Etiopathogenesis, Diagnosis

and Staging of cervical

 Most common gynecological cancer

in women
Most common cancer in women in
developing world.

Risk factors
Human papillomavirus infection (HPV) Primary factor
HPV 16, HPV 18, HPV 31, HPV 33, HPV 45
50-70% are caused by HPV 16 AND 18
Sexual behavior
Smoking
HIV infection
Chlamydia infection
Diet
Oral contraceptives
Multiple pregnancies
Low socioeconomic status
Diethylstilbestrol (DES)
Family history

Pathogenesis

Human Papilloma Virus

Virus of Papillomaviridae family

Single copy Double stranded DNA
Icosahedral
Codes for eight proteins early(E)
and late (L) proteins
LCR (Long control region) between E
and L regions promotes and
enhances the viral gene expression.

 Epitheliotropic
5 genera alfa, beta, gamma, mu,
nu
HPV can be identified in >99% of
cervical cancers.
Necessary but not sufficient
Most infections are transient.
Persistence of infection is a risk
factor.

 During HPV infection, the different viral

proteins are expressed sequentially
Infects 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 extrachromosomal elements or episomes(most
commonly, integration into host DNA seen in
high grade CIN/ Carcinoma)

Expression of E6 leads mainly to the ubiquitindependent 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 cytokeratins

E4 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 replication

 E5 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 Sphase of cell cycle promoting cellular
transformation

Screening

Screening and Diagnosis

Pap smear
2 main specimen types
- Conventional
- Liquid based preparation

 Conventional
Advantages:
- Low cost
- No specia
equipment
Disadvantages:
- Lack of uniformity
in specimen
preparation
- Unsatisfactory
smears

Liquid based
Advantages:
- Uniformity
- Less unsatisfactory
samples
Disadvantages:
- 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

LSIL

HSIL

HPV testing
Using hybrid capture 2 and PCR.
When combined with Pap smear :
- Higher negative predictive value of >95%
- Sensitive in detecting High grade dysplasia
Hybrid capture technique has excellent
interlaboratory reliability and reproducibility
Useful in women >30yrs
Testing discouraged below 30yrs.
Sherman et al., Clavel et al.,

Screening recommendations

Colposcopy
Examination 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 branching

 Indications:
- Abnormal appearing cervix
- Persistent post coital bleeding /
discharge
- Persistent CIN 1,2,3 o cytology
- In utero exposure to DES
- ASCUS 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 biopsies

Conization biopsy
Surgical removal of Squamocolumnar junction
- Classical cold knife technique
- Thermal cautery with loop excision
Indications:
- Inadequate colposcopy
- Positive ECC
- Persistent CIN 1(>1yr), CIN2,3,or CIS
- Discrepancy between Cytologic,
colposcopic or pathologic findings

Staging evaluation
Clinical examination is the predominant
tool for staging cervical cancer.
- Pelvic examination including PV and DRE
- CXR, Cystoscopy, Sigmoidoscopy,
Barium enema, Examination under
anesthesia are optional
- MRI pelvis for tumor diameter, uterine
extension, and parametrial extension
esp in early cancer.

 CECT thorax and abdomen

PET / CT for nodal evaluation
Most accurate non-invasive method for
diagnosis of nodal metastasis (82% sneitivity and
95% specificity)

FIGO staging
Clinical
FIGO 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.