Overview
This lecture uses skin cancer and uterine cervical cancer as the two worked examples of the pre-cancer (stage 0) to invasive-cancer sequence. It covers what defines a precancerous lesion, the UV-driven mechanism behind skin carcinogenesis and its precursor (solar keratosis), the main invasive skin cancers, then HPV biology and the E6/E7 mechanism behind cervical dysplasia, the CIN/cytology grading systems, how cervical dysplasia is diagnosed, and the staging and survival of invasive cervical carcinoma.
Precancerous lesions
- Certain non-neoplastic conditions and some benign neoplasms carry a well-defined increased malignancy risk.
- Precancerous lesions are sites of cellular proliferation with genetic alterations, probably reflecting changes in precursor adult stem cells.
- Epithelial lesions range across a spectrum from mild dysplasia to the most severe end, carcinoma in situ.
- Not all precancerous lesions progress to invasive cancer; some regress.
- Because they are usually small and non-invasive, they rarely cause symptoms or show on serum markers, but they have the greatest chance of cure.
- Carcinoma-in-situ occurs across organ systems (non-exhaustive): skin (squamous cell carcinoma in situ/Bowen’s disease; basal cell carcinoma in situ), genitourinary tract (cervical CIN I-III; bladder carcinoma in situ; penile intraepithelial neoplasia PeIN; vulvar/vaginal intraepithelial neoplasia VIN; prostatic intraepithelial neoplasia; anal intraepithelial neoplasia AIN), breast (ductal carcinoma in situ DCIS, in the milk ducts; lobular carcinoma in situ LCIS, in the lobules, which some experts do not consider cancer but treat as a risk marker), and the digestive tract (oral intraepithelial neoplasia; Barrett oesophagus, a precursor to adenocarcinoma; oesophageal squamous cell carcinoma in situ; colorectal carcinoma in situ, often in adenomatous polyps or flat lesions).
UV carcinogenesis and skin precursor lesions
- UV light’s cellular effects: inhibition of cell division, inactivation of enzymes, induction of mutations, and, at sufficient dose, cell death.
- UVB’s carcinogenicity is attributed to formation of pyrimidine dimers in DNA, repaired by the nucleotide excision repair (NER) pathway.
- NER has two sub-pathways: global genome repair and transcription-coupled repair. Both converge on recognition of the lesion (XPC, or stalled RNA polymerase II via CSA/CSB), assembly of the TF_IIH complex (XPB/XPD/XPG/XPA/RPA), excision of the damaged strand, and gap-filling synthesis/ligation (PCNA/POL/RFC/ligase) to restore the double helix.
- If NER is overwhelmed, DNA damage remains unrepaired, causing large transcriptional errors and, in some instances, cancer. As with other carcinogens, UVB causes mutations in oncogenes and tumour suppressor genes; mutant RAS and p53 have been detected in both human skin cancers and UVB-induced mouse skin cancers.
- Xeroderma pigmentosum: autosomal recessive, extreme photosensitivity, up to 10,000-fold increased skin cancer risk in sun-exposed skin. At least seven variants, each from a mutation in a different NER gene.
- Solar (actinic) keratoses are progressively dysplastic epidermal changes that precede overt malignancy and are confined by the basement membrane. Not all progress to skin cancer, but enough do to warrant local eradication (treatment: gentle curettage, freezing, or topical chemotherapeutic agents). Degree of risk depends on the type of UV rays, intensity of exposure, and quantity of light-absorbing melanin in the skin; exposure to ionising radiation, hydrocarbons and arsenicals can induce similar lesions.
Skin cancers
UV exposure increases the incidence of:
- Cutaneous squamous cell carcinoma (cSCC): common and curable, but metastasises. Risk factors: age, sex, UV exposure (professional/recreational), skin phototype, immunosuppression, genetic syndromes, viral infections. Histology shows invasive squamous nests with keratin pearls.
- Basal cell carcinoma (BCC): risk factors modify DNA structure with direct effects on transcription - age, sex, UV exposure, skin phototype, genetic syndromes, immunosuppression, pharmacological therapy/radiotherapy, family history of skin tumours. Histology shows a well-circumscribed basaloid tumour nest with peripheral palisading of nuclei.
- Malignant melanoma of the skin, with subtypes:
- Superficial spreading melanoma - most common, linked to severe sunburns at an early age.
- Nodular melanoma - nodular, with no epidermal component.
- Acral lentiginous melanoma - palms, soles, nail bed; not associated with UV exposure; accounts for about 50% of melanoma in non-Caucasian populations.
- Lentigo maligna - flat, occurs on sun-exposed skin in the elderly, associated with lifetime chronic sun exposure.
- Amelanotic melanoma - non-pigmented, under toenails.
- Australia and NZ have the highest and increasing rates of skin cancer.
- Melanoma warning signs (ABCDEFG): Asymmetry, Border irregularity, Colour variation, Diameter increase, Evolution/elevation, Firmness, Growth.
HPV biology and the transformation zone
- The cervix: endocervix is lined by columnar cells, exocervix by squamous cells. The transformation zone lies between the “original” squamocolumnar junction (SCJ) and the “current” SCJ, and is where HPV infection and dysplastic change typically begin.
- Oncogenic HPV genomes integrate into and form stable associations with the host cell genome, and can remain latent for years.
- Viral proteins drive neoplastic transformation by inactivating tumour suppressor gene products and activating oncogenes.
- HPV is found in over 95% of squamous cell carcinoma cases: HPV-16 (~50%), HPV-18 (~20%), with HPV-31, 33 and 35 much less frequent.
- Low-risk HPV types (e.g. 6, 11, 42, 44, 53, 54, 62, 66) are associated with condylomata; high-risk types (e.g. 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68) are associated with cervical cancer.
- E6 and E7 mechanism: E6 binds and degrades p53 (among many other binding partners, mostly with anti-apoptotic effects and deregulation of the cell cycle/differentiation); E7 binds and inhibits pRb (among other partners), releasing E2F and activating S-phase genes.
- Normal DNA-damage response: TP53 is activated by DNA damage/hypoxia, upregulates p21 (CDK inhibitor, causing G1 arrest) and GADD45 (DNA repair); repair either succeeds (normal cells) or fails, triggering BAX-mediated apoptosis. In TP53-mutant cells, DNA damage triggers neither cell cycle arrest nor repair, so mutant cells expand and accumulate further mutations, forming a malignant tumour.
- E6 inhibits p53/BAK (reducing apoptosis) and activates telomerase and SRC kinases (increasing proliferation); a p16-mediated feedback loop via E2F release can still promote cell death. E7 inhibits pRb (releasing E2F, driving proliferation), inhibits p21/27, and activates Cyclin A/E (proliferation) and centriole amplification (aneuploidy). Both arms converge on cell immortalisation; p16 forms a negative feedback loop onto both E6 and E7.
- Resulting morphology: HPV infection causes epidermal hyperplasia of the squamous epithelium, with koilocytes (virally infected squamous cells with a perinuclear halo and irregular nucleus) in the superficial/intermediate zone, and papillomatous (exophytic, finger-like) proliferation - the basis of condylomata/warts. Different HPV types cause the common skin wart versus genital warts.
Natural history and grading of cervical dysplasia
- Natural history of HPV infection: exposure -> acute infection with viral replication -> either (a) subclinical, self-limiting infection with viral clearance, or retention of HPV genomes as latent infection with possible reactivation under immunosuppression; or (b) clinically evident infection (condylomata, CIN 1) -> persistent infection (with co-factors) -> high-grade cellular dysplasia (CIN 2/3) -> carcinoma in situ -> invasive cancer.
- Approximate timeline: initial HPV infection (0) branches at 3-6 months to persistent infection or CIN 1 (either can revert to cleared infection); persistent infection progresses to CIN 2/3 at 4-5 years (with added viral, host and environmental co-factors); CIN 2/3 progresses to cervical cancer at 9-15 years.
- Two parallel naming/classification systems exist:
- Cytology (Pap smear): LGSIL (low grade) vs HGSIL (high grade) vs invasive carcinoma.
- Histology (colposcopy biopsy): cervical intraepithelial neoplasia, CIN 1 -> CIN 2 -> CIN 3 -> cancer, with increasing full-thickness replacement of the epithelium by atypical cells (at CIN 1, infectious viral particles bud from superficial cells above the basement membrane).
- HPV risk type correlates with cytology grade (low risk vs high risk).
- The non-invasive (precancerous) stage may last as long as 20 years, or as little as several months. These changes are a continuum with indistinct boundaries; they do not invariably progress and may spontaneously regress, with risk of persistence/progression increasing with severity.
Diagnosis of cervical dysplasia
Three methods:
- HPV swab for viral presence (including a self-swab: insert and rotate for 30 seconds, then seal and label).
- Pap smear: sample collected via speculum with a spatula/brush, transferred to a slide and fixed; cytology looks for clusters of atypical squamous cells.
- Colposcopy, allowing a biopsy to be taken; cervical changes on biopsy progress Normal -> LSIL -> HSIL -> cervical cancer, with increasing epithelial disorganisation and eventually full-thickness involvement at the invasive stage.
Invasive cervical carcinoma
- Squamous cell carcinoma is the most common type, showing nests of malignant squamous cells with keratin pearls infiltrating stroma with an inflammatory infiltrate.
- Adenocarcinoma is the second most common subtype (about 15-20% of cervical cancers), arising within glands in the endocervix, with irregular, crowded glands lined by atypical columnar epithelium infiltrating stroma.
- FIGO staging reflects increasing tumour extent: IA (IA1, IA2 - microscopic disease confined to the cervix), IB (IB1 <=4cm, IB2 >4cm - visible cervical tumour), IIA/IIB (extension into upper vagina/parametrium), IIIA/IIIB (extension to lower vagina and/or pelvic sidewall), IVA (extension into bladder/rectum), IVB (distant organ spread).
- Five-year survival by stage: stage IA at least 95%; stage IB 80-90%; stage II 75%; stage III and higher 50%.
- Most stage IV deaths result from local extension (e.g. into the urinary bladder and ureters, causing ureteral obstruction, pyelonephritis and uraemia) rather than distant metastases.
- Historically (50 years before this lecture), cervical carcinoma was the leading cause of cancer death in women in the US; the death rate has since declined by two-thirds to the eighth leading cause of cancer mortality.
Fifty years ago cervical cancer was the leading cause of cancer death in US women; screening (HPV testing, Pap smear, colposcopy biopsy) and treatment of the precancerous stage have cut mortality by two-thirds.
Summary
- Skin cancer includes neoplasms differentiated towards epithelial cells (cSCC, BCC) and towards melanocytes (malignant melanoma).
- cSCC and BCC have solar keratoses as a precancerous form.
- Melanoma has precancerous naevi and a radial growth phase.
- Cervical cancer has a precursor stage screenable by HPV testing and Pap smear, confirmed by colposcopy biopsy.
- All these cancers have treatable precancerous forms.
Self-test
- Define a precancerous lesion and explain why such lesions are rarely detected by serum markers.
- Describe the mechanism by which UVB causes skin cancer, including the role of the NER pathway.
- Explain why xeroderma pigmentosum patients have such a markedly increased skin cancer risk.
- List the five subtypes of malignant melanoma described, with one distinguishing feature of each.
- Distinguish cutaneous squamous cell carcinoma from basal cell carcinoma in terms of histological appearance.
- Describe the location and significance of the cervical transformation zone.
- Describe the steps by which HPV E6 and E7 proteins drive cervical cell immortalisation.
- Explain what happens to a cell’s response to DNA damage when TP53 function is lost.
- Describe the natural history of HPV infection from exposure to invasive cervical cancer, including the approximate timescale.
- Distinguish the cytological (Pap smear) and histological (CIN) classification systems for cervical dysplasia.
- List the three methods used to diagnose cervical dysplasia.
- Distinguish squamous cell carcinoma from adenocarcinoma of the cervix in terms of frequency and site of origin.
- What is the approximate 5-year survival rate for stage IA versus stage III or higher cervical cancer?
- Why do most stage IV cervical cancer deaths result from local extension rather than distant metastasis?
Answers
Reveal answers
- A precancerous lesion is a site of cellular proliferation with genetic alterations, probably reflecting changes in precursor adult stem cells, that carries a well-defined increased risk of malignancy; because such lesions are usually small and non-invasive they are unlikely to cause symptoms or be detected via serum markers, though they have the greatest chance of cure.
- UVB causes pyrimidine dimers in DNA. These are normally repaired by the nucleotide excision repair (NER) pathway (global genome repair or transcription-coupled repair, converging on lesion recognition, TF_IIH assembly, excision and gap-filling/ligation). If NER is overwhelmed, damage remains unrepaired, causing large transcriptional errors and mutations in oncogenes and tumour suppressor genes (e.g. RAS, p53), leading to cancer.
- Xeroderma pigmentosum is caused by mutations in genes required for the NER pathway, so UV-induced DNA damage cannot be repaired, giving up to a 10,000-fold increased risk of skin cancer in sun-exposed skin.
- Superficial spreading (most common, linked to severe early-life sunburn); nodular (no epidermal component); acral lentiginous (palms/soles/nail bed, not UV-related, ~50% of melanoma in non-Caucasian populations); lentigo maligna (flat, sun-exposed skin of the elderly, chronic sun exposure); amelanotic (non-pigmented, under toenails).
- cSCC shows invasive nests of squamous cells with keratin pearls. BCC shows a well-circumscribed basaloid tumour nest with peripheral palisading of nuclei.
- The transformation zone lies between the original and current squamocolumnar junctions, where columnar endocervical epithelium meets squamous exocervical epithelium; it is the site where HPV infection and dysplastic change typically begin.
- E6 binds and degrades p53 and BAK (reducing apoptosis) and activates telomerase and SRC kinases (increasing proliferation). E7 binds and inhibits pRb, releasing E2F and driving S-phase gene expression, and inhibits p21/27 while activating Cyclin A/E (proliferation) and centriole amplification (aneuploidy). Both pathways converge on cell immortalisation.
- Normally, DNA damage activates TP53, which upregulates p21 (G1 arrest) and GADD45 (DNA repair), leading to successful repair or, if repair fails, BAX-mediated apoptosis. Without functional TP53, damage triggers neither arrest nor repair, so mutant cells survive, expand and accumulate further mutations, forming a malignant tumour.
- Exposure to HPV leads to acute infection; this either resolves (subclinical, self-limiting, viral clearance, or latent with possible reactivation) or becomes clinically evident (condylomata, CIN 1) and persistent, progressing through high-grade dysplasia (CIN 2/3) to carcinoma in situ and then invasive cancer. Approximate timescale: CIN 1 or clearance by 3-6 months, CIN 2/3 by 4-5 years, cervical cancer by 9-15 years.
- Cytology (Pap smear) grades LGSIL (low grade) versus HGSIL (high grade) versus invasive carcinoma. Histology (colposcopy biopsy) grades CIN 1, 2, 3 through to cancer, based on the proportion of full epithelial thickness replaced by atypical cells.
- HPV swab (for viral presence), Pap smear (cytology), and colposcopy with biopsy.
- Squamous cell carcinoma is the most common type, arising from the squamous exocervix. Adenocarcinoma is the second most common (15-20% of cases), arising within glands of the endocervix.
- Stage IA: at least 95% 5-year survival. Stage III and higher: about 50%.
- Because the tumour tends to extend locally into the bladder and ureters, causing ureteral obstruction, pyelonephritis and uraemia, which are the usual cause of death, rather than distant metastatic spread.