Cervical histology and aetiology of cervical neoplasia Flashcards
What are the risk factors for cervical precursor lesions?
- Multiple sexual partners
- Young age at first intercourse
- High parity
- Persistent infection of high oncogenic risk HPV, e.g., HPV16 & HPV18 (prevalence increases with age, peaks at about 25)
- Immunosuppression
- Certain HLA subtypes
- Use of oral contraceptives
- Use of nicotine
What are the three parts of the cervix?
The cervix can be divided into three parts:
- ectocervix: comprises the squamous mucosa
- sturdy
- Superficial: polygonal shape, pyknotic nucleus w/o any identifiable chromatin pattern, ample pink cytoplasm containing glycogen
- Intermediate: slightly bigger nucleus with open chromatin
- Parabasal: dark staining with large nucleus but more cytoplasm than basal cells - higher in post-menopausal women when not enough hormones
- Basal: very dark cells that are stem cells - play a role in reproduction ∴ have large nucleus (nucleus > cytoplasm)
- Basement membrane
- squamo-columnar junction: zone of metaplasia from glandular to squamous cells
thus inherently unstable
- this is the site of persistence (i.e. within stem cells) and viral integration of HPV with subsequent carcinogenesis
- Note: this zone is also more prone to infection, trauma, dysplasia and malignancy
- endocervix: glandular mucosa
- tasked with secretion with lubrication, keeps environment moist
- tall columnar cells with basally located smaller nuclei
- apical mucin produces paler zone in apical region
- glands surrounded by stroma
Where does HPV persist in the cervix?
- squamo-columnar junction: zone of metaplasia from glandular to squamous cells
- this is the site of persistence and viral integration of HPV with subsequent carcinogenesis
Discuss the pathogenesis of HPV
- HPVs infect immature basal cells of squamous epithelium, In areas of epithelial breaks or immature metaplasia present in squamo-columnar junction.
- Embed into genome
- Area of investigation
Describe HPV virus and its biology
- 70 distinct types
- Low risk (types 1, 2, 4, 7) causes warts
- High risk (types 16, 18) causes cancers
- DNA type virus, non-enveloped
- To replicate, HPV has to induce DNA synthesis in the host cell
- They infect basal immature cells but replicate in mature non-proliferating squamous cells, where they re-activate mitotic cycle
- Always see pathognomic “Koilocyte-cell” at superficial squamous layer
hybridisation or PCR (to distinguish between them).
What does cervical swab test for?
High-Risk HPV Testing (cervical swab): Detects 13 HR-HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) +/- LR types via hybridisation or PCR.
Distinguish between low and high risk HPV
-
Low-Risk HPV
- Types 6, 11
- Usually exist in circular episomal form in the infected cells
- Usually cause warts +/- low-grade dysplasia (LSIL)
-
High-Risk (Oncogenic) HPV
- At least 13 types (types 16, 18 = 70% of cases): HPV causes almost all cervical cancers
- Capability of integrating into host genome with disruption of cell cycle proteins (carcinogenic)
- Can cause LSIL + at risk of causing HSIL +/- invasive carcinoma depending on other cofactors
- NOTE: BOTH TYPES OF INFECTION ARE USUALLY ASYMPTOMATIC
Describe the pathogenesis of high-risk HPV
- High-risk HPVs inactivate tumor suppressors e.g. p53 and p21, activate cyclins, inhibit apoptosis, and combat cellular senescence.
- E6 and E7 inactivate p53 and activates, then inhibits, RB proteins.
What are some cofactors of the pathogenesis of high-risk HPV?
Cofactors include smoking, COCP, pregnancy, folate deficiency, other infections, immunosuppression, immune factors (cell-mediated), genetics
Describe HIV transmission and transformation of cervix over time
(natural history)
- Epithelium-to-epithelium transmission via shedding of HPV-infected keratinocytes at surface ± auto inoculation
- Productive life cycle is 2-3 weeks
- After 1-2 years, it is persistent, and there is a lack of clearance (CIN1)
- After up to 20 years, HPV-induced malignancy results as a result of oncogene activation and/or integration. Actions of E6 and E7 have perturbed the cell cycle, and all cells have been transformed (CIN2/3)
- Infects basal cells (stem cells) with progressive gene expression as infected cell moves to surface –> invasive carcinoma
Long latency, hence the value of prevention with cervical screening.
Describe the key events of cervical carcinogenesis
- Self-limiting productive viral infections are characterized by HPV DNA loops episomally within the nucleus of squamous cells.
- Integration of HPV DNA into the host squamous epithelial genome is a key event.
- DNA loop opened up, disrupting the normal regulatory sequence of genes in the loop.
- A closely related correlate of HPV DNA integration is PERSISTENCE of infection. i.e. not cleared
- No agreed definition of persistence; operational definition is 1 year.
- HPV DNA tests identify the presence of HPV DNA in exfoliated cells.
- A single HPV DNA test cannot distinguish a self-limiting HPV infection from a persistent infection. (although most self-limiting infections occur in young women)
- HPV is a necessary but not sole cause of cervical carcinoma (accounts for 92-94% of cervical cancers)
- Cladogram shows ancestry of HPV DNA across animals
- High risk strains associated with cervical squamous carcinoma
- Low risk types associated with genital warts
- 10 year lag between developing infection and precursor becoming malignant
Discuss the terminology for histopathology of squamous precursors
- Koilocytosis ~ CIN1 ~ Productive viral infection ~ Episomal (HPV status)
- Mild dysplasia (not really dysplasia) ~ CIN1 ~ Productive ~ Episomal
- Moderate ~ CIN2 ~ Mix of florid pructive viral infection and pre-neoplastic lesion ~ episomal OR integrated
- Severe dysplasia/CIN ~ CIN3 ~ Pre-neoplastic lesion ~ Integrated
- Invasive carcinoma ~ Invasive carcinoma ~ Pre-neoplasticlesion ~ Integrated
Define and describe dysplasia
A clonal, neoplastic process in epithelium that has mutations driving unregulated growth, **with architectural or maturational, and cytologic abnormalities, but is limited by the basement membrane. ^[metaplasia, on the other hand, is the transformation of one differentiated cell type to another differentiated cell type]
Premalignant neoplastic changes to cells that may be due to stress or trauma to epithelium, causing cells to change and adapt.
It is irreversible, therefore it needs removal so that carcinoma does not evolve.
Dysplastic cells are usually large, with irregular nuclei, hyperchromasia, high NCR, pleomorphic and have high mitotic activity.
Discuss histological classification of cervical lesions (Squamous)
- CIN 1/2/3 - Histology
- LSIL/HSIL - Cytology
- CIN1: Involves lower 1/3rd layer of squamous mucosa, mild dysplasia, BM intact
- CIN2: Involves lower 2/3rd layer of squamous mucosa, moderate dysplasia, BM intact
- CIN3: Involves full-thickness layer of squamous mucosa, BM intact
- In SCC - histological classification is CIN3, but BM is breached, and cells branch into underlying connective tissue, with possibility of metastatic spread
- 80% of cervical cancer, adenocarcinoma ~20%
- regular screening is reliable at preventing 80-90% of invasive cancers
Discuss the bethesda system
- A system of terminology of CYTOLOGY
- Koilocytosis and mild dysplasia are the same thing biologically.
- Moderate/Severe Dysplasia/CIS are the same thing biologically.
-
Two Tiers:
- LSIL = Low-grade Squamous Intra-epithelial Lesion - corresponds to productive viral infection
- HSIL = High-grade Squamous Intra-epithelial Lesion - corresponds to CIN2/3 inbiopsy, true pre-neoplastic precursor lesion
Note also:
- normal
- unsatisfactory: no cells, or sample uninterpretable
- ASCUS - abnormal squamous cells undetermine significance: morphologic abnormalities intermediate between N and LSIL- mixture of benign CIN1/2/3 and rarely carcinoma
- ACS - H - abnormal squamous cells - HSIL not excluded - differential diagnosis between N and HSIL
