Anal Intraepithelial Neoplasia (AIN)

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Anal Intra-epithelial Neoplasia (AIN) is a risk factor for anal cancer. AIN is graded based on whether the involvement is only of the outer third of skin (AIN1), or the outer two thirds of skin (AIN2) or the entire thickness of skin (AIN3). AIN1 is also called low-grade anal squamous intra-epithelial lesion (LSIL). AIN2 & AIN 3 are also called high-grade anal squamous intra-epithelial lesion (HSIL).  

LSIL is considered a risk factor for anal cancer, but does not progress to AIN2 or AIN3.  HSIL is considered pre-cancerous, and over time can develop into invasive cancer.

RISK FACTORS
The risk factors for AIN are the same as for anal cancer, and include the immunosuppressed (eg HIV and transplant patients), and those with previous anal warts.

PREVENTION
Since February 2013, the HPV vaccine (Gardasil®) has been provided free of cost through the school-based program for males and females aged 12-13 years occurring in the first year of secondary school.

This vaccine has been shown to reduce the risk of anal and cervical dysplasia and cancer by targeting the Human Papilloma Virus (HPV) serotypes 16, 18, 6 and 11. There is possibly a very small advantage to those already with HPV infection and severe dysplasia also having the vaccine to help them eliminate the wart virus however this is contentious and remains debated.

TREATMENT OF AIN
AIN1 does not need to be treated.  AIN 3 treatment is aimed at eradicating AIN and preventing anal cancer with minimal disturbance to anal function. There are currently no uniform treatment guidelines largely due to the uncertain natural history of AIN, the variable extent of disease, and the fact there is not a universally effective treatment modality. Ablative therapy(electrocoagulation) has been shown to be more effective than topical agents.[1-2]

TOPICAL AGENTS
Imiquimod cream 5% (Aldara ®) can be applied to the area 3 times a day, and can be used for up to 16 weeks. It is an immunomodulatory agent and that attacks the virus responsible for warts, but also has anti-tumour effects [2]. There is some evidence that it not only slows the progression of AIN, but causes regression, with one study showing that 3/4 of men with AIN had their AIN completely cleared at the end of treatment[3]. It also has the added benefit in those with warts of causing regression of these, and in some cases eradication of the HPV virus. The main disadvantage is relapse in a quarter of cases after cessation of therapy[4].
Side effects of imiquimod include erythema, “flu‐like” illness and erosions, which are usually mild. It should not be applied prior to sexual intercourse. A systematic review showed a compliance rate of less than 5% because of side effects, mainly related to incompatibility with sexual life [5-6].
Topical 5-Fluorouracil 5% cream (Efudix®) can be applied to the area 1-2 times a day, and the largest study showing a recurrence of high grade AIN in only 8% of patients when used for 9-12 weeks[7].

PHOTODYNAMIC THERAPY
Photodynamic therapy (PDT) involves the application of a cream (topical sensitizer) such as 5-Flourouracil (Efudix®) and subsequent exposure of the anal region to light and oxygen to generate oxygen intermediates that damage areas with AIN [8]. Although there is little evidence, there is a suggestion that early AIN responds to this treatment [9-10].

INFRARED PHOTOCOAGULATION
Infrared photocoagulation is the same as photodynamic therapy except that it only uses light with a wavelength longer than visible light. It’s use for AIN was first described by Goldstein and colleagues [10], who showed that up to 2/3 of AIN can be cured and is effective in preventing progression to cancer.

SURGERY
The treatment of widespread AIN3 is controversial. Most do not advocate surgery, as even with surgery there is a one third risk of recurrence [10-11]. Previous traditional surgical approaches were quite morbid and involved extensive excision with split skin grafting. The high recurrence rate with these procedures is thought to be related to ongoing HPV, multi‐focal lesions that are not all treated, and a generalised field change. Because of the high recurrence rate and extensive surgery required for widespread AIN3, most advocate just close surveillance with regular annual digital rectal examination  (DRE), so that early invasive anal cancer can be picked up early and treated accordingly.

RADIOTHERAPY
Radiotherapy has no role for AIN 3. Its only role is for confirmed anal cancer.

FOLLOW-UP
All high risk patients with AIN3 should have an annual digital rectal examination (DRE) to allow early detection of anal cancer.

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REFERENCES
1.Richel O, Wieland U, de Vries HJ, et al.Topical 5-fluorouracil treatment of anal intraepithelial neoplasia in human immunodeficiency virus-positive men. Br J Dermatol. 2010 Dec;163(6):1301-7. doi: 10.1111/j.1365-2133.2010.09982.x. Epub 2010 Nov 4.
2.Fox PA.Treatment options for anal intraepithelial neoplasia and evidence for their effectiveness. Sex Health. 2012 Dec;9(6):587-92. doi: 10.1071/SH11157.
3. Fleshner PR, Chalasani S, Chang GJ, et al. Practice parameters for anal squamous neoplasms. Dis. Col. Rectum. 2008;51:2‐9
4. Wieland U, Brockmeyer NH, Weissenborn SJ, et al. Imiquimod treatment of anal intraepithelial neoplasia in HIV‐positive men. Arch. Dermatol. 2006;142:1438‐1444.
5. Wieland U, Brockmeyer NH, Weissenborn SJ, et al. Imiquimod treatment of anal intraepithelial neoplasia in HIV‐positive men. Arch. Dermatol. 2006;142:1438‐1444.
6. Moore RA, Edwards JE, Hopwood J, Hicks D. Imiquimod for the treatment of genital warts: a quantitative systematic review. BMC Infect. Dis. 2001;1:3.
7. Strum HM. Bowen’s disease and 5‐Fluorouracil. J. Am. Acad. Dermatol. 1979;1:513‐522
8. Abbasakoor F, Boulos PB. Anal intraepithelial neoplasia. Br. J. Surg. 2005;92:277‐290
8. Hamdan KA, Tait IS, Nadeau V, et al. Treatment of grade 3 anal intraepithelial neoplasia with photodynamic therapy. Dis. Col. Rectum. 2003;46:1555‐1559
9. Webber J, Fromm D. Photodynamic therapy for carcinoma in situ of the anus. Arch. Surg. 2004;139:259‐261
10. Goldstone SE, Kawalek AZ, Huyett JW. Infrared coagulator™: A useful tool for treating anal squamous intraepithelial lesions. Dis. Col. Rectum. 2005;48:1042‐1054