Multiple risk factors have been associated with the development of carcinoma of the anal canal. Benign conditions such as hemorrhoids, fissures, and anal fistulas have not been determined to be causal factors (5). Rather, it has been postulated that these benign conditions may instead represent the initial symptoms of anal cancer (5).
The pathogenesis of developing anal cancer is largely related to infection with specific subtypes of human papillomavirus (HPV), most commonly with HPV-16 or HPV-18. Common risk factors associated with anal cancer include a history of more than 10 sexual partners; receptive anal intercourse before the age of 30; and sexually transmitted diseases, including condyloma acuminata (genital warts, attributed to HPV), gonorrhea, herpes virus, hepatitis, Chlamydia trachomatis, or a history of infection with human immunodeficiency virus (HIV) (6,7,8). Women with a history of cervical, vaginal, or vulvar cancer are three to five times more likely to develop anal cancer as opposed to stomach or colon cancer, demonstrating the link between sexual activity and likely field cancerization effects from prior high-risk HPV infection (9).
Human papillomavirus is the most common sexually transmitted disease in the United States and has been strongly associated with the development of anal carcinoma (10). It is estimated that 75% of men and women of reproductive age have been infected with genital HPV.
High-risk subtypes HPV-16 and HPV-18 are associated with anal cancer—and also cervical dysplasia—and may result in anal intraepithelial neoplasia (AIN). Human papillomavirus subtype 16 reportedly results in a greater incidence of high-grade AIN (11). However, unlike cervical dysplasia, AIN is a premalignant condition for which standard screening methods currently have not been universally recommended and have been limited to select high-risk individuals.
A systematic literature review on HPV type distribution in anal cancer showed a combined prevalence of HPV-16 and/or HPV-18 of 72% in invasive anal cancer, with the prevalence of HPV-16 being the highest in these cases, as in cervical cancer (12). A cohort of patients with metastatic SCC of the anal canal at the University of Texas MD Anderson Cancer Center (MDACC) revealed the presence of HPV, via detectable HPV DNA and/or expression of the protein p16, in 68 (95%) of 72 tumor samples analyzed (13). Therefore, HPV appears to be found in the vast majority of anal cancers.
The presence of HPV also has been reported to be a positive prognostic biomarker for patients with nonmetastatic SCC of the anal canal. In one study of patients with stages I to III anal cancer, HPV was detected in 120 (88%) of 137 tumors analyzed. In a multivariate analysis, p16 expression was determined to be associated with an improvement both in overall survival and disease-specific survival relative to patients with HPV-negative tumors (14).
Introduction in 2006 and 2009 of the prophylactic vaccines Gardasil and Cervarix, respectively, directed against primary infection by HPV has demonstrated efficacy in reducing precancerous anogenital lesions caused by the targeted subtypes 6, 11, 16, and 18 (15,16,17). In late 2014, the US Food and Drug Administration (FDA) approved the introduction of a nonavalent vaccine targeting nine HPV subtypes (6, 11, 16, 18, 31, 33, 45, 52, and 58). A large, double-blind placebo-controlled study of men who have sex with men between 16 and 26 years of age demonstrated that the use of a quadrivalent vaccine against HPV not only was safe and well tolerated but also decreased the incidence of precancerous AIN (18). These findings generate early optimism that this preventative approach may decrease the incidence of this disease in the future. Even though initially approved for the vaccination of adolescent females, Gardasil has subsequently received extended FDA approval for males of the same age category after it was shown to be efficacious and may offer a promising primary prevention strategy in both genders (19).
Human Immunodeficiency Virus
Although a direct relationship between HIV and carcinoma of the anal canal has not been clearly established, a strong correlation exists between HIV and HPV. Compared with HIV-negative patients, HIV-positive patients are two to six times more likely to be diagnosed with HPV regardless of sexual practices and are also more likely to have a persistent infection (20,21). Human immunodeficiency virus–positive men and women exposed to HIV are less likely to clear the virus and become HPV negative (21,22). For patients who are infected with HIV, the prevalence of anal carcinoma is greater and cancer presents at a younger age of onset than in HIV-negative patients (23).
Solid organ transplantation has been associated with a 10-fold increased risk of developing anal cancer and a 20-fold increased risk for vulvar and vaginal cancers (24). A recent population-based cohort study conducted using the Danish National Patient Registry and the Danish Cancer Registry (DCR) from 1978 to 2005 found that HIV infection, solid organ transplantation, hematologic malignancies, and a range of specific autoimmune diseases were strongly associated with increased risk of anal SCC (25).
Prior case-control studies have indicated that chronic tobacco use may result in a two- to five-fold increased likelihood of developing anal cancer (26). Moreover, tobacco smoking appears to be associated with recurrence of anal carcinoma and is related to increased mortality; thus, smoking cessation should be encouraged once a diagnosis of anal carcinoma is made (27).