What are the primary risk factors for anal cancer?

Risk Factors for Anal Cancer

Human papillomavirus (HPV) infection, particularly high-risk types HPV-16 and HPV-18, is the primary cause of anal cancer, detected in 80-90% of cases, with immunosuppression and smoking being the most critical modifying factors that facilitate HPV persistence and malignant transformation. 1, 2

Primary Causative Agent: HPV Infection

HPV is the dominant etiologic factor, with the following key characteristics:

• HPV-16 and HPV-18 are detected in 72-84% of anal cancer specimens, making anal cancer second only to cervical cancer in its association with HPV 1, 2
• The CDC estimates that 86-97% of anal cancers are attributable to HPV infection 1
• HPV-16 specifically accounts for approximately 73% of HPV-positive anal cancers 1
• Anal squamous cell carcinoma develops through precursor lesions called anal intraepithelial neoplasia (AIN), which are HPV-driven 2, 3

Critical Immunosuppression-Related Risk Factors

Immunosuppression dramatically amplifies anal cancer risk by facilitating persistent HPV infection:

HIV Infection (Highest Risk)

• People living with HIV (PLWH) have a 15- to 35-fold increased risk of anal cancer compared to the general population 1, 2
• HIV-positive men who have sex with men (MSM) have the highest incidence: 75-135 per 100,000 person-years 2
• Even HIV-positive patients on antiretroviral therapy (ART) with high CD4+ counts remain at elevated risk 1
• Low CD4 count (<350 cells/mm³) specifically increases risk of carcinogenic HPV infection (OR 3.65) 4

Solid Organ Transplantation

• Transplant recipients have a 10-fold increased risk of anal cancer due to chronic immunosuppressive therapy 1, 5
• Immunosuppression accelerates progression from precancerous lesions to invasive cancer 5, 3

Other Immunosuppressive Conditions

• Hematologic malignancies increase anal cancer risk 1
• Autoimmune disorders requiring immunosuppressive therapy 1, 2
• Long-term corticosteroid use 2

Sexual and Behavioral Risk Factors

These factors increase HPV exposure and transmission:

• History of receptive anal intercourse is strongly associated with anal cancer risk 1, 2
• High lifetime number of sexual partners increases HPV acquisition risk 2, 6
• History of sexually transmitted diseases 1
• Men who have sex with men (MSM) have significantly elevated risk, with incidence of approximately 35 per 100,000 in HIV-negative MSM 2

Tobacco Smoking

Cigarette smoking is an independent risk factor that modulates HPV persistence:

• Smoking increases risk of anal precancer among HPV-positive individuals (OR 2.71) 4
• Duration, recency, and dose of smoking all correlate with increased anal precancer risk 4
• Smoking appears to affect progression from HPV infection to cancer rather than initial HPV acquisition 2, 4

History of Other HPV-Related Cancers

Prior HPV-associated malignancies significantly increase anal cancer risk:

• History of cervical, vulvar, or vaginal cancer 1, 2
• These cancers share the same HPV etiology and indicate susceptibility to HPV-driven malignancies 2

Demographic Patterns

Understanding epidemiologic trends helps identify at-risk populations:

• Incidence is increasing at 2.1-2.9% per year in the United States 1
• Greatest increases occur in individuals ≥50 years of age 1
• Women ≥50 years have shown particularly notable increases in incidence 1
• Median age at diagnosis is 69 years, reflecting long latency from HPV infection to cancer 2, 3
• Female-to-male ratio is approximately 2:1 in the general population (6,580 vs 3,180 cases in 2023) 1

Clinical Pitfalls to Avoid

• Do not dismiss rectal bleeding as hemorrhoids without proper examination, as this is the most common presenting symptom and leads to delayed diagnosis 2, 3, 7
• Do not assume absence of traditional risk factors excludes anal cancer—approximately 10-15% of cases occur in HPV-negative individuals 2, 7
• Do not overlook screening in high-risk populations, particularly HIV-positive MSM and transplant recipients, despite lack of formal national screening guidelines 2, 5
• Remember that early-stage disease is typically asymptomatic, requiring high clinical suspicion in at-risk populations 2, 3

Prevention Opportunities

• HPV vaccination prevents 77.5% of high-grade anal intraepithelial neoplasia caused by HPV types 6,11,16, or 18 2
• Vaccination should ideally occur before transplantation in transplant candidates to ensure optimal immunogenicity 5
• Quadrivalent or nonavalent HPV vaccines are recommended for immunosuppressed patients given high prevalence of anogenital warts 5