Cervical Cancer
Basics:
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Cervix is divided into:
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Exocervix.
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Transformation zone (squamou- columnar junction).
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Endocervix.
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Tumor suppressor proteins:
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P53:
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Function: Governs G1, apoptosis, and halts progression when DNA is damaged.
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Retinoblastoma (RB):
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Regulates the cell division by E2F-1.
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Figure 1: Cervical zones
Incidence:
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Second MOST COMMON malignancy in females and the third common overall.
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Low incidence in Saudi women, suggesting low prevalence to HPV infection.
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Due to environmental, cultural and genetic factors.
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Incidence is progressively decreasing in the developed countries.
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Due to effective screening.
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Higher incidence in developing countries: No easy access to health care.
Types:
Cervical Cancer Types
Squamous cell
carcinomas (75%)
(most common)
Adenocarcinomas & mixed adenosquamouscarcinomas
(20%)
2nd most common
Small cell neuroendocrine
carcinomas (< 5%)
Risk Factors:
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HPV infection (well-established cause of Cervical cancer).
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Persistent HPV infection -> especially type 16 and 18.
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Both squamous cell & adenocarcinoma are related to HPV.
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Early onset of sexual activity.
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Multiple sexual partners OR high risk sexual partner.
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History of vulvar or vaginal lesions.
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Smoking.
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Immunosuppression.
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Oral contraceptive pills.

Molecular Pathology of Cervical Cancer:
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Human Papilloma Virus (HPV):
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Double-stranded DNA virus (Papillomavirus family).
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Transmission:
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Direct skin-to-skin contact (epithelium to epithelium).
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Most common sexually transmitted disease.
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Classified according to DNA sequencing (structure and function of E6 & E7) into:
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High risk: 16,18,31, and 33:
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Give rise to cervical intraepithelial neoplasia (CIN): when DNA is integrated into the host genome.
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Progresses to cancer
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Low risk: 6 & 11:
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Give rise to benign lesions (condylomas): when DNA is located extra-chromosomally (episomally) in the nucleus.
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Replication begins with entry into the cells of the basal epithelial layer then progress to -> the cells on the surface.
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Role of the immune response:
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Primarily through cell-mediated immunity (cytotoxic T-cell).
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Humeral immune response:
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Systemic IgA -> correlated with clearance.
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Systemic IgG -> correlated with persistent HPV infection.
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Role of Genetics in Cervical Cancer:
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Normally: E2 causes modulation of transcription & replication, & down-regulation of oncoproteins E6 and E7.
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When E2 is deleted or inactivated Expression of E6 & E7 oncoproteins will be increased. (Seen mainly in high-grade lesions).
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E6 bind to P53 & inactivate it.
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E7 bind to Rb & inactivate it (by increasing E2F-1 activity).
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Overexpression
of E6 & E7
Inactivation of
p53 and Rb
Increase
proliferation
rate & genomic
instability
Accumalation of
damaged DNA in
the host cells
Transformation
into
cancerous cells
Pathogenesis of Cervical Cancer:
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Initiated by HPV infection of the cervical epithelium (persistent HPV infection).
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Oncogenisity of HPV is related to expression of oncogenes E6 & E7 will bind to p53 & Rb respectively, neutralizing their function.
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The primary lesion begins as Cervical Intraepithelial Neoplasia (CIN):
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CIN I: < 1/3 of the epithelial thickness.
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CIN II: < 2/3 of the epithelial thickness.
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CIN III: less than the entire epithelial thickness.
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CIN IV (carcinoma in situ): involving the entire epithelial thickness.
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CIN II & III are considered the only cervical cancer precursors progressing into CIN IV then true cervical cancer.
High-grade
lesion progression
Integration of the
viral DNA into
the host cells +
E2 deletion.
(increase E6 and E7)
Cervical
Cancer

Figure 2: Sequence of development of cervical cancer
Clinical Presentation:
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Asymptomatic (50% of cases).
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Abnormal vaginal bleeding (postcoital, intermenstrual) -> Most common symptom.
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Vaginal discharge.
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Invasion of the anterior uterine wall into the bladder blocking the ureters.
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Hydronephrosis and post-renal failure is a common cause of death in advanced cervical cancer.
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Investigations:
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History & Clinical examination (lymphadenopathy, pelvic exam..)
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PAP smear (for screening and Diagnosis).
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Colposcopy.
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Cervical biopsy.
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Imaging:
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CT (modality of choice).
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MRI (more sensitive than CT for staging used only if CT was inconclusive).
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Staging:
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It is mainly dependent on the clinical & FIGO criteria.

Figure 3: Simplified FIGO Staging

Treatment:
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Early stages (up to stage IIA) -> surgery:
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IA - Lympho-vascular space invasion: Cone OR simple hysterectomy • Fertility is conserved.
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IA + Lympho-vascular space invasion= Modified radical hysterectomy & Pelvic lymph node dissection (PLND).
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IB, IIA = Radical hysterectomy & Pelvic lymph node dissection (PLND)
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Advanced stages (involvement of parametrium (IIB) and beyond) -> chemotherapy +radiation.
Follow-up & Screening:
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Every 3 months for 2 years THEN every 6 months for 3 years THEN once/year.
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Clinical (examination) + radiological (mainly CT).
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Screening:
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Pap smear is performed at the age of 21 and repeat the pap smear every 3 years until the age of 65.
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Recurrence:
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Management of recurrence:
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Pelvic exenteration or pelvic evisceration.
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Chemotherapy.
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Radiotherapy.
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Ureteral
obstruction
Recurrence
triad
Unilateral
leg edema
Sciatica
Prevention:
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HPV vaccines (Gardasil, and Cervarix) against 16, 18, 6, 11: reducing the risk of developing persistent HPV infection and type-specific cervical dysplasia.
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Effective for 5 years.
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Best to be administered before evidence of sexual exposure to the virus.
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References:
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Sattar H. Fundamentals of pathology. Chicago: Pathoma.com; 2011.
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Cecil R, Goldman L, Ausiello D. Cecil medicine. Philadelphia: Saunders Elsevier; 2008.
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Le T, Bhushan V, Singh Bagga H. First aid for the USMLE step 2 CK. New York: McGraw-Hill Medical; 2010.
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Le T, Bhushan V, Sochat M, Sylvester P, Mehlman M, Kallianos K. First aid for the® USMLE.
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Kumar V, Abbas A, Aster J, Cotran R, Robbins S. Robbins and Cotran Pathologic Basis of Disease.
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Dueñas-González A, Lizano M, Candelaria M, Cetina L, Arce C, Cervera E. Molecular Cancer. 2005;4(1):38.
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Human papillomavirus (HPV) and cervical cancer [Internet]. World Health Organization. 2016 [cited 27 May
2016]. Available from: http://www.who.int/mediacentre/factsheets/fs380/en/
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Burd E. Human Papillomavirus and Cervical Cancer. Clinical Microbiology Reviews. 2003;16(1):1-17.
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367. Cervical Cancer Screening and Prevention [Internet]. Clevelandclinicmeded.com. 2016 [cited 27 May 2016].
Available from: http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/womens-
health/cervical-cancer/ (Figure 2).
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fourstar1cervical cancer - Stages of Cervical Cancer [Internet]. Cancercervical.wikispaces.com. 2016 [cited 27
May 2016]. Available from:
https://cancercervical.wikispaces.com/Stages+of+Cervical+Cancer?responseToken=0a333b7f9475a219ba69a9d 1dc5c8bd3a (Figure 3).
Written by: Roaa Amer and Haifa Al-Issa
Format editor: Hanan AlGhamdi
Reviewed by: Abdullah AlAsaad, Lama Al Luhidan , and Thamir Al Dahmashi