Without prevention, novel screening, and treatment of premalignant lesions, I am afraid we will have at least 30 years of an increasing burden from HPV-related cancers.
—Erich M. Sturgis, MD, MPH
A lot of papers describing the prevalence of disease [anal precancerous lesions/high-grade squamous intraepithelial lesions] in women have grossly underestimated the amount of disease that is there. It’s higher than most people think.
—J. Michael Berry-Lawhorn, MD
More than 7,200 cases of anal cancer were diagnosed in 2014—approximately 2,600 in men and 4,600 in women—representing an increase of more than 4,000 from 8 years ago. In more than 90% of patients, infection with the human papillomavirus (HPV) is the cause, tagging anal cancer as a largely preventable malignancy. However, this fact is often ignored, reflective of the anemic acceptance of the merit of the HPV vaccine.
“We have found that the number one reason parents do not vaccinate boys is that their pediatrician did not recommend it. We are making efforts to educate our pediatric and primary care colleagues that boys need this vaccination, too,” said Erich M. Sturgis, MD, MPH, of MD Anderson Cancer Center, Houston, one of several speakers at a session on HPV disease at the American College of Surgeons (ACS) Annual Meeting.
“The HPV epidemic is happening. Without prevention, novel screening, and treatment of premalignant lesions, I am afraid we will have at least 30 years of an increasing burden from HPV-related cancers,” he said.
Most squamous cell anal cancers are associated with HPV-16, the subtype that also causes cancers of the cervix, vagina, vulva, penis, and oropharynx. HPV is transmitted via skin-to-skin contact with an infected area of the body; although sexual contact is a primary means of transmission, intercourse is not necessary. An HPV infection can also spread from one part of the body to another, for example, originating in the genitals and then spreading to the anus.
HPV infection is very common and usually clears on its own. When it persists, especially the high-risk HPV subtypes, cancer can develop at the site of infection. Individuals aged 15 to 24 are most at risk for the infection, but its clinical manifestation occurs many years later.
Anal cancer accounts for 14% of HPV-related malignancies. Cervical cancer numbers are declining in the developed world due to screening programs, but anal cancer is increasing in both men and women (oropharyngeal cancer is increasing primarily among men) and across ethnic groups, according to Dr. Sturgis.
Anemic Vaccination Rates
HPV vaccination in youth is recommended as a means of preventing both cervical and anal cancers and potentially HPV-related oropharyngeal cancer. “The problem is our vaccination rates. We are far behind other developed countries,” Dr. Sturgis noted.
Although the goal is an 80% vaccination rate, in the United States, only 58% of girls receive one shot, and less than 38% complete the series. For boys, about one-third receives the first shot, and only 14% are fully immunized, he said.
A study presented at the American Public Health Association 2014 Annual Meeting confirmed these numbers and also found that state legislation supporting vaccination has no impact on uptake. In March 2007, the Advisory Committee on Immunization Practices (ACIP) recommended that females aged 9 to 26 receive the HPV vaccine; in 2009, males were included in the recommendation. Subsequently, about half the states have introduced legislation to encourage HPV vaccination.
Darius Taylor, MPH, of the School of Public Health at the University of North Texas Health Science Center, Fort Worth, Texas, and colleagues hypothesized that the political climate, as measured by the status of HPV vaccine legislation, would encourage vaccine update. To study this, they examined the National Immunization Survey data (obtained through a telephone survey) from 2010 to 2012 to determine the prevalence of vaccine initiation, vaccine completion and intention patterns, and the influence of the primary care physician.
Over half the respondents lived in states that produced legislation between 2006 and 2012. Among residents of states with no legislation, 45.3% of females and 9.4% of males were vaccinated. This was no higher than for states that endorsed HPV vaccination, with rates of 45.2% and 10.1%, respectively. “The effect of current health policy had little influence on HPV vaccine initiation,” Mr. Taylor reported.
The primary care physician’s influence was also similar across the states: Physicians recommended vaccination for only 58% of female patients and 16% of boys. “For parents reporting a visit to a primary care physician within the past month, those with sons were 86% less likely to have HPV vaccines recommended than parents of daughters,” he said.
Risk Factors for Anal Cancer
Although HPV-related infection is an equal-opportunity disease, risk for HPV-related anal cancer is greatly increased among certain groups. At the ACS meeting, J. Michael Berry-Lawhorn, MD, of the University of California, San Francisco, noted the incidence per 100,000 persons, according to risk group: HIV-infected individuals, 78 to 144; HIV-negative men having sex with men, 35; HIV-positive women, 9.4 to 30; women in the general population, 1.5; and heterosexual men, 1.
Anna Barbara Moscicki, MD, of the University of California, San Francisco, also speaking at the meeting, zeroed in on the “super risk factors” among women. HIV infection imparts a sevenfold risk (rising to 130-fold in the youngest age groups); other HPV-associated cancers, including cervical cancer and cervical intraepithelial neoplasia grade 3, impart a sixfold risk; and vulvar and vaginal cancers impart a 17- to 20-fold increased risk for anal cancer.
The risk among the general population of women is relatively low, but Dr. Berry-Lawhorn noted that high-resolution anoscopy identifies cases that might otherwise be missed. “A lot of papers describing the prevalence of disease in women have grossly underestimated the amount of disease that is there. It’s higher than most people think,” he maintained.
One reason for this may be the rising acceptance of anal intercourse among females. According to Dr. Moscicki, “Anal sex is risky for infection because of the vulnerability and fragility of the tissue itself. Adolescents have been using anal sex for birth control. We have to do a better job of education and assuring they have appropriate birth control.”
Dr. Berry-Lawhorn added, however, anal intercourse is not necessary for HPV transmission to the anal area. “Sex is a very moist experience, and HPV travels all over the place,” he said.
Progression From Premalignant to Malignant Disease
The trick is finding the precursors—anal high-grade squamous intraepithelial lesions—before they progress to anal cancer. Dr. Berry-Lawhorn and colleagues recently demonstrated direct progression of high-grade squamous intraepithelial lesions to cancer by following 138 HIV-infected men who have sex with men diagnosed with anal canal or perianal squamous cancer between 1997 and 2011.1
All patients were followed with digital anorectal examination, high-resolution anoscopy, and high-resolution anoscopy-guided biopsy. Although treatment for high-grade squamous intraepithelial lesions and follow-up were recommended, not all patients were treated, and some were lost to follow-up.
Prevalent cancer was found in 66 men; the other 72 HIV-infected men who have sex with men developed anal cancer while under observation. In 27 of these 72 men, anal cancer developed at a previously biopsied site of a high-grade squamous intraepithelial lesion (45 were not analyzed due to inadequate documentation of its location). Progression to cancer occurred over approximately 5 years.
High-grade squamous intraepithelial lesions are found in 50% of HIV-infected men who have sex with men, 25% of HIV-negative men who have sex with men, and up to 40% of HIV-positive women (data are lacking in heterosexual men). Persons most likely to have high-grade squamous intraepithelial lesions are those who are HIV-infected (especially men who have sex with men), immunocompromised, older than age 35 with genital warts, symptomatic with extensive perianal lesions, and women with a history of vulvar high-grade squamous intraepithelial lesions, he indicated.
Persons with abnormal anal cytology should be referred for high-resolution anoscopy. If found, high-grade squamous intraepithelial lesions can be excised or ablated, but Dr. Berry acknowledged, “there is no definitive proof that ablation prevents anal cancer.”
Proof could come from a study by the National Cancer Institute, which will screen approximately 17,000 HIV-infected persons to identify 5,000 high-grade squamous intraepithelial lesions, randomizing them to ablation or surveillance for 5 years. The goal is to reduce the number of incident cancers by 75%. (For more information, visit www.theanchorstudy.org.)
As debate continues about whom and when to screen for anal cancer, there seems to be agreement that the best screening means is digital anorectal examination and anal cytology, with referral to high-resolution anoscopy. Unfortunately, according to Dr. Berry-Lawhorn, digital anorectal examination is not performed often enough when patients present with anal pain and bleeding, and the number of clinicians experienced in high-resolution anoscopy remains “quite limited.” Thus, recognition and treatment of HPV-related anal cancer remain a work in progress. ■
Disclosure: Drs. Sturgis and Berry-Lawhorn reported no potential conflicts of interest. Dr. Moscicki is a member of the advisory board for Merck.
1. Berry JM, Jay N, Cranston RD, et al: Progression of anal high-grade squamous intraepithelial lesions to invasive anal cancer among HIV-infected men who have sex with men. Int J Cancer 134:1147-1155, 2014.