Anal Intraepithelial Neoplasia (AIN)

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Anal Intra-epithelial Neoplasia (AIN) is a pre-cancerous condition of the skin surrounding the anus. In the early stages of AIN there are abnormal skin cells (epithelial cells) in the outer third of the skin (epithelium). This is called AIN1 (also called a low-grade anal squamous intra-epithelial lesion (LSIL). This can progress to AIN2, where the outer 2/3 of the skin contains abnormal cells, which in turn can result in AIN3 where there are abnormal cells involving the full thickness of skin (AIN2 and AIN3 are also called high-grade anal squamous intra-epithelial lesions (HSIL). The next step is for these abnormal cells to cross a barrier at the base of the skin called the basement membrane. Once this occurs, it is invasive cancer (carcinoma).

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
The vaccine currently offered to women to reduce the risk of cervical cancer targets the Human Papilloma Virus (HPV) serotypes 16, 18, 6 and 11. Although not approved for this purpose, this vaccine may have a role for reducing the risk of AIN and anal cancer in high risk populations who do not yet have HPV infection.

TREATMENT OF AIN
Treatment is aimed at eradicating AIN and preventing anal cancer with minimal disturbance to anal function. There is currently no uniform treatment 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.

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 [1]. 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[2]. 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[1].
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 noncompliance rate of less than 5% because of side effects, mainly related to incompatibility with sexual life [3-4].
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[5].

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 [6]. Although there is little evidence, there is a suggestion that early AIN responds to this treatment [7-8].

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 [9], 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 advocate surgery, however even with surgery there is a one third risk of recurrence [10-11]. If surgery is performed, it consists of either local excision or 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. Beacuse of the high recurrence rate and extensive surgery required for widespread AIN3, many advocate just close surveillance with regular (3-6 monthly) biopsies, 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
Follow‐up should involve anoscopic examination, with or without the aid of high‐resolution anoscopy. AIN 1 should be reviewed every 6‐12 months with discharge from follow up upon resolution of AIN. AIN 3, especially in HIV‐positive patients should be followed more closely every 3‐6 months with or without treatment. The follow‐up of AIN 2 is less clear, as the natural history of this condition is so uncertain. A regime somewhere between that of AIN 1 and 3 is advised, with HIV‐positive or immunosuppressed patients being followed more like patients with AIN 3.

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REFERENCES
1. Fleshner PR, Chalasani S, Chang GJ, et al. Practice parameters for anal squamous neoplasms. Dis. Col. Rectum. 2008;51:2‐9
2. Wieland U, Brockmeyer NH, Weissenborn SJ, et al. Imiquimod treatment of anal intraepithelial neoplasia in HIV‐positive men. Arch. Dermatol. 2006;142:1438‐1444.
3. Wieland U, Brockmeyer NH, Weissenborn SJ, et al. Imiquimod treatment of anal intraepithelial neoplasia in HIV‐positive men. Arch. Dermatol. 2006;142:1438‐1444.
4. 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.
5. Strum HM. Bowen’s disease and 5‐Fluorouracil. J. Am. Acad. Dermatol. 1979;1:513‐522
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7. 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
8. Webber J, Fromm D. Photodynamic therapy for carcinoma in situ of the anus. Arch. Surg. 2004;139:259‐261
9. Goldstone SE, Kawalek AZ, Huyett JW. Infrared coagulator™: A useful tool for treating anal squamous intraepithelial lesions. Dis. Col. Rectum. 2005;48:1042‐1054
10. Lyons M, Francis N, Allen‐Mersh TG. Treatment of grade 3 anal intraepithelial neoplasia by complete anal mucosal excision without fecal diversion. Dis. Col. Rectum. 1999;42:1342‐1344
11. Reynolds VH, Madden JJ, Franklin JD, et al. Preservation of anal function after total excision of the anal mucosa for Bowen’s disease. Ann. Surg. 1984;199:563‐568