Clinical overview
Human papillomavirus (HPV) is the single most important infectious cause of cancer in the female genital tract, and in South Africa — where cervical cancer is the leading cause of cancer death in women and where HIV co-infection is endemic — understanding its pathology is not academic. Almost every squamous cervical cancer, the large majority of vulvar and vaginal high-grade lesions, most anal cancers, and a substantial fraction of oropharyngeal cancers share a common molecular driver: persistent infection with a high-risk HPV genotype and the integration of its oncogenes into the host epithelial cell. The clinical spectrum runs from clinically silent transient infection (the rule, cleared by most immunocompetent women within 1–2 years), through benign productive lesions (condylomata acuminata, low-grade squamous intraepithelial lesions), to high-grade precancer (HSIL/CIN 2–3) and frank invasive carcinoma.
For the registrar, the pathology of HPV is the conceptual spine that connects the screening programme, the colposcopy clinic, and the oncology ward. The reason we screen with HPV-DNA tests, the reason we treat HSIL but observe much LSIL, the reason an HIV-positive woman needs more frequent surveillance, and the reason a single-dose prophylactic vaccine can plausibly eliminate the disease — all flow directly from how the virus behaves inside the epithelium. This chapter describes those pathological features: the virology, the gross and microscopic morphology of each lesion grade, the molecular carcinogenesis, and the WHO 2020 terminology that has reshaped how we report them. See also CIN pathophysiology and Cervical carcinogenesis for the dysplasia/invasion sequence in more depth, and Cervical screening SA for the South African programme that operationalises all of this.
Core knowledge
The virus and its targets
Figure D7.1 — The HPV virion and its ~8 kb circular genome: the roles of E6, E7, E2 and L1, and high-risk (16/18) vs low-risk (6/11) types.
HPV is a small, non-enveloped, double-stranded circular DNA virus (~8 kb) of the Papillomaviridae. Over 200 genotypes are described; the genital tract is colonised by the alpha-papillomaviruses. The clinically critical division is by oncogenic potential:
- High-risk (oncogenic) types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and others. HPV 16 and 18 alone cause roughly 70% of cervical cancers worldwide; HPV 16 dominates squamous carcinoma and HSIL, while HPV 18 is over-represented in adenocarcinoma.
- Low-risk types: 6 and 11 cause ~90% of anogenital warts (condylomata acuminata) and recurrent respiratory papillomatosis, and are associated with LSIL but essentially never with invasion.
The virus genome encodes early (E) and late (L) proteins. The oncogenes E6 and E7 are the engine of malignant transformation; E1 and E2 regulate replication and transcription (E2 represses E6/E7); L1 and L2 are the capsid proteins (L1 self-assembles into the virus-like particles that are the basis of the vaccine).
The vulnerable cell: the transformation zone
HPV infects basal keratinocytes reached through micro-abrasions, but the cell type that matters most is the metaplastic squamous epithelium of the cervical transformation zone (TZ) — the dynamic interface between the original squamous epithelium of the ectocervix and the columnar epithelium of the endocervical canal. The squamocolumnar junction migrates with hormonal status (everted and exposed in adolescence and pregnancy, receding into the canal after menopause). Immature metaplastic cells of the TZ are uniquely susceptible to HPV-driven transformation, which is why cervical precancer and cancer overwhelmingly arise here, and why the position of the TZ governs colposcopic adequacy and the choice of ablative versus excisional treatment (see Colposcopy and CIN management).
Productive infection: the cytopathic signature
Figure D7.2 — The HPV life cycle tied to squamous maturation: basal infection, episomal amplification, koilocyte formation, and surface shedding.
In a permissive (productive) infection, the viral life cycle is coupled to keratinocyte differentiation. The virus maintains its genome as a low-copy episome in basal cells, then amplifies and assembles capsids as the cells differentiate towards the surface. This produces the diagnostic cytopathic effect:
- Koilocytosis — the morphological hallmark of productive HPV infection. A koilocyte is a superficial/intermediate squamous cell with a large, sharply demarcated perinuclear halo (clear cytoplasmic cavity), a condensed peripheral rim of cytoplasm, and an enlarged, hyperchromatic, irregular ("raisinoid") nucleus, often binucleation. The halo reflects cytoskeletal collapse driven by the E4 protein.
- Dyskeratosis, parakeratosis and acanthosis accompany koilocytosis in warts and LSIL.
- These features are most florid in LSIL/CIN 1 and condylomata, where viral replication is most active.