice of a specific treatment is mainly based on the experience and training of the anoscopist and availability of equipment.

Electrocautery is a treatment method in which direct or alternating current is passed through a resistant metal wire electrode, generating heat. Following an injection of local anesthesia, the electrode is applied to internal anal HSIL tissue to achieve focal tissue ablation.²⁴ As superficial coagulated tissue dries, it becomes less electrically conductive, preventing the current from continuing to heat the underlying tissue and hence limiting the depth of coagulation.²⁵ This treatment method is widely available and is routinely used in various other specialties including dermatology, ophthalmology, otolaryngology, plastic surgery, and urology.²⁶

Limited data on effectiveness and safety of ECA for the treatment of anal HSIL are available. One prospective study in a group of 231 patients with anal HSIL treated with ECA reported a cure rate of 75% and 85% in HIV-positive and HIV-negative MSM, respectively, after one ECA session.¹⁸ A randomized trial compared efficacy and tolerability of imiquimod, topical fluorouracil, and ECA that included both low- and high-grade anal and perianal dysplastic lesions in HIV-positive MSM. Response rates of ECA, imiquimod, and 5-fluorouracil were 39%, 24%, and 17%, respectively, with significantly less adverse events (AEs) seen in the ECA group.²⁰ Recently, a Spanish group reported a complete response rate of 32.5% and a partial response rate of 33.7% of ECA for anal HSIL after a mean follow-up of 12 months.¹⁹

The management of anal HSIL in populations at high risk of SCCA remains a challenge. Evidence justifies the use of ablative methods^16–20 such as ECA but there are still several limitations to these therapies, such as limited efficacy and high recurrence rates. Being aware of variables that allow clinicians to choose a therapy tailored to the patient may be a valid strategy for intra-anal HSIL.

The aim of this study was to increase data on effectiveness and safety of ECA and identify variables that impact treatment response.

Material and methods

This study was a retrospective analysis of a prospectively followed cohort of patients treated with ECA for intra-anal HSIL in Barcelona, Spain. The protocol (code HCB/2018/0688) was approved by the University Hospital Clínic of Barcelona ethics committee and was conducted in accordance with the Declaration of Helsinki and national and institutional standards. All patients included gave informed consent to use information available in the electronic database and medical records. The enrolment, screening, and treatment of anal dysplasia were performed exclusively at the University Hospital Clínic in Barcelona, Spain.

HIV-positive MSM 18 years of age or older with anal HSIL/s diagnosed by biopsy from January 2014 to December 2015 were eligible. Only patients with anal HSILs who received at least one ECA session, in which no other treatments were used, and who were followed for at least 18 months after the first treatment were included in the analysis. The following potential patients were excluded from the analysis: women, HIV-negative MSM, subjects who refused ECA treatment, those with perianal HSIL or lesions larger than half of the total anal circumference, and those with anal HSIL who did not complete 18 months of follow-up after the first EAC treatment. A response to treatment was defined as a reduction in grade of the index lesion to LSIL or normal epithelium at 18 months of follow-up after first ECA session.

Demographic data collected included age, smoking habit, origin, result of previous anal cytology, and previous anal HPV-related pathology (condyloma, dysplasia, or cancer regardless of location). Data on HIV infection included CD4 T-cell count at the time of diagnosis, nadir CD4 T-cell count, HIV viral load (VL) at the time of diagnosis, length of time with undetectable VL before diagnosis, log10 viral load zenith, CD4/CD8 ratio at the time of diagnosis, CD4/CD8 ratio nadir, antiretroviral treatment at the time of diagnosis, time since HIV diagnosis, and type of combined antiretroviral treatment (cART) at the time of diagnosis.

Following the standard protocol used in our anal cancer screening program, two physicians (a specialist in infectious diseases -JLB- and a dermatologist -IF-) performed all HRAs using a technique described elsewhere, including the topical application of 5% acetic acid followed by Lugol’s iodine to the anal canal to identify HSILs that were confirmed by biopsy.^27,28 All anal biopsies were processed in the pathology department and classified using the Lower Anogenital Squamous Terminology standardization project.²⁹ Following HSIL diagnosis, patients were scheduled for a follow-up HRA and treatment within 3–5 months.

After confirming visual appearances of HSIL at the previous biopsy location, the area was infiltrated with 0.2% mepivacaine and ECA was performed. Lesions were treated using the Hyfrecator 2000 (ConMed, Utica, NY) electrosurgical system at 30–35W with 5 mm spheres. All lesions were treated up to a total of half the anal circumference due to the theoretical risk of anal stenosis. During follow-up, biopsies were taken of the index site in cases where no clinical signs of persistent HSIL were observed, in addition to any new lesions clinically suspicious for HSIL. Subsequent ECA sessions were scheduled every 3–5 months until biopsy-proven clearance to either low-grade squamous intraepithelial lesions (LSIL) or normal epithelium.

Response to treatment was assessed by histology: (i) complete response (CR) was defined as an absence of any dysplasia and (ii) partial response (PR) in cases where LSIL was observed in the control biopsies. No response at 18 months (NoR) was considered in cases of (i) persistence of HSIL in control biopsy, (ii) no histological control by persistence of visual suspicion of HSIL within 18 months after the first ECA session, and (iii) local recurrence of HSIL observed within 18 months. Local recurrence (LR) was strictly considered in cases where biopsy-proven HSIL reappeared at the site of the index lesion or ≤1 octant around the index lesion after histological CR/PR was achieved. Metachronous lesions were considered when biopsy-proven HSIL appeared at a new site distinct from the index lesion. At every posttreatment visit, information was collected on severity and length of any AEs related to ECA. Adverse events were recorded after each ECA session according to the 2017 Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events.³⁰

Descriptive statistics of qualitative variables was performed using absolute frequency and percentage and of quantitative variables using median values and interquartile range (IQR). Characteristics associated to response were identified using logistic regression clustering on patients since some patients presented more than one HSILs. Variables evaluated in the final multiple model were chosen by clinical judgment and statistical criteria (p-value from simple model <0.1) and were entered in the logistic model in a stepwise fashion. All test were two-sided with significance level set at <0.05. All analyses were performed using Stata (version 15) (StataCorp, College Station, TX).

Results

Between January 2014 and December 2015, 348 HSILs from 208 patients were diagnosed in the anal cancer screening program of our center. Of these, 128 HSILs from 91 patients met the inclusion criteria (Figure 1). The main reasons for exclusion from the analysis were loss to follow-up in 79% (n = 174) and use of combined treatments with ECA in 21% (n = 46) of all patients.

Figure 1.

High-grade squamous intraepithelial lesion disposition.

All patients were HIV-positive MSM with a mean age of 42 years [interquartile range (IQR): 36; 46]. Regarding smoking status, 45% and 5% were current or previous cigarettes smokers, respectively, and the remaining 50% had never smoked cigarettes. Thirty-five per cent of all patients were non-Spanish nationals. Median time since HIV diagnosis at HSIL diagnosis was 9 years (IQR: 5; 14), 96% were taking cART, and in 90% HIV load was below 50 copies/mL. The median nadir CD4 T-cell count was 317 cells/μL (IQR: 177; 414) with a median CD4 T-cell count at the time of HSIL diagnosis of 727 cells/μL (IQR: 509; 982). Patient characteristics at the time of study inclusion are summarized in Table 1.

Table 1.

Demographic and HIV data results.

Variable		N (%)
Origin	Non-Spanish	32 (35%)
Origin	Spanish	59 (65%)
Age in years (IQR)		42 (36; 46)
N° of HSIL according to patient’s age	≤40	59 (46%)
N° of HSIL according to patient’s age	>40	69 (54%)
Smoking history	Ex-smokers	6 (5%)
	Current smokers	52 (44%)
	Non-smokers	59 (50%)
CD4 T-cell nadir (IQR)		317 (177; 414)
CD4/CD8 T-cell nadir	<0.5	69 (54%)
CD4/CD8 T-cell nadir	≥0.5	58 (46%)
CD4 T-cell at HSIL diagnosis		727 (509; 982)
CD4/CD8 T-cell at HSIL diagnosis		0.77 (0.49; 1.11)
CD4/CD8 at HSIL diagnosis	<1	85 (68%)
CD4/CD8 at HSIL diagnosis	≥1	40 (32%)
Viral load at HSIL diagnosis	Detect	13 (10%)
Viral load at HSIL diagnosis	Indect	115 (90%)
Last period with undetectable VL before HSIL diagnosis (years) (IQR)		3 (2; 6)
Years since HIV diagnosis (IQR)		9 (5; 14)
Years on ART (IQR)		5 (3; 10)
Previous anal cytology results	Normal	5 (4%)
	LSIL	52 (42%)
	HSIL	47 (38%)
	ASC-US	12 (10%)
	ASC-H	9 (7%)
	No	59 (46%)
Previous anal HSIL	Yes	60 (47%)
Previous anal HSIL	No	68 (53%)
Number of ECA sessions	1	66 (52%)
	2	34 (27%)
	≥3	28 (22%)
Pretreatment grade of dysplasia	AIN2	90 (70%)
Pretreatment grade of dysplasia	AIN3	38 (30%)
Adverse events according to DAIDS toxicity table for proctitis	None	28 (38%)
	Grade 1	37 (50%)
	Grade 2	9 (12%)
	Grade 3	0 (0%)
	Grade 4	0 (0%)
Duration of adverse events (IQR)		1 (0; 3)
Time from diagnosis to 1st ECA session (days) (IQR)		126 (79; 150)
Time to first HRA follow-up (IQR)		741 (594; 889)
Time of follow-up after fist ECA session		760 (446; 1197)
3° drug ART	IN	12 (9%)
	IP	45 (35%)
	IP, IN	1 (1%)
	IP, IN, R5	1 (1%)
	IP, NN	1 (1%)
	NN	63 (49%)
	NN, IN	1 (1%)
	Naive	4 (3%)

IQR: interquartile range; VL: viral load; AIN: anal intraepithelial neoplasia; SCCA: squamous cell cancer of the anal canal; HSIL: high-grade squamous intraepithelial lesion; LSIL: low-grade squamous intraepithelial lesion; ASC-US: atypical squamous cells of undetermined significance; ASC-H: atypical squamous cells, cannot exclude high-grade lesion; ECA: electrocautery; ART: antiretroviral treatment.

At month 18, response was achieved in 90 of 128 (70%) HSILs [CR and PR was initially observed in 71 (55%) and 19 (15%) lesions, respectively]. No response was observed in 38 (30%) HSILs: (i) LR within 18 months after clearance of HSIL was observed in 3 (2%) HSILs; (ii) biopsy-proven persistence of HSIL in 11 (9%); and (iii) persistence of clinical suspicion of HSIL in 24 (19%). Metachronous lesions were detected in 29 (23%). Considering ML as a recurrence, the overall recurrence rate of 18 months was found in 32 lesions (25%). No patient developed ASCC.

The average time from diagnosis of HSIL to first ECA session, from first ECA session to confirmatory biopsy or last control HRA within the study period were 126 (IQR: 77.5; 150) and 271.5 (IQR: 154; 485) days, respectively. The average number of ECA sessions was 1.5 (range 1–3) in the group of CR; 1.4 (1–3) for PR, and 2.4 (1–7) for NoR HSIL. Of all HSIL which responded, 57 (63%) required only one ECA session and 36 (43%) required at least two ECA sessions. Finally, average time of follow-up after first treatment session was 760 days (IQR: 446; 1197).

All patients included in the study have been followed in the clinic after treatment and no grade 3 or 4 AEs were reported. Data on AEs were systematically recorded after 74 ECA treatment sessions. From those, grade 1 and grade 2 AEs were recorded in 37 (50%) and 9 (12%), respectively. These patients classified as grade 1-2 AEs experienced mild local pain and/or mild bleeding within 24–48 h after ECA treatment. The average duration of all reported AEs was 1 day (IQR: 0; 3). There were no reported infections.

Our data did not show significant differences in response to treatment according to demographic or HIV-related data (see Table 2). Previous cytology results or grade of HSIL dysplasia (AIN2 vs AIN3) was also not associated with differences in response to treatment. Treatment of two or more anal HSILs was significantly associated with lack of response to treatment (p = 0.04) in the unadjusted analysis, but this variable became nonsignificant in the adjusted analysis.

Table 2.

Comparison of demographic, clinical, and HIV data according to response.

Variable		n	Unadjusted odds ratio	(95% conf. interval)	p-value	Adjusted odds ratio	95% CI	p-value
Origin	Non-Spanish	128	1		0.8932
Origin	Spanish	128	1.06	(0.47; 2.38)	0.8932
Smoking history	Non-smoker	117	1		0.5105
Smoking history	Current/ex-smokers	117	0.76	(0.33; 1.73)	0.5105
Age at diagnosis in years^a		128	1.02	(0.96; 1.08)	0.6007
Viral load at diagnosis	Detectable	128	1		0.9287
Viral load at diagnosis	Undectable	128	1.06	(0.30; 3.70)	0.9287
CD4 T-cell nadir^b		127	0.99	(0.89; 1.09)	0.8345
CD4/CD8 T-cell nadir^a		127	0.86	(0.28; 2.62)	0.7941
CD4 T-cell at diagnosis^b		128	0.99	(0.93; 1.06)	0.8056
CD4/CD8 at diagnosis	<1	125	1		0.6655
CD4/CD8 at diagnosis	≥1	125	1.23	(0.48; 3.11)	0.6655
Years on ART^a		119	1.02	(0.97; 1.09)	0.4168
VIH infection length^a		127	1.01	(0.95; 1.08)	0.7372
Pretreatment grade of dysplasia	AIN2	128	1		0.1497
Pretreatment grade of dysplasia	AIN3	128	1.87	(0.80; 4.41)	0.1497
Number of anal HSIL	1	127	1		0.0439
	2		0.32	(0.13; 0.81)
	3–5		0.37	(0.12; 1.17)
Previous anal cytology	Normal	125	1		0.5315
	LSIL		1.81	(0.65; 5.01)
	HSIL, ASC-H		1.53	(0.54; 4.35)
	ASC-US		0.93	(0.29; 3.05)
Previous anal dysplasia	Yes	128	1		0.0715	1		0.0243
Previous anal dysplasia	No	128	2.01	(0.94; 4.30)	0.0715	2,83	(1,14; 7,02)
Number of ECA sessions	1	128	1		0.0007	1		0.0001
	2		0.33	(0.12; 0.90)		0,36	(0,13; 1,01)
	≥3		0.13	(0.05; 0.38)		0,10	(0,04; 0,29)

VL: viral load; AIN: anal intraepithelial neoplasia; SCCA: squamous cell cancer of the anal canal; HSIL: high-grade squamous intraepithelial lesion; LSIL: low-grade squamous intraepithelial lesion; ASC-US: atypical squamous cells of undetermined significance; ASC-H: atypical squamous cells, cannot exclude high-grade lesion; ECA: electrocautery ablation; ART: antiretroviral treatment.

^aUnadjusted odds ratio per unit increase

^bUnadjusted odds ratio per 50 units increase.

However, we found a significant association between the number of ECA sessions required and lack of response at 18 months. The probability of reaching CR/PR after 18 months of follow-up was lower for patients with more than one ECA session compared to those with only one (2 ECA sessions vs 1: aOR = 0.36 (95%CI 0.13–1.01); ≥3 sessions vs 1: OR = 0.10 (95%CI (0.04–0.29); p = 0.0001) and it was higher for those with history of previous anal HPV-related pathology (previous anal lesions vs no previous lesions aOR = 2.83 (95%CI 1.14–7.02), p = 0.0243).

Individuals who were current or ex-smokers tended to have more ML than never smokers, but these differences did not achieve statistical significance (p = 0.07). When considering recurrence in a wider context (LR and ML), no significant differences were identified in relation to the variables studied. Comparison of demographic and HIV data according to LR and metachronous HSILs are shown in Table 3.

Table 3.

Comparison of demographic, clinical, and HIV data according to onset of metachronous lesions.

Variables		Metachronous lesions
Variables		n	Unadjusted odds ratio	(95% conf. interval)	p-value
Origin	Non-Spanish	128	1		0.3513
Origin	Spanish	128	1.64	(0.58; 4.60)	0.3513
Smoking history	Non-smoker	117	1		0.0691
Smoking history	Current/ex-smokers	117	2.71	(0.93; 7.92)	0.0691
Age in years^a		128	0.98	(0.92; 1.05)	0.6412
VL at diagnosis	Detectable	128	1		0.0942
VL at diagnosis	Undetectable	128	0.29	(0.07; 1.23)	0.0942
CD4 T-cell nadir^b		127	1.08	(0.94; 1.26)	0.2842
CD4 T-cell at diagnosis^b		128	0.99	(0.93; 1.04)	0.6144
CD4/CD8 at diagnosis^a		125	0.75	(0.28; 2.04)	0.5788
CD4/CD8 nadir	<0.5	127	1		0.4252
CD4/CD8 nadir	≥0.5	127	0.66	(0.24; 1.82)	0.4252
CD4/CD8 at diagnosis	<1	125	1		0.1160
CD4/CD8 at diagnosis	≥1	125	0.41	(0.13; 1.25)	0.1160
Years on ART		119	0.96	(0.88; 1.03)	0.2532
VIH infection length		127	0.99	(0.93; 1.06)	0.7775
Previous anal cytology	Normal	120	1		0.9799
	LSIL		0.90	(0.19; 4.32)
	HSIL, ASC-H		1.00	(0.22; 4.65)
	ASC-US		1.00	—
Grade of dysplasia pre-ECA treatment	AIN2	128	1		0.8490
Grade of dysplasia pre-ECA treatment	AIN3	128	1.09	(0.46; 2.55)	0.8490

^aUnadjusted odds ratio per unit increase

^bUnadjusted odds ratio per 50 units increase.

Discussion

This study analyzed ECA, a widely available and well-tolerated minimally invasive technique for the treatment of anal HSIL, in a group of HIV-positive MSM at high risk of ASCC. The overall response rate at 18 months in our series was 70% per lesion with a LR rate of 3%, with no serious AEs. We found that the number of ECA sessions required and history of previous HPV-related anal pathology have a significant negative impact on the response to this treatment.

Our observed response rate of 70% per lesion at 18 months is consistent with the higher rates found in previous prospective and observational studies that have assessed ECA efficacy for anal HSIL^16–20 that ranged from 21% to 73%.^16–20 Our rate of local recurrence was significantly lower than that previously reported of 25%–79% at a median time of 12–24 months following treatment that could be explained by the strict criteria we used to define LR. Previous studies have unified the definition of recurrence, LR, and ML, and some others have recorded persistence along with LR, making it difficult to compare this specific data. Using the same criteria as those used in previous studies, our rates of recurrences would be similar to those previously reported.^18,20 It is important to note that there are currently no randomized studies with which to compare this data.

Our data showed that a response at 18 months was significantly decreased for anal HSIL that required more than one ECA session, a finding that has been previously reported.¹⁹ Although increasing the frequency of ECA, such as is used in the treatment of external condylomata with cryotherapy could be an option in these cases, our results suggest that other treatment modalities should be considered for persistent HSIL after one ECA treatment without resolution.

Our data also showed that previous resolved anal HPV-related pathology was associated with a better response to ECA treatment. This association has not been previously described. We may hypothesize that these are patients with a stronger immune response to genital type-specific HPV infections that will allow them to better control HPV-associated pathology.

In the unadjusted analysis, we found that anal HSIL from patients with multiple lesions presented a lower probability of responding to ECA which is consistent with findings from previous studies on ablative therapies; however, this association became insignificant in the adjusted analysis.^13,16,17

Diagnoses of metachronous HSIL tended also to be more frequent in patients who were current smokers. In female studies, smoking has been consistently linked with higher prevalence of cervical HPV infection and progression to HPV-related cancers in large population-based studies.^31,32 It has also been associated with a poorer response to imiquimod treatment³³ in previous studies on anal HSIL management. There was no association between tobacco and response to ECA in this study or previously observed.¹⁹ However, the association between tobacco and ASCC remains and patients should be counseled accordingly.³⁴ It would be interesting to evaluate the impact on the incidence of ML of combining a circumferential treatment (such as imiquimod) to ablative treatment.

We are aware that our study is subject to several limitations besides being retrospective and unicentric. The potential for spontaneous regression of anal HSIL as well as the subjectivity inherent in the clinical assessment are limitations. Underestimation of LR in our series may be related to the fact that recurrences were confirmed histologically and biopsies were done based on clinical suspicion for HSIL recurrence. However, most of our patients have been followed up for a considerable period of time, and we presume that these possible recurrences should have been identified in subsequent HRAs. Alternatively, considering ML as a recurrence (as previous studies have done), our overall recurrence rate at 18 months increases to 25%. Furthermore, lesions size was not measured, so reduction or increase in extent of disease was not considered as a response. We also did not assess presence of HPV in anal samples. However, previous studies have found no difference in response to the ECA according to HPV type in high-risk patients for anal cancer;¹⁹ however, further studies may be needed to confirm this point.

Conclusions

To be aware of factors that predict poor response to a specific therapy may be useful to guide treatment of anal HSIL in high-risk patients. We found an acceptable response rate of these lesions to ECA therapy with a limited rate of LR and no treatment-related serious adverse events. According to our data, a history of previous HPV-related anal pathology is a marker of better response, while persistence of anal HSIL after one ECA session is a marker of poorer response to ECA therapy. We have not identified predictors of recurrence after ECA treatment. These factors may be considered by clinicians to triage further treatment of intra-anal HSIL according to patient characteristics.

Footnotes

Acknowledgements

All participants in the study. Administrative and nursing from the Anal Dysplasia Clinic of the Hospital Clinic (Barcelona, Spain).

Authors’ contribution

Study conception and design: Irene Fuertes and José Luis Blanco

Acquisition of data: Irene Fuertes, Ross D. Cranston, and Jose Luis Blanco

Analysis and interpretation of data: Elisa de Lazzari, Leonardo Rodríguez–Carunchio, Ross D. Cranston, Irene Fuertes, and José Luis Blanco

Drafting of manuscript: Irene Fuertes, Ross D. Cranston, and José Luis Blanco

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Irene Fuertes

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