by Jason Wasserman MD PhD FRCPC
February 25, 2025
Anal intraepithelial neoplasia is a condition that affects the cells lining the anus. It is considered a precancerous disease, which means that while the cells show abnormal changes, they are not yet cancer. However, in some cases, these abnormal cells can develop into a type of cancer called squamous cell carcinoma over time. The risk of developing cancer depends on the grade of the disease, which is determined by how much the cells have changed. Another name for anal intraepithelial neoplasia is squamous intraepithelial lesion (SIL).
Where does anal intraepithelial neoplasia start?
Anal intraepithelial neoplasia starts in the thin layer of cells that line the anal canal. The anal canal is the short passage at the end of the digestive tract that connects the rectum to the outside of the body. The cells in this area are similar to those found on the skin and are called squamous cells. When these squamous cells develop abnormal changes, they can be classified as anal intraepithelial neoplasia.
What are the symptoms of anal intraepithelial neoplasia?
Anal intraepithelial neoplasia does not typically cause any symptoms and the condition is usually during routine screening of the anus or when the anus or anal canal are examined for another reason. However, for some patients, this condition is associated with symptoms such as bleeding from the anus or itchiness of the anus or surrounding skin.
What causes anal intraepithelial neoplasia?
Most cases of anal intraepithelial neoplasia are caused by long-standing infection with human papillomavirus (HPV). Low grade anal intraepithelial neoplasia (AIN1) is typically associated with low-risk subtypes of HPV (6, 11, 42, 43, 44) whereas high grade anal intraepithelial neoplasia (AIN2 and AIN3) is typically associated with high-risk subtypes of HPV (subtypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68).
Is anal intraepithelial neoplasia a type of cancer?
No. Anal intraepithelial neoplasia is not a type of cancer. However, anal intraepithelial neoplasia is an abnormal growth that can change into a kind of anal cancer called squamous cell carcinoma over time.
What is the risk of developing cancer?
The risk of developing cancer after a diagnosis of anal intraepithelial neoplasia depends on the grade of the disease, the presence of human papillomavirus (HPV) infection, and a person’s overall health. Low-grade anal intraepithelial neoplasia (AIN1) has a very low risk of turning into cancer and often goes away on its own. High-grade anal intraepithelial neoplasia (AIN2 and AIN3) is more serious, with AIN3 having the highest risk. Studies suggest that if left untreated, about 10-15% of people with AIN3 may develop anal cancer within 5 to 10 years.
Certain factors increase the risk of progression. HPV infection, especially high-risk types like HPV-16, plays a major role. A weakened immune system, such as in people with HIV or those who have had organ transplants, also increases the likelihood of anal intraepithelial neoplasia turning into cancer. Other risk factors include smoking and chronic irritation or inflammation of the anal area.
To lower the risk, doctors may recommend regular monitoring, HPV vaccination, or treatments like laser therapy, topical medications, or surgery in some cases. The best approach depends on the grade of AIN and individual risk factors, so follow-up care is important to prevent progression to cancer.
How is this diagnosis made?
Pathologists make this diagnosis by examining a sample of tissue under the microscope. The sample may be taken through a small biopsy, which is a procedure where a doctor removes a tiny piece of tissue from the anal lining for examination. Under the microscope, the pathologist looks for specific changes in the squamous cells to determine if anal intraepithelial neoplasia is present. The diagnosis may also involve additional tests to check for certain viruses, such as human papillomavirus (HPV), which is commonly associated with this condition.
How is anal intraepithelial neoplasia graded?
Anal intraepithelial neoplasia is divided into three categories – AIN1, AIN2, and AIN3 – based on the degree of cytologic atypia, the location of the abnormal cells within the epithelium, and the number and location of mitotic figures (cells dividing to create new cells). The grade is important because the chance of developing anal cancer from anal intraepithelial neoplasia is much greater for AIN2 and AIN3 compared to AIN1.
Anal intraepithelial neoplasia 1 (AIN1)
The abnormal cells in AIN1 are located within the lower 1/3 of the epithelium. Abnormal squamous cells infected with HPV, called koilocytes, are often seen. Another name for AIN1 is low grade squamous intraepithelial lesion (LSIL). AIN1 that sticks out from the surface of the anus or anal canal is called condyloma acuminatum.
Anal intraepithelial neoplasia 2 (AIN2)
The abnormal cells in AIN2 involve the lower 2/3 of the epithelium and the cells often appear larger and darker than the cells in AIN1. An increased number of mitotic figures (cells dividing to create new cells) are also typically seen. Another name for AIN2 is high grade squamous intraepithelial lesion (HSIL).
Anal intraepithelial neoplasia 3 (AIN3)
The abnormal cells in AIN3 involve almost the entire epithelium and the cells are larger and darker than the cells in AIN1 and AIN2. Many mitotic figures (cells dividing to create new cells) are also typically seen. Another name for AIN3 is high grade squamous intraepithelial lesion (HSIL).
Immunohistochemistry for p16
When cells are infected with certain types of human papillomavirus (HPV), they start making large amounts of a protein called p16. Because of this, increased p16 is commonly seen in moderate to severe anal intraepithelial neoplasia (AIN2 and AIN3). To check for this, pathologists perform a special test called immunohistochemistry, which helps them see if the cells are producing extra p16. If the test shows a high level of p16, the result is called positive or reactive. A positive result supports the diagnosis of AIN2 or AIN3 and helps rule out other conditions that may look similar under the microscope.
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