What is the relationship between infections, such as human papillomavirus (HPV), hepatitis B, and Helicobacter pylori (H. pylori), and the development of cancer in high-risk populations or individuals with underlying medical conditions?

Association Between Infections and Cancer

Infections are responsible for approximately 16% of all new cancer cases globally and 4.3% of cancers in the United States, with the primary causative agents being Helicobacter pylori, human papillomavirus (HPV), hepatitis B and C viruses, and Epstein-Barr virus. 1, 2

Global and Regional Burden

The worldwide burden of infection-attributable cancers is substantial but varies dramatically by geography and economic development:

• In 2018, approximately 2.2 million new cancer cases globally were attributed to infections, corresponding to an age-standardized incidence rate of 25.0 cases per 100,000 person-years 1
• The burden is disproportionately higher in less developed regions (23% of cancers) compared to more developed regions (7% of cancers) 3
• Eastern Asia has the highest infection-attributable cancer incidence (37.9 per 100,000 person-years), followed by sub-Saharan Africa (33.1 per 100,000), while northern Europe (13.6 per 100,000) and western Asia (13.8 per 100,000) have the lowest rates 1

Primary Infectious Agents and Associated Cancers

Helicobacter pylori

H. pylori is the leading infectious cause of cancer worldwide, responsible for approximately 810,000 cases annually (ASIR 8.7 per 100,000 person-years) 1. The mechanism involves:

• Progression from chronic active gastritis → atrophic gastritis → metaplastic epithelia → intraepithelial neoplasia → invasive gastric carcinoma 4
• All infected individuals develop gastritis and remain at risk for gastric cancer throughout their lifetime 4
• Eradication of H. pylori halts the progression of risk but does not eliminate existing risk, making early detection and treatment critical 4
• In high-risk populations (e.g., Matsu Islands), organized screening and eradication programs reduced gastric cancer incidence by 53% and cancer-related deaths by 25% 4

Human Papillomavirus (HPV)

HPV accounts for approximately 690,000 cancer cases annually worldwide (ASIR 8.0 per 100,000 person-years) 1, with specific high-risk subtypes driving oncogenesis:

• HPV-16 and HPV-18 are detected in 72% of invasive anal cancers and are responsible for 86-97% of all anal cancers 4
• In the United States, HPV was responsible for 38,230 cancer cases in 2017, including cervical (12,829 cases), oropharyngeal (12,430 cases), and other anogenital cancers 2
• The cancer burden shows a clear inverse relationship with country income level, ranging from 6.9 per 100,000 in high-income countries to 16.1 per 100,000 in low-income countries 1

High-risk populations for HPV-associated anal cancer include:

• Men who have sex with men (MSM) with HIV: 131 per 100,000 person-years 4
• Men with HIV: 40-60 per 100,000 person-years 4
• Women with HIV: 20-30 per 100,000 person-years 4
• MSM without HIV: 14 per 100,000 person-years 4

Hepatitis B and C Viruses

Hepatitis B virus (HBV) causes approximately 360,000 cancer cases annually (ASIR 4.1 per 100,000), while hepatitis C virus (HCV) causes 160,000 cases (ASIR 1.7 per 100,000) 1:

• In the United States (2017), HBV accounted for 2,310 cancer cases and HCV for 9,006 cases 2
• Together, these viruses were responsible for 10,017 hepatocellular carcinoma cases in the US in 2017 2
• China accounts for a disproportionate burden, with HBV-attributable cancer ASIR of 11.7 per 100,000 1

Epstein-Barr Virus (EBV)

EBV is associated with 7,581 cancer cases in the United States in 2017, including nasopharyngeal carcinoma, Burkitt lymphoma, Hodgkin lymphoma, and non-Hodgkin lymphoma 5, 2. Among children and adolescents (≤19 years), EBV accounts for 2.2% of all cancers 2.

Age and Sex Distribution

The burden of infection-attributable cancers varies significantly by age and sex:

• Women aged 20-34 years have the highest proportion of infection-attributable cancers (9.6%), declining to 3.2% in women ≥65 years 2
• Men aged 20-34 years have 6.1% infection-attributable cancers, declining to 3.3% in men ≥65 years 2
• This age-related decline reflects the predominance of HPV-associated cancers in younger populations 2

Immunosuppression as a Risk Amplifier

Immunosuppression dramatically increases infection-associated cancer risk, particularly for HPV-related malignancies:

• People living with HIV (PLWH) have a 15- to 35-fold increased risk of anal cancer compared to the general population 4
• The standardized incidence rate of anal carcinoma in PLWH increased from 19.0 per 100,000 person-years (1992-1995) to 78.2 per 100,000 (2000-2003), reflecting improved survival with antiretroviral therapy but persistent cancer risk 4
• Solid organ transplant recipients and patients with hematologic malignancies also face elevated risks 4

Clinical Implications for Cancer Prevention

Widespread application of existing public health interventions could substantially reduce the global cancer burden:

• Vaccination programs (HPV, hepatitis B) 3
• Safer injection practices and quality-assured blood screening 3
• Antimicrobial eradication treatments (H. pylori) 4, 3
• Safer sexual practices, including condom use and limiting lifetime sexual partners 3

For H. pylori specifically, organized screening programs in high-risk populations are cost-effective, particularly when targeting young adults before irreversible molecular damage occurs 4.

Important Caveats

While infections are important causes of morbidity and mortality in cancer patients 4, the relationship is bidirectional: the malignancy itself and cancer treatments (particularly chemotherapy-induced neutropenia) predispose patients to severe or recurrent infections 4. This creates a complex interplay requiring individualized risk evaluation and preventive strategies throughout the cancer care continuum 4.

The estimates provided represent minimum attributable fractions, as emerging evidence continues to identify new infection-cancer associations beyond the well-established pathogens 6. Geographic and demographic variations in infection prevalence mean that targeted interventions in high-risk subpopulations offer the greatest potential for cancer burden reduction 1, 6.