Pathogenesis

Etiopathogenesis, Diagnosis and Staging of cervical cancerMost common gynecological cancer in women

Most common cancer in women in developing world.

Risk factorsHuman papillomavirus infection (HPV) Primary factorHPV 16, HPV 18, HPV 31, HPV 33, HPV 4550-70% are caused by HPV 16 AND 18Sexual behaviorSmokingHIV infectionChlamydia infectionDietOral contraceptivesMultiple pregnanciesLow socioeconomic statusDiethylstilbestrol (DES)Family history

Pathogenesis

Human Papilloma VirusVirus of Papillomaviridae familySingle copy Double stranded DNAIcosahedralCodes for eight proteins early(E) and late (L) proteinsLCR (Long control region) between E and L regions promotes and enhances the viral gene expression.

Epitheliotropic5 genera alfa, beta, gamma, mu, nuHPV can be identified in >99% of cervical cancers.Necessary but not sufficientMost infections are transient.Persistence of infection is a risk factor.

During HPV infection, the different viral proteins are expressed sequentiallyInfects the basal cell layer (mediated by Heparan sulfate and glycosaminoglycans attachment of virion capsid protein L1)Internalisation via Clathrin coated vesicles Disassembly of virion particles and delivery of Viral DNA into nucleus mediated by L2.Persist as Autonomous replicating extra-chromosomal elements or episomes(most commonly, integration into host DNA seen in high grade CIN/ Carcinoma) Expression of E6 leads mainly to the ubiquitin-dependent proteolysis of p53. &The E7 expression to the liberation of the transcription factor E2F by sequestration of pRb Promote cellular proliferation and genome instability throughout the infected tissue.

E4 binds to zinc, cytoskeleton and cytokeratinsE4 may alter the normal keratinization process to benefit the viral cycle progress and generate a cytoskeleton collapse inducing apoptosis to liberate viral particles.Sequesters the CDK1/Cyc B1 complex onto the cytokeratin network Preventing their nuclear accumulation.Therefore inducing inhibition of the G2/M transition of the cell cycle. Allowing viral and genomic DNA replicationE5 transforming activity is through - Increasing the half-life of the tyrosine kinase-containing growth factor receptors like EGFR, - The phosphorylation state of this receptor or both - Targets molecular components of the MAPKs cascade and prolong S-phase of cell cycle promoting cellular transformation

Screening

Screening and DiagnosisPap smear2 main specimen typesConventionalLiquid based preparationConventionalAdvantages: - Low cost - No specia equipmentDisadvantages: - Lack of uniformity in specimen preparation - Unsatisfactory smearsLiquid basedAdvantages: - Uniformity - Less unsatisfactory samplesDisadvantages: - Higher cost - Special equipment needed

Classification systems

LSIL : Enlarged (>3times normal) dark nuclei, with irregular, thickened nuclear membranes. Koilocytes.

HSIL : Dark nuclei, irregular nulcear membranes, high nuclear to cytoplasmic ratio.

ASCUS : When findings fall short of LSIL

HSILLSILHPV testingUsing hybrid capture 2 and PCR.When combined with Pap smear : - Higher negative predictive value of >95% - Sensitive in detecting High grade dysplasiaHybrid capture technique has excellent interlaboratory reliability and reproducibilityUseful in women >30yrsTesting discouraged below 30yrs.

Sherman et al., Clavel et al.,Screening recommendations

ColposcopyExamination of lower genital tract vulva, vagina and cervical epithelium and opening of endocervix.Acetic acid and Lugols solution(Schillers test) used to highlight abnormal and dysplastic changes

Suspicious lesions biopsied: - Aceto white plaques - Vascular abnormalities punctations, mosaicism, abnormal branchingIndications: Abnormal appearing cervixPersistent post coital bleeding / dischargePersistent CIN 1,2,3 o cytologyIn utero exposure to DESASCUS smears with positive high risk HPV testing

Entire transformation zone must be fully visualised.Endocevical curettage (ECC) can be helpful, routine use is debated

PPV can be increased by multiquadrant biopsiesConization biopsySurgical removal of Squamocolumnar junction - Classical cold knife technique - Thermal cautery with loop excisionIndications: - Inadequate colposcopy - Positive ECC - Persistent CIN 1(>1yr), CIN2,3,or CIS - Discrepancy between Cytologic, colposcopic or pathologic findings

Staging evaluationClinical examination is the predominant tool for staging cervical cancer.Pelvic examination including PV and DRECXR, Cystoscopy, Sigmoidoscopy, Barium enema, Examination under anesthesia are optionalMRI pelvis for tumor diameter, uterine extension, and parametrial extension esp in early cancer.

CECT thorax and abdomenPET / CT for nodal evaluation Most accurate non-invasive method for diagnosis of nodal metastasis (82% sneitivity and 95% specificity)FIGO stagingClinicalFIGO does not incorporate evidence of lymph node metastasis gained by surgical staging or advanced imaging studies in the stage Surgical findings and radiographically guided biopsies of suspected lesions such as LN or lung metastasis cannot be used to modify clinical FIGO staging.If there is ambiguity regarding the correct stage, the lower stage is assigned.