Clinical overview
Cervical cancer is the one common solid malignancy of women that we understand almost completely, from the first molecular insult to the invasive tumour — and it is the one we can almost completely prevent. That paradox is the heart of why South Africa carries one of the heaviest cervical cancer burdens in the world while the disease is being eliminated in countries with mature vaccination and screening. For the FCOG(SA) registrar, "discuss carcinogenesis" is not a request for a list of risk factors; it is a request to reason from a single virus, through a defined precursor lesion, to invasion — and to use that mechanistic chain to justify every preventive and therapeutic intervention you will offer.
The chain is deceptively simple: persistent infection of the cervical transformation zone with a high-risk human papillomavirus (HPV), integration of the viral genome with dysregulated expression of two oncoproteins (E6 and E7), progressive disruption of the host cell cycle and genome, and the emergence of a high-grade squamous intraepithelial lesion (HSIL) that, if unchecked, breaches the basement membrane. Each step is a clock that ticks over years to decades, and each step is a place to intervene — which is exactly why the WHO 90-70-90 elimination strategy targets vaccination (prevent infection), screening (detect the precursor), and treatment (excise the precursor or the early cancer) at three different points on the same curve. In a South African population with very high HIV prevalence, that clock runs faster and the precursor stage is more crowded, which reshapes how we screen and how aggressively we treat. This chapter builds the mechanism so the later staging and treatment objectives have foundations. See HPV pathology and CIN pathophysiology for the lesion-level detail, and Cervical screening SA and CIN management for the preventive programme this biology justifies.
Core knowledge
The transformation zone — where it all happens
Cervical carcinogenesis is anatomically anchored. The ectocervix is lined by non-keratinising stratified squamous epithelium; the endocervical canal is lined by simple columnar (glandular) epithelium. Between them lies the squamocolumnar junction, and because that junction migrates over a woman's life (everted onto the ectocervix at menarche and in pregnancy under oestrogen, then retreating into the canal after the menopause), the intervening band of metaplastic squamous epithelium — the transformation zone — is created by active metaplasia. It is the immature, dividing metaplastic cells of the transformation zone, not mature squamous or glandular cells, that are uniquely vulnerable to HPV-driven transformation. This is why almost all cervical squamous cancers and their precursors arise in the transformation zone, why colposcopy concentrates on it, and why an excisional treatment such as LLETZ aims to remove the whole zone. Knowing this anatomy explains the screening test (you must sample the zone) and the treatment (Colposcopy localises it). See Genital anatomy.
HPV — the necessary cause
Figure D9.1 — The cervical carcinogenesis cascade: transient HPV → persistence → HSIL precancer → microinvasion → invasive carcinoma over ~10–20 years, with the three chances to interrupt it.
HPV is a small, non-enveloped, double-stranded circular DNA virus. More than 200 genotypes exist; about 14 are oncogenic ("high-risk", hrHPV), with HPV-16 and HPV-18 alone causing roughly 70% of cervical cancers worldwide. HPV-16 dominates squamous carcinoma; HPV-18 is over-represented in adenocarcinoma. Persistent infection with a high-risk type is a necessary cause — virtually no cervical cancer occurs without it — which is the single most important concept in this objective: it transforms cervical cancer from an idiopathic malignancy into an infectious disease with a precursor, and that is what makes vaccination and a molecular screening test rational.
The virus infects basal keratinocytes exposed through micro-abrasions in the transformation-zone epithelium. Most infections are transient: 80–90% clear within 1–2 years through cell-mediated immunity. It is persistence — the same high-risk type detectable over repeated tests — that defines risk. The viral life cycle is normally tied to keratinocyte differentiation, with the genome maintained as a low-copy episome.
E6 and E7 — the two oncoproteins
Figure D9.2 — The molecular engine: E6/E7 drive genomic instability, immortalisation (hTERT) and loss of cell-cycle control after integration disrupts E2.
Transformation is driven by sustained over-expression of two early viral genes, E6 and E7. In the WHO 2020 framework these map directly onto the histological grades:
- E7 binds and degrades retinoblastoma protein (pRb). pRb normally restrains the cell cycle by sequestering the E2F transcription factor at the G1/S checkpoint. Inactivating pRb releases E2F, forcing the cell into S-phase and continuous proliferation. A diagnostically useful consequence is over-expression of p16^INK4a — the cell raises p16 in a futile attempt to brake the cycle, so strong, block-positive p16 immunohistochemistry is a surrogate marker of high-risk HPV transcriptional activity and is used to confirm HSIL.
- E6 binds and targets p53 for proteasomal degradation (via the E6AP ubiquitin ligase). p53 is the guardian of the genome: it triggers cell-cycle arrest and apoptosis in response to DNA damage. Removing p53 disables apoptosis, so a cell that should die instead survives and divides. E6 also activates telomerase (hTERT), conferring replicative immortality.