“Squamous cell carcinoma of the anus incidence has increased dramatically in elderly women and young black men,” according to a study of recent trends in incidence and mortality. “Advanced-stage [anal squamous cell carcinoma] incidence tripled with a prominent rise in … mortality,” researchers reported in the Journal of the National Cancer Institute.1
Although squamous cell carcinoma of the anus is preventable with the human papillomavirus (HPV) vaccine, vaccination coverage “remains suboptimal,” the authors noted. “Furthermore, no evidence-based [squamous cell carcinoma of the anus] screening guidelines exist except for expert opinion-based recommendations for persons with human immunodeficiency virus (HIV).”
The relationship to a sexually transmitted infection, the anatomic site, and its relative uncommonness have kept [squamous cell carcinoma of the anus] in the shadows for a long time.— Keith Sigel, MD, PhD, MPH
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Squamous cell carcinoma of the anus is the most common histologic subtype of anal cancer. Although both incidence and mortality rates for this subtype are increasing, anal cancer is still is an uncommon cancer and represents a very small proportion of cancer cases in the United States, said Keith Sigel, MD, PhD, MPH, a coauthor of the study and Associate Professor of Medicine, Icahn School of Medicine at Mount Sinai, New York, in an interview with The ASCO Post. “The relationship to a sexually transmitted infection, the anatomic site, and its relative uncommonness have kept [squamous cell carcinoma of the anus] in the shadows for a long time,” he noted.
Building on Momentum
The recent study, however, was covered by major media, including CNN, the Today show, and the NBC News website.2,3 “Because it received so much mainstream press, many people approached us, asking about these results. It opened up a lot of people’s eyes to the fact that this is becoming a more important cancer,” Dr. Sigel said.
“In the medical realm, people have been very supportive of this paper,” he continued, “and we want to try to use some of this momentum to determine whether or not we should be screening for anal cancer more aggressively, because except for people with HIV, we are not screening for it. And yet we screen for cervical cancer, which is becoming much less common and is also linked to HPV infection.”
“If increasing [anal cancer] incidence trends continue in older women, and cervical cancer incidence continues to decline, [squamous cell carcinoma of the anus] may surpass cervical cancer over the next 10 to 15 years to become the leading HPV-associated cancer in elderly U.S. women,” the researchers predicted.
Major Trends
Using the U.S. Cancer Statistics data set, the researchers examined trends in anal squamous cell carcinoma incidence from 2001 to 2015 and in mortality from 2001 to 2016. Among the 68,809 individuals in the incidence analysis, 64.9% were women, 81.8% were non-Hispanic white, and 79.5% were aged 50 years or older.
Overall, the incidence of anal squamous cell carcinoma increased 2.7% per year, the researchers reported, “with pronounced increases in age groups 50 years and older.” Distant-stage incidence of the disease tripled and regional-stage incidence nearly doubled. The average annual percentage change for localized stage was 1.3% in men and 2.3% in women.
“Among men, the most pronounced rise was observed in those who were black,” the researchers reported. Younger black men—those born circa 1986—had a nearly fivefold higher risk of squamous cell carcinoma of the anus than men born circa 1946; for white men, the risk was doubled. Incidence increased rapidly among white women (3.7% per year) and black women (2.6% per year).
Anal cancer mortality rates increased 3.1% per year, “with statistically significant increases in age groups 50 years and older,” according to the study report.
Changes in Sexual Practices
“[Squamous cell carcinoma of the anus] risk is associated with sexual behaviors, including the number of sexual partners and receptive anal intercourse, reflecting HPV acquisition. Therefore, this increase may have been caused by the increased number of sexual partners following the ‘sexual revolution’ of the 1950s to 1960s and the increased prevalence of anal sex in recent birth cohorts of women,” the authors wrote.
“Probably in all groups, men and women of all races, among older people, we are going to continue to see increases in anal cancer, because sexual practices evolved over the course of the 1960s to 1980s, and so there is likely to be more HPV infection and more anal cancer,” Dr. Sigel commented.
Contributing Factors
The report pointed out, “Noteworthy increases in [anal squamous cell carcinoma] mortality rates among the elderly population [are] likely to be associated with the rising rates of advanced-stage [squamous cell carcinoma of the anus] among people older than 50 years, which may reflect an increasing prevalence of immunosuppressed adults in the United States due to medical conditions or treatments.”
Dr. Sigel elaborated, “Therapeutic immunosuppression or disease-related immunosuppression is a cancer risk factor in general and has been linked to several different cancers. For instance, lung cancer seems to be pretty strongly associated with both immunodeficiencies from medication and immunodeficiencies from factors such as HIV.”
He continued, “Epidemiologic studies are looking at whether the increasing prevalence of immunosuppression for various reasons is leading to more aggressive HPV-related disease. We are trying to see if, among the non–HIV-infected population, these therapeutic or acquired immunodeficiencies are strongly contributing to the reason why we are seeing more advanced-stage disease. We are using national cancer incidence data linked to diagnostic data to try to understand that on a population level.”
Investigators at Mount Sinai are also examining tissue specimens of several thousand adults screened for anal cancer. “We are looking at those lesions using state-of-the-art techniques to see where the immune system is not functioning properly and allowing HPV to persist and drive these lesions toward cancer.”
Other risk factors mentioned in the report include prior lower genital tract dysplasia or malignancy and perhaps age and detection of high-risk cervical HPV infection. An association with anal squamous cell carcinoma risk was also noted for current smoking and obesity in men.
“We know that smoking makes clearance of HPV more difficult, so that is certainly a place to intervene,” Dr. Sigel said. “Age in general is one of the most potent risk factors for any cancer but is unfortunately unavoidable. Obesity is much more controversial,” he noted, and while it is a risk for several cancers, obesity is not considered a major risk factor for anal cancer.
‘Suboptimal’ Vaccination Coverage
“[Squamous cell carcinoma of the anus] is preventable through HPV vaccination; however, vaccination coverage (50% in 2017) remains suboptimal in the United States, and less than 30% of vaccine-eligible individuals or their family members received a recommendation for HPV vaccination from their health-care professionals,” the researchers reported. “Even if high HPV vaccine coverage is attained in the next 5 years, the benefits of vaccination may not be evident for at least 15 to 20 years given the lengthy time between initial HPV infection and development of [disease].”
Overall, the trends in anal cancer are not helped by the fact that for many groups, we still do not do a great job of vaccinating against HPV.— Keith Sigel, MD, PhD, MPH
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“Overall, the trends in anal cancer are not helped by the fact that for many groups, we still do not do a great job of vaccinating against HPV,” Dr. Sigel acknowledged. “In addition, people who are getting anal cancer, particularly the women, are older and very unlikely to have been vaccinated. The other component is there is no recommended screening for that group.”
Limited Screening
Current screening efforts are largely limited to persons known to be infected with HIV. “Anal cancer is a particularly important cancer for people with HIV because, for reasons that we don’t totally understand, people with HIV are less likely to clear HPV infection, and people with HIV are at a greater than 20-fold increased risk of anal cancer compared to people in the general population,” Dr. Sigel stated. “We are seeing people who have been infected with HIV for a long time, and as they get older, there is a greater risk of several different cancer types. Cancer is becoming the next epidemic among people with HIV.”
He added, “We think that the trends we noted among younger black men are related to HIV infection. We didn’t have HIV information, but based on the timing and our knowledge of the demographics of the HIV epidemic, we suspect that the trend we saw with black men in the study was related to HIV.”
The ANCHOR study is a large prospective randomized study that is enrolling 6,000 patients with HIV who have high-grade anal precancers and are randomly assigned to either treatment or observation. The purpose of that is to determine whether treating precancers detected in the screening process lowers the incidence of invasive cancers,” Dr. Sigel explained. The results could then be used to develop an optimal screening regimen. Another coauthor of the currently reported paper, Joel M. Palefsky, MD, of the University of California, San Francisco, is principal investigator of the ANCHOR trial.
“There also needs to be further study in the HIV-unaffected group, to see if there are other special high-risk groups that should be enrolled in early-detection programs,” Dr. Sigel said. “There are more aggressive forms of HPV—HPV-16 and HPV-18 are the most carcinogenic forms. People with the most aggressive carcinogenic forms should consider being screened for anal cancer, or at least talking with their doctor about the best course of action.”
Anal Pap Smear
“The most common initial test for screening is an anal Pap smear, the analogous test to a cervical Pap smear, which is not a complicated test to perform. It becomes much more complicated when that test is positive, because then it requires a practitioner with expertise in anoscopy to look for high-grade lesions and then treat them,” Dr. Sigel said.
“In many centers now, the same specimen can be used to test for HPV and [anal cancer]. Here at Mount Sinai, when I screen a patient for anal cancer, I do the anal Pap smear, and that same specimen is sent for HPV testing.” Currently under investigation at Mt. Sinai and other centers is the question of how best to use the cytology information in combination with the HPV testing to figure out which patients need further evaluation,” Dr. Sigel said. “There may be advantages to early detection that lead to the ability to have a surgical cure, which in the long term has better outcomes with regard to quality of life.”
Treatment Can Be Debilitating
“Most people do survive after a diagnosis of anal cancer, particularly early-stage anal cancer,” Dr. Sigel said. “Early detected tumors can be treated surgically, which tends to have the least amount of long-term consequences,” Dr. Sigel said. “Here at Mount Sinai, we have been finding a lot more of these very early-stage tumors that can be treated with surgical resection.”
For later-stage disease, “the treatment is more difficult. It can be debilitating and involve radiation of the anus, and that can cause a lot of long-term side effects,” Dr. Sigel said. He added that advances in targeted radiation have decreased levels of toxicity.
“For more advanced anal cancers, there do seem to be promising results with immunotherapy,” Dr. Sigel said. “HPV-associated cancers in general seem to be pretty responsive to immunotherapy.” ■
DISCLOSURE: Dr. Sigel reported no conflicts of interest.
REFERENCES
2. Pawlowski A: What are the symptoms of anal cancer? Disease is on the rise in the U.S. November 19, 2019. Available at nbcnews.com. Accessed December 9, 2019.
3. Rogers K: Anal cancer rates and deaths are climbing in the US, study says. November 19, 2019. Available at cnn.com. Accessed December 9, 2019.
