Causes of Cervical Cancer
Persistent infection with high-risk human papillomavirus (HPV) is the primary cause of cervical cancer, detected in 99% of cervical tumors, with HPV types 16 and 18 being the most oncogenic subtypes. 1
Primary Etiologic Agent: HPV Infection
- HPV is necessary for cervical cancer development, with virtually all cases (99%) attributable to persistent infection by oncogenic HPV types 1
- HPV type 16 is the single most carcinogenic genotype, accounting for 55-60% of all cervical cancers worldwide and 50-60% of invasive squamous cell carcinomas 1, 2
- HPV type 18 is the second most common, responsible for 10-15% of cervical cancers and causes a disproportionately higher percentage of adenocarcinomas (32%) compared to squamous cell carcinomas (8%) 1, 2
- Together, HPV 16 and 18 cause approximately 70% of all cervical cancers globally, including 68% of squamous cell cancers and 83% of adenocarcinomas 2
- Approximately 10 other high-risk HPV genotypes (including HPV 31,33,45,52, and 58) collectively cause the remaining 25-35% of cervical cancers 1, 2
Mechanism of Carcinogenesis
- HPV acquisition occurs through sexual and genital skin-to-skin contact, with prevalence peaking within a few years after sexual debut 1
- Most HPV infections (~90%) are transient, becoming undetectable within one to two years 1
- Persistent HPV infection is the critical step, as women whose infections persist are at significant risk of developing precancerous lesions 1
- One-year or two-year HPV persistence, especially by HPV 16, strongly predicts a 20-30% risk of CIN3+ (high-grade precancer) over 5 years 1, 2
- Untreated CIN3 has a 30% probability of becoming invasive cancer over 30 years, though only about 1% of properly treated CIN3 will progress 1
Co-factors That Modify Risk Among HPV-Positive Women
While HPV infection is necessary, the following co-factors increase the risk of progression to cervical cancer in HPV-positive women:
- Cigarette smoking increases the risk of severe cervical intraepithelial neoplasia (OR = 1.53) 3, 4
- Long-term oral contraceptive use (five or more years) modifies risk among HPV-positive women 3
- High parity (five or more full-term pregnancies) is associated with increased risk 3
- Previous exposure to other sexually transmitted infections, including Chlamydia trachomatis and Herpes Simplex Virus type 2 3
- Chronic immunosuppression, particularly HIV infection, increases risk for HPV infection, HPV DNA persistence, and progression of HPV lesions to cervical cancer 1, 3
- Early age of onset of coitus and larger number of sexual partners are epidemiologic risk factors 1
HPV-Independent Cervical Cancer (Rare)
- Approximately 5-11% of cervical carcinoma cases are HPV-independent, representing a distinct entity with unique histopathological and molecular features 5
- These tumors exhibit specific mutations such as TP53, PIK3CA, KRAS, STK11, and PTEN, leading to alternative oncogenic pathways rather than requiring HPV E6 and E7 oncogenes 5
- Histopathological forms include gastric-type adenocarcinoma, clear-cell, mesonephric, and endometrioid carcinoma 5
Critical Clinical Pitfall
The large geographic variation in cervical cancer rates reflects differences in screening availability (which allows detection and removal of precancerous lesions) and HPV infection prevalence, with nearly 90% of cervical cancer deaths occurring in developing countries 1. This underscores that while HPV infection is ubiquitous, the progression to cancer is largely preventable through screening and vaccination programs.