Anal cancer is rare. Although the lifetime risk for anal cancer is about one in 500 in the general population, this increases 30- to 100-fold in high-risk groups, and both incidence and mortality have been increasing over the past several decades at a rate of about 2.2% per year.

“That’s a bit of a cause for alarm,” said Rebecca A. Levine, MD, a colon and rectal surgeon at Montefiore Medical Center, and an assistant professor of surgery at the Albert Einstein College of Medicine, in New York City.

At the 2021 Controversies, Techniques and Problems in Surgery meeting, Dr. Levine discussed the risk factors for anal cancer, ongoing research that promises to clarify the topic and what surgeons need to know to prevent anal cancer.

Risk Factors

Most anal cancers are squamous cell carcinomas. The disease is more frequent in women, and although more cases occur in absolute numbers in the HIV-negative population, HIV-positive status is the highest risk factor for the disease.

Other risk factors include smoking, any form of irritation (hemorrhoids, fistulas), exposure to HPV, men who have sex with men (MSM) and various forms of immunosuppression.

“But HIV remains the greatest risk factor. In the highest risk groups that risk increases 100-fold,” Dr. Levine said.

Some data show a correlation of anal cancer with lower CD4 counts, but this has been inconsistent; and anal cancer is not an AIDS-defining malignancy.

“In fact, the longer people survive with chronic HIV, the more likely they are to develop anal cancer. And the incidence in this high-risk group is higher than cervical cancer incidence anywhere in the world, including places that don’t have access to screening or vaccine,” Dr. Levine said.

Antiretroviral therapy is not protective against anal cancer. Since the therapy debuted in 1996, the incidence of anal cancer has shot up dramatically, increasing fivefold.

“The bottom line is, antiretroviral therapy is not protective, which makes prevention even more important.”

Etiology

Most squamous cell anal cancers are linked to HPV, which tends to adhere to and crawl along the skin, often finding its way to the anus. The theory on HPV’s role in anal cancer is that a break or abrasion in the mucosal barrier allows the virus to enter the epithelium and cause an infection that leads to low-grade dysplasia.

The infection might clear or it might continue, “leading to coinfection with oncogenic subtypes that cause high-grade dysplasia, which is thought to evolve into anal cancer,” Dr. Levine said.

Most studies of MSM and the HIV-positive population have found that nearly all of those patients have HPV.

“Unlike cervical HPV, which declines with age, anal HPV levels tend to remain stable, and this is thought to be due to continued exposure through sexual activity,” Dr. Levine said.

Anal intraepithelial neoplasia (AIN) is also most prevalent in HIV-positive MSM, followed by HIV-negative MSM and then HIV-positive women. One population study of AIN in MSM found high-grade dysplasia in 30% overall; in HIV-positive MSM, the proportion jumped to 43% (Ann Intern Med 2008;149:300-306).

“Why do we care about high-grade dysplasia? Over the years, multiple centers following groups of patients with high-grade squamous intraepithelial lesions [HSILs] have found cases of cancer, which provided some indirect evidence of progression. Most patients with these cancers have coexisting HSIL overlying or adjoining the malignant lesion,” Dr. Levine said.

Most of these lesions will not progress to cancer, but it’s not clear which ones will develop into cancer. Furthermore, some studies have found spontaneous regression of HSILs in up to 30% of patients.

“So, if most of these lesions don’t progress and a huge proportion of them regress, why not just prospectively manage these patients?” Dr. Levine asked.

Some retrospective studies support expectant management, but the long-term data are not yet in from prospective trials such as SPANC (Study of Prevention of Anal Cancer), which is following 617 HIV-positive and HIV-negative gay men, nearly all with HPV, who are being intensively screened but not treated. The purpose of the trial is to define the natural history of HPV and progression to cancer.

Baseline data from the SPANC trial has found HSILs far more prevalent in patients who are HIV-positive than in those who are HIV-negative, at 47% and 32%, respectively. Until the final results are in, preventive measures should include HPV vaccination and screening and treatment of precursor lesions.

Screening and Prevention

Currently, there are no formal guidelines for screening. Dr. Levine suggests that at-risk patients should be prioritized. “That would include all HIV-positive patients, some women with gynecologic dysplasia and patients with immunosuppression.”

Screening begins with cytology followed by high-resolution anoscopy (HRA) with biopsy if the results are abnormal; low-grade dysplasia is monitored and high-grade dysplasia is treated. Unfortunately, multiple studies have found patients to have high-grade dysplasia on biopsy, even when their cytology was benign; HRA, which magnifies up to 24 times, is the gold standard for screening.

“We stain the mucosa with acetic acid to highlight the HPV changes, and you can use your biopsy tool of choice,” Dr. Levine said. Examining mucosa from the proximal anus to the peri-anus, she uses various descriptors to classify lesions and suspicion of high-grade dysplasia, commenting on the vasculature and uptake of Lugol’s iodine.

“Some low-grade dysplasia is less obvious—flatter and more subtle. High-grade lesions tend to have more prominent vasculature. And while HSIL is generally invisible and asymptomatic, cancer should be more obvious—palpable and symptomatic,” Dr. Levine said.

The rationale for treatment of HSILs is to prevent progression to cancer. Patients are treated for anal warts if they are symptomatic or if the lesions obscure HRA. There are many options and modalities for treatment, the choice of which depends on the volume of disease, patient preference and other factors.

“Multiple treatments are often needed, and you can also combine modalities. It’s key to rule out cancer before treating because all of these treatment mechanisms destroy the tissue,” Dr. Levine said.

Her preferred mode of treatment is to burn off mucosa at the location of the lesion with electrocautery. “You can accomplish a lot in a single session with minimal morbidity and very minimal anesthesia. You do need a smoke evacuator, though, so you don’t inhale HPV particles.” She reserves surgical excision for large, bulky lesions and cases that require inspection by the tissue pathology unit.

There are numerous drawbacks to screening and treating anal dysplasia, Dr. Levine acknowledged; it’s time-consuming with a steep learning curve and demands a lot from staff. “Though morbidity is mild, it does exert a large psychological toll on patients who have to keep coming back frequently for repeated procedures.”

Therefore, these challenges raise the question: If so many lesions regress, do screening and treatment prevent cancer, or do both cause more harm than good? A couple of small trials suggest that this approach offers a significant protective advantage against anal cancer. This has led to the ANCHOR (Anal Cancer HSIL Outcomes Research) trial, which randomized 4,446 HIV-positive men and women with HSILs to treatment or active monitoring with HRA. Enrollment was halted early in September 2021 due to the high success of treatment.

“This is the cliff-hanger: I cannot share the raw data yet, but it’s quite impressive,” Dr. Levine said. “I think we will finally be able to say, based on level I evidence from a phase 3 trial, that treatment of HSIL significantly reduces progression to anal cancer compared to expectant management.”