Evolving Options and Views on Anal Dysplasia

“The difficulty lies not so much in developing new ideas as in escaping from old ones.”

—John Maynard Keynes

“Progress is impossible without change, and those who cannot change their minds cannot change anything.”

—George Bernard Shaw, playwright and critic

“The greatest obstacle to discovery is not ignorance—it is the illusion of knowledge.”

—Daniel J. Boorstin, American historian and former Librarian of Congress

“Medicine is a science of uncertainty and an art of probability.”

—William Osler, one of the founding professors of Johns Hopkins Hospital

“People don't resist change. They resist being changed.”

—Peter Senge, systems scientist and author of The Fifth Discipline

This volume of Clinics in Colon and Rectal Surgery focuses on the care of patients with anal dysplasia. The quotes listed above each tell a part of the story relative to this disease, its evaluation and management, and prognosis. Despite a relatively vast increase in the understanding of and published literature regarding dysplasia and its progression, it remains a relatively controversial topic—even among experts. Whether discussing the method of screening/surveillance, treatment or outcomes, symposiums abound in conferences, online forums, and opinion pieces that at times can go beyond the emotions of typical disagreement or choice.[1] Even various nomenclature changes have occurred over the past several years that result in confusion or incongruity. Low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), low-grade anal intraepithelial neoplasia (LGAIN), high-grade anal intraepithelial neoplasia, Bowen's disease, and anal carcinoma in situ—to name a few—yet, dysplasia is at its core simply a precursor lesion to squamous cell carcinoma (SCC) of the anal canal. Cells (d)evolving from their normal state along a path toward cancer. Anal dysplasia, while similar to cervical intraepithelial neoplasia (CIN), and like CIN, is graded by the severity of epithelial invasion, has various classification systems has also led to some misunderstanding in the literature.

The rationale for this controversy, like many, is hard to pinpoint. Most agree that primary risk factors for anal dysplasia include human papillomavirus (HPV) infection, HIV seropositivity, immunosuppression, multiple sexual partners, anoreceptive intercourse, cigarette smoking, and a history of other HPV-associated malignancies, such as cervical cancer, CIN, vulvar cancer, and vulvar intraepithelial neoplasia. Anal dysplasia can also be detected incidentally during surgeries performed for other reasons, such as hemorrhoid removal. HPV infection remains the most consistent and significant risk factor, with certain serotypes linked to anogenital warts versus others to cancer. HIV-positive individuals are also at significantly higher risk for developing anal dysplasia, with some studies reporting a prevalence of up to 60%, depending on screening, intervention, and concomitant risk factors. As such, strategies aimed at reducing exposure to or the effects of these risk factors on patients seem obvious as a collective point to unite around.[2] Yet, in practice, it seems somewhat more difficult than in theory.

As pointed out by the authors in this volume, screening is recommended for high-risk populations, although the ideal screening methods have not been universally agreed upon. Screening tools include anal cytology, colposcopy, biopsy, and high-resolution anoscopy (HRA). Anal Pap smear cytology is conducted by obtaining epithelial cell samples from the anal canal, typically using a moistened Dacron swab inserted 3 to 4 cm past the anal verge. The sample is then preserved on a glass slide or in liquid medium. Unfortunately, the sensitivity of anal cytology ranges from 69 to 93% and specificity ranges from 32 to 59%, causing difficulty with interpreting the results. Furthermore, cytology specimens are often challenging for pathologists to interpret.

It is also important to remember that anal cytology in high-risk cohorts such as men who have sex with men (MSM) has false-negative rates of up to 23% in HIV-negative patient and 45% in HIV-positive patients.[3] Therefore, close follow-up of all high-risk patients is likely to be the best strategy, along with control of primary HIV infection, keeping viral loads undetectable.

HRA involves the application of 3% acetic acid with or without Lugol's iodine solution to the anal canal, followed by high-resolution microscopy. Acetic acid denatures cytoplasmic proteins and dehydrates intracellular spaces, causing HPV-infected cells to appear white under microscopy. Directed biopsies are taken from any suspicious areas, along with focal destruction. While HRA is highly sensitive and specific, it is not as widely utilized—though becoming more common over the last decade.

The management of anal dysplasia also remains controversial, with lack of clear consensus regarding the rate of progression for low- and high-grade lesions. Further, due in part to the rate of recurrence and underlying field defect, the impact of destructive therapy at various stages of progression has been disputed. Treatment options include watchful waiting, topical therapies (e.g., 5-fluorouracil [5-FU], imiquimod, podophyllotoxin), photodynamic therapy, cryotherapy, surgical excision, and cautery ablation. Given the generally low malignant potential of low-grade anal dysplasia in immunocompetent individuals, some advocate for a watchful waiting approach to avoid the morbidity associated with repeated focal destruction. However, targeted treatments, such as HRA-guided biopsies and therapy, have been shown to clear anal dysplasia in up to 80% of cases, supporting the use of targeted management.

In high-risk populations, such as HIV-positive individuals and MSM, the recurrence rate of anal dysplasia remains high even after aggressive treatments. Some studies suggest that expectant management, with surveillance every 4 to 6 months, may be a reasonable option. In one study, only 3 out of 40 HIV-positive patients with dysplasia who were followed with expectant management developed invasive carcinoma. These cancers were either excised or treated with chemoradiation, suggesting that close clinical surveillance may be a viable approach in high-risk cohorts.

Several topical therapies are available for treating anal dysplasia. Imiquimod, a topical immune response modifier, has both anti-HPV and antitumor properties, with reported response rates ranging from 48 to 86%. However, side effects like local irritation, burning, and skin erosions can limit patient compliance. Recurrence and new HPV-induced anal lesions are also significant concerns, necessitating close long-term follow-up. Topical 5-FU is another approved treatment for anal dysplasia, with response rates up to 90% after a treatment period of 9 to 16 weeks. However, recurrence rates remain as high as 50%.[4] Factors contributing to recurrence include poorly defined areas of involvement, follicular involvement, diminished immune response, dense scar tissue, and poor patient compliance. Photodynamic therapy, which involves the use of photosensitizing agents followed by light exposure, has also been explored in treating anal dysplasia, but has yet to catch on as a mainstay of therapy.

More aggressive treatments, such as wide local excision (WLE), have been described in the past for anal intraepithelial neoplasia (AIN). This approach typically involves excising the lesion with 1-cm margins, guided by frozen section analysis, and may require skin grafting or the mobilization of local flaps to cover large defects. However, WLE carries a risk of significant complications, including recurrence (reported in 13–63% of cases), anal stenosis, and incontinence. HRA-guided cautery ablation is another effective treatment, offering a less invasive approach with lower morbidity compared with WLE. It has been shown to prevent progression to invasive cancer, though recurrence rates remain high, especially in HIV-positive patients, with persistent or recurrent disease reported in up to 80% of cases.[5]

The release of the much-anticipated Anal Cancer-HSIL Outcomes Research (ANCHOR) trial brought about another option.[2] This phase 3 trial at 25 U.S. sites included HIV+ patients who were 35 years of age or older and who had biopsy-proven anal HSIL. They were randomly assigned, in a 1:1 ratio, to receive either HSIL treatment or active monitoring without treatment. Treatment included a plethora of well-described and used options, including office-based ablative procedures, ablation or excision under anesthesia, or the administration of topical fluorouracil or imiquimod. The primary outcome was progression to anal cancer in a time-to-event analysis. Participants in the treatment group were treated until HSIL was completely resolved. All the participants underwent HRA at least every 6 months; biopsy was also performed for suspected ongoing HSIL in the treatment group, annually in the active-monitoring group, or any time there was concern for cancer. The study found that the rate of progression to anal cancer was lower in the treatment group than in the active-monitoring group by 57%. In addition to primary prevention techniques, vaccines have also been efficacious in reducing the incidence of HPV infection. In the general screening population, HPV vaccine efficacy was almost 100% for cervical intraepithelial neoplasia, vulvar and vaginal intraepithelial neoplasia, and anogenital condyloma. In MSM, the use of quadrivalent HPV vaccine significantly reduced the rates of moderate and high-grade anal intraepithelial neoplasia. Although the vaccinated populations were HPV naïve, there are some data indicating the effectiveness of HPV vaccines in preventing reinfection or reactivation of disease. A study of HPV-vaccinated men who had been previously treated with high-grade anal intraepithelial neoplasia was noted to have a reduction in anal intraepithelial neoplasia recurrence.

So, where does that leave us? Certainly, further along the lines of consensus than before, but still lacking a uniform, standardized approach. Only through continued research, understanding, and long-term follow-up will we be able to get there. It is unknown how the most current data will impact various societies' guidelines, including the American Society of Colon and Rectal Surgeons, as well as the practice patterns of individual providers. More importantly, what will that result in the long-term impact on patient outcomes? No matter the treatment chosen, the intent is to preserve function while reducing the potential for disease progression to invasive cancer. Evolution in both thought and practice will get us there.

Publication History

Article published online:
23 June 2025

• References

• 1 Stier EA, Clarke MA, Deshmukh AA. et al. International Anal Neoplasia Society's consensus guidelines for anal cancer screening. Int J Cancer 2024; 154 (10) 1694-1702
• 2 Palefsky JM, Lee JY, Jay N. et al.; ANCHOR Investigators Group. Treatment of anal high-grade squamous intraepithelial lesions to prevent anal cancer. N Engl J Med 2022; 386 (24) 2273-2282
• 3 Palefsky JM, Giuliano AR, Goldstone S. et al. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. N Engl J Med 2011; 365 (17) 1576-1585
• 4 Goldstone RN, Goldstone AB, Russ J, Goldstone SE. Long-term follow-up of infrared coagulator ablation of anal high-grade dysplasia in men who have sex with men. Dis Colon Rectum 2011; 54 (10) 1284-1292
• 5 Crawshaw BP, Russ AJ, Stein SL. et al. High-resolution anoscopy or expectant management for anal intraepithelial neoplasia for the prevention of anal cancer: is there really a difference?. Dis Colon Rectum 2015; 58 (01) 53-59