What is the pathophysiology of cervical cancer?

Pathophysiology of Cervical Cancer

Cervical cancer develops through a well-defined sequence: acquisition of high-risk HPV through sexual contact, viral persistence (rather than clearance), progression to precancerous lesions (CIN3), and ultimately invasion—with persistent HPV infection being necessary in nearly 100% of cases. 1

The Essential Role of HPV Infection

HPV infection is the obligate causative agent, with epidemiologic case series demonstrating that nearly 100% of cervical cancer cases test positive for high-risk HPV genotypes. 1 The virus is detected in 99% of cervical tumors, establishing it as a necessary (though not sufficient) factor for cervical cancer development. 1, 2

HPV Type Distribution and Carcinogenicity

• HPV16 is the most carcinogenic genotype, accounting for approximately 55-60% of all cervical cancers. 1, 2
• HPV18 is the second most carcinogenic type, responsible for 10-15% of cervical cancers. 1, 2
• HPV18 demonstrates a distinct predilection for glandular cancers, causing approximately 32% of adenocarcinomas and adenosquamous carcinomas versus only 8% of squamous cell carcinomas. 1
• Approximately ten other HPV genotypes (including HPV 31,33,35,45,52, and 58) cause the remaining 25-35% of cervical cancers. 1
• HPV causes all common and most rare histologic types of cervical cancer. 1

The Carcinogenic Pathway: A Four-Stage Model

The establishment of HPV's causal link has led to a clear model for cervical carcinogenesis with four distinct stages: 1

Stage 1: HPV Acquisition

• Genital HPV is acquired through sexual and genital skin-to-skin contact. 1
• HPV prevalence peaks within a few years after the median age of sexual debut (17 years in the U.S.). 1

Stage 2: HPV Persistence versus Clearance (The Critical Determinant)

• Most (~90%) HPV infections are transient, becoming undetectable within one to two years. 1, 2
• Women whose infections persist are at significant risk of developing precancerous lesions—this persistence is the key pathophysiologic event that separates transient infection from cancer risk. 1
• One-year and two-year HPV persistence, especially by HPV16, strongly predicts CIN3 or more severe diagnoses (CIN3+) in subsequent years. 1
• Specifically, persistent HPV16 infection carries a 20-30% risk of CIN3+ over 5 years. 1, 2

Stage 3: Progression to Precancer (CIN3)

• Persistent infection with high-risk HPV genotypes is necessary for development of cervical intraepithelial neoplasia (CIN) grade 3, the immediate precursor lesion to invasive cancer. 1
• Untreated CIN3 has a 30% probability of becoming invasive cancer over a 30-year period. 1, 2
• However, only about 1% of properly treated CIN3 will become invasive. 1

Stage 4: Invasion

• The final stage represents progression from precancer to invasive cervical carcinoma. 1

Molecular Mechanisms of HPV-Induced Carcinogenesis

Viral Integration and Oncogene Expression

• Integration of the HPV genome into the host chromosome of cervical epithelial cells is a key early event in neoplastic progression. 3
• The viral oncoproteins E6 and E7 are primarily responsible for the initial malignant changes in epithelial cells. 4, 3

Inactivation of Tumor Suppressor Proteins

• E6 and E7 viral proteins inactivate two main tumor suppressor proteins: p53 and retinoblastoma (pRb). 3, 5
• Inactivation of p53 disrupts DNA repair mechanisms and apoptosis. 3
• Inactivation of pRb disrupts cell cycle control, leading to rapid cell proliferation. 3
• This genomic instability encourages HPV-infected cells to progress toward invasive carcinoma. 3

Cellular Origin

• The cellular origin of most cervical cancers is thought to be cells in the squamocolumnar junction (SCJ) of the uterine cervix, also known as the transformation zone. 6
• This anatomical location is critical for understanding screening and treatment approaches. 7, 6

Cofactors That Modify Progression Risk

While HPV infection is necessary, several cofactors increase the risk of progression from infection to invasive cancer: 2

• Older age increases progression risk. 2
• Long-term oral contraceptive use (five or more years). 2
• High parity (five or more full-term pregnancies). 2
• Smoking increases risk of progression in HPV-positive women. 2
• HIV infection and immunosuppression reduce clearance of HPV. 2
• Early age at first sexual intercourse increases cumulative exposure time to HPV. 2

Important caveat: Many factors previously thought to be independent risk factors for cervical cancer are now recognized as indicators of HPV exposure rather than independent risk factors. 2

Histologic Considerations

• Squamous cell carcinomas comprise 70-80% of cervical cancers and are related to HPV infection in almost all cases. 1
• Adenocarcinomas account for 10-15% of cervical cancers. 1
• Endocervical adenocarcinoma of usual type and its precursor (adenocarcinoma in situ) are positive for HPV in nearly 90% and 100% of cases, respectively. 1
• The presence of HPV18 DNA is associated with poor prognosis. 1