Understanding The Relationship Between HPV and Anal Cancer

Anal Cancer Incidence & Risk Factors

Anal cancer is rare in the general population but increasing significantly among some groups of people, especially those infected with HIV, men who have sex with men (MSM), women with cervical cancer, tobacco smokers, and people who are immunocompromised due to organ transplants, steroid use, or the use of any medications that suppress the immune system (Roberts, 2017) (Gaisa, 2014). Rates are especially high among MSM who are infected with HIV and among black men, who have a higher rate of HIV infection.

A study of North Americans found anal cancer incidence rates per 100,000 person-years ranged from 131 for HIV-infected MSM to 46 in other HIV-infected men and 30 in HIV-infected women; the incidence in MSM is highly correlated with the HIV epidemic (GAisa, 2014). There are about 7000 new cases of anal cancer in the USA each year and the 5-year survival rate is 65.7%. There is no routine screening for the disease, even among those at high risk, and it is not covered by insurance (in the USA), as screening for cervical cancer is. As a result, a diagnosis of anal cancer is often delayed until the disease has progressed, resulting in a high rate of morbidity that could be prevented (Leeds, 2016). Data and studies about anal cancer are usually focused on anal squamous cell carcinoma (ASCC), the most common anal cancer.

Role of HPV in Anal Cancer

There has been a great deal of research over the past decade about ASCC and the sexually transmitted Human Papilloma Virus (HPV). HPV-related cancers include cervical, anal, oropharyngeal (mouth and throat), and penile cancers. A recent study estimated the global incidence of HPV-associated cancers in 2012 to be 630,000 new cases that year and 35,000 of those were anal cancer (De Martel, 2017). Another study of the global incidence of anal cancer by country found that it was increasing significantly in men and women in higher income nations such as Australia, Canada, Denmark, France, Italy, Netherlands, the UK and the USA, while it increased only in women in Colombia, Estonia, the Russian Federation, Slovakia, and Switzerland.

The risk of anal cancer is highest among those who have a persistent or chronic HPV infection. Persistent HPV is often associated with HIV infection, receptive anal intercourse, multiple sexual partners, unprotected sex, and a history of HPV-related genital cancer. In North America, rates of anal cancer are higher among people living with HIV and much higher among HIV-positive MSM.

While HPV infection has become extremely common among the general population, most people clear it from their bodies over time through their immune system response (Shridhar, 2015, CA). The longer the duration of an HPV infection, the greater the chance that it will lead to cellular changes called anal intraepithelial neoplasia (AIN), and later to anal cancer. A meta-analysis has concluded that high-risk HPV is the cause of anal cancer. But it is also likely that the progression of AIN to anal cancer is associated with immunosuppression. It is suspected that HIV infection, as well as other immune-compromising conditions, promote HPV persistence indirectly due to immune system suppression. CD4 is a type of white blood cell active in immune response, and studies indicate that a low CD4 count in HIV-positive individuals is a risk factor for AIN and invasive anal cancer.

Continued Lack of Anal Cancer Screening Standards

Decades of PAP test screening in women to detect precancerous changes in cervical cells has been directly correlated with a significant reduction in cervical cancer. For the past two decades, it has been suspected that the use of anal PAP tests could detect AIN in the same manner, before cellular changes in anal epithelium progress to cancer. However, medical societies have still not established standards for anal cancer screening; even though a 2014 review by seven agencies concluded that it may be beneficial. Practice patterns by infectious disease specialists suggest that anal dysplasia screening of high-risk individuals is becoming common, but only the AIDS Institute of the New York State Department of Health has established formal screening guidelines for HIV-positive individuals.

The AIDS Institute recommends routine annual examination of the anus in all HIV-infected adults and cytologic (pap) testing in higher risk HIV-positive patients such as men who have sex with men (MSM), those with a history of genital infection, and women with cervical or vulvar dysplasia (Shrindhar, 2015). The AIDS Institute also refers to updated guidelines for HIV-positive patients posted in May 2018 by the U.S. Department of Health and Human Services (HHS) AIDS Info website, which states that positive cytology requires follow-up with HRA and that visible lesions should be biopsied. The updated HHS guidelines also address AIN treatment.

Current AIN and Anal Cancer Treatment Standards

Those who diagnose and treat anal cancer caution providers to distinguish signs of anal cancer (i.e. anorectal bleeding, pain, and/or fullness, and sphincter incontinence) from similar signs of hemorrhoids and colon cancer. Precancerous lesions of AIN are not always visible on routine examination and require both a digital anorectal exam and high-resolution anoscopy (HRA). HRA requires both specialized equipment and extensive training that is not available at many medical facilities, so patients should be referred to expert centers that can interpret tests, perform HRA, and treat AIN. The recurrence rates of AIN also warrant significant post-treatment surveillance.

While the HPV vaccine is currently recommended only as a preventive immunization for youth between the ages of 9 to 26, clinical trials have indicated that the quadrivalent vaccine reduces both genital lesions and AIN and may be effective in keeping AIN from progressing to anal cancer. Some studies indicate that the 9-valent HPV vaccine may be helpful in preventing recurrent AIN, especially in those at increased risk for SCCA. Unvaccinated patients above age 26 who are at high risk of anal cancer may want to ask their care provider about getting either the quadrivalent or 9-valent HPV vaccine. Since this is an off-label use of both vaccines, it may be challenging to obtain health insurance coverage for them.

Lab tests of those with anal cancer symptoms should include a complete blood count, renal and hepatic function and HIV status. When AIN or anal cancer is detected, scans of the chest, abdomen, and pelvis should be ordered to rule out metastatic disease. Radical surgery is no longer the first option in the primary treatment of anal cancers. Precancerous lesions can be treated with topical therapies and electrocautery to preserve sphincter function. Local excision is only advised for anal margin squamous tumors and not for anal canal squamous cancers. More involved anal cancers may require a combination of surgery, chemotherapy and radiation treatments; the standard of care in 2015 was chemoradiation with Fluorouracil (5FU) and mitomycin (MMC). Those with HIV-related complications, such as opportunistic infections, may need MMC dosage reduced (Shridhar, 2015). See the HHS AIDS Info website for more information on AIN treatment.

Anal cancer and its treatment often take a heavy psychological toll on survivors. Side effects include diarrhea, nausea, fecal incontinence, buttock pain, rectal urgency and flatulence, all of which may discourage survivors from returning to social and sexual activity. Greater attention is needed to identify and intervene with interdisciplinary approaches during long-term follow-up to assure a better quality of life for survivors.

Recommendations For Prevention

Anal cancer can be prevented. The clearest path to prevention is the new two-dose HPV quadrivalent vaccine, which the CDC recommends for people of all gender identities and sexual orientations, starting at age 11 or 12. Since it is intended to be given before sexual activity begins, it can be given as early as 9 years of age. ACIP also recommends vaccination through age 26 years for those who were not adequately vaccinated previously, including gay, bisexual, and other men who have sex with men, transgender people, and immunocompromised persons (including those with HIV infection) (CDC, 2018). Although it is considered an off-label use of the vaccine, studies indicate that it is effective in slowing the progression from AIN to anal cancer, and thus, anyone diagnosed with AIN may benefit from the vaccine.

Barriers to Overcome​​​​​​​

There is a lack of knowledge among medical practitioners and patients in high-risk groups about the prevention, diagnosis and treatment of chronic HPV infection, AIN and anal cancer. To start, healthcare providers need to learn how to ask their patients about their sexual activities, regardless of stated or assumed sexual orientation, to better understand who is at risk. In addition, medical providers need better training to screen and treat those at high risk and to educate their patients about the risks. Medical facilities need to invest in the equipment and training required for high-resolution anoscopy (HRA). To that end, the International Anal Neoplasia Society (IANS) has defined minimum standards for services and clinical practice in the investigation of anal cancer precursors (Hillman, 2016). These standards offer guidance to HRA practitioners about the set-up and implementation of high-resolution anoscopy, the provision of information to patients, staffing, infection control, medical notes, and follow-up referrals to and communication with a team of specialists.

There is a need for prevention education among high-risk patient groups, such as men who have sex with me, including how high-risk sexual practices such as receptive anal intercourse and the failure to use condoms are associated with persistent HPV infection and AIN. Patients of all genders who are HIV positive, have had other HPV-associated cancers, or have a suppressed immune system should be considered at high risk for AIN and anal cancer. Anal pap testing and HRA are highly recommended for these patients.

National LGBT Cancer Network HPV & Anal Cancer

Given the high rate of sexually transmitted diseases and anal cancer in MSM, further research should examine gaps between recommendations and reported experiences of men who have sex with men, especially about health care providers’ efforts to ensure that MSM is offered recommended sexual health services, such as screening for STDs and HPV vaccination.

There is also a need for more research, including randomized control studies when possible, that will result in clear guidance from medical societies about screening for and treatment of anal cancer. In the meantime, medical practitioners and patients at risk can urge health insurance plans to cover anal pap smears and HRA for high-risk groups in order to identify and treat the disease in its earliest phases.

As this article was being written, a new study focused on cervical cancer found that primary screening for HPV resulted in fewer cases and a lower rate of precancerous conditions than traditional cytological (pap test) screening (Ogilvie, 2018). Only further research about HPV testing can assess whether similar findings might apply to AIN and anal cancer.