Module 9 - HPV and Genital Neoplasia Flashcards
Aetiology of CxCa (Cervical Cancer)
HrHPV DNA Immune status - e.g. immune suppression via HIV Smoking Hormones - contraception Vitamin A deficiency Early first sexual intercourse Multiple sex partners
High and Low Risk HPV Types
High risk
- 14 types
- HPV 16 most commonly associated with cx cancer, identified in ~50% of all tumors
- HPV 18 accounts for 10-15% of lesions
- HPV 31, 33, 45 and 58 each account for ~2-5%
Low risk
- all the other types that aren’t high risk
Molecular Biology of HPV
HPV is a double stranded non-enveloped DNA virus Genome contains approx. 8000 base pairs which encode 2 classes of proteins The virus genome exists inside the capsid and harbours 8 overlapping reading frames 6 early (E1 - E6) and 2 late proteins (L1 - L2)
HPV Pathogenesis
Low risk HPV causes exophytic growth
High risk HPV assoc. with malignant phenotype
HPV initially infects the basal layer of squamous epithelium
Viral capsid breaks and releases viral genome particles in the nucleus
HPV Oncogenes
E6 and E7 produced during integration of HPV DNA into the host genome, disrupting the E2 gene
E6 binds and inhibits p53 inhibiting apoptosis
E6 activates telomerase allowing cells to replicate continuously
E7 binds to retinoblastoma protein (pRb) and inactivates transcription factor E2 allowing the cell to evade cell cycle control at the G1/S1 transition phase
HPV Infection
HPV virus infects cells of the basal layer of epithelium at the junction between the vagina and ectocervix
Viral replication includes replication of early proteins E1 and 2 in the basal layers
E6 and 7 expressed at more distant layers
These proteins promote cell proliferation and delay differentiation
As infected cells differentiate into sq cells, the E4 protein and L1 and 2 later proteins are expressed
As dead cells are sloughed off viral particles are released to infect other cells/hosts
P16 Stain
The P16 protein is a cyclin-dependent kinase (CDK) inhibitor that decelerates the cell cycle by inactivating the CDK’s that phosphorylate retinoblastoma (Rb) protein
Marked overexpression of P16 protein, is observed in all cervical cancers and preneoplastic lesions with infection by high and intermediate risk HPV types (16, 18, 33, 52 and 58)
HPV Diagnosis
Clinical
Cytology
Histopathology
DNA genotyping
HPV Diagnosis - Clinical
Gross appearance Coloscopy - exophytic lesions - acetowhite flat lesions - can't visualise the endocervical canal
HPV Diagnosis - Cytology
Koilocyte seen mainly in intermediate and superficial sq cells Dense peripheral polychromatic cytoplasm Cells present singly or in clusters Showing nuclear enlargement and hyperchromasia, multinucleation and binucleation Dyskeratocytes, parakeratosis Pitfalls: - cell changes in inflammation - perinuclear clearing - heavily glycogenated cells - changes in glandular cells not obvious
HPV Diagnosis - Histopathology
Koilocytosis Basal cell hyperplasia Dyskeratosis Accentuated rete pegs and elongated dermal papillae Associated CIN features Atypical immature metaplasia - P16 IHC
Cervical Intraepithelial Neoplasm (CIN)
The abnormal growth of precancerous cells in the cervix
Previously referred to as cervical dysplasia
Mild = LSIL
Moderate = CIN II
Severe = CIN III
Important because if we can recognise precancerous cells on an LBC smear, then we can initiate treatment to prevent the development of CxCa
Biggest Problems with the Cervical Screening Test
Not the missed abnormalities (though these occur)
Not the high cost follow up (though this is significant)
It is the lack of screening be it in developing countries or unscreened women in developed countries
Chromatin
Euchromatin (pale) and Heterochromatin (dark)
Normal nuclei - heterochromatin is finely granular and evenly distributed
CIN nuclei - increased heterochromatin (dark) which becomes clumped and coarse granular
Pitfalls (False Positives) - CIN
Reactive/inflammatory changes Atrophy Metaplastic squamous cells Endocervical cells Endometrial cells and histiocytes Lymphocytes - follicular cervicitis Recent chemotherapy Radiation changes
