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Cervical Cancer

Basics:

  • Cervix is divided into:

    • Exocervix.

    • Transformation zone (squamou- columnar junction).

    • Endocervix.

  • Tumor suppressor proteins:

    • P53:

      • Function: Governs G1, apoptosis, and halts progression when DNA is damaged.

    • Retinoblastoma (RB):

      • Regulates the cell division by E2F-1.

Figure 1: Cervical zones

Incidence:

  • Second MOST COMMON malignancy in females and the third common overall.

  • Low incidence in Saudi women, suggesting low prevalence to HPV infection.

    • Due to environmental, cultural and genetic factors.

  • Incidence is progressively decreasing in the developed countries.

    • Due to effective screening.

  • 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:

  • HPV infection (well-established cause of Cervical cancer).

    • Persistent HPV infection -> especially type 16 and 18.

    • Both squamous cell & adenocarcinoma are related to HPV.

  • Early onset of sexual activity.

  • Multiple sexual partners OR high risk sexual partner.

  • History of vulvar or vaginal lesions.

  • Smoking.

  • Immunosuppression.

  • Oral contraceptive pills.

Molecular Pathology of Cervical Cancer:

  • Human Papilloma Virus (HPV):

    • Double-stranded DNA virus (Papillomavirus family).

    • Transmission:

      • Direct skin-to-skin contact (epithelium to epithelium).

      • Most common sexually transmitted disease.

    • Classified according to DNA sequencing (structure and function of E6 & E7) into:

      • High risk: 16,18,31, and 33:

        • Give rise to cervical intraepithelial neoplasia (CIN): when DNA is integrated into the host genome.

        • Progresses to cancer

      • Low risk: 6 & 11:

        • Give rise to benign lesions (condylomas): when DNA is located extra-chromosomally (episomally) in the nucleus.

    • Replication begins with entry into the cells of the basal epithelial layer then progress to -> the cells on the surface.

    • Role of the immune response:

      • Primarily through cell-mediated immunity (cytotoxic T-cell).

      • Humeral immune response:

        • Systemic IgA -> correlated with clearance.

        • Systemic IgG -> correlated with persistent HPV infection.

Role of Genetics in Cervical Cancer:

  • Normally: E2 causes modulation of transcription & replication, & down-regulation of oncoproteins E6 and E7.

  • When E2 is deleted or inactivated Expression of E6 & E7 oncoproteins will be increased. (Seen mainly in high-grade lesions).

    • E6 bind to P53 & inactivate it.

    • E7 bind to Rb & inactivate it (by increasing E2F-1 activity).

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: ​

  • Initiated by HPV infection of the cervical epithelium (persistent HPV infection).

    • Oncogenisity of HPV is related to expression of oncogenes E6 & E7 will bind to p53 & Rb respectively, neutralizing their function.

  • The primary lesion begins as Cervical Intraepithelial Neoplasia (CIN):

    • CIN I: < 1/3 of the epithelial thickness.

    • CIN II: < 2/3 of the epithelial thickness.

    • CIN III: less than the entire epithelial thickness.

    • CIN IV (carcinoma in situ): involving the entire epithelial thickness.

  • 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:

  • Asymptomatic (50% of cases).

  • Abnormal vaginal bleeding (postcoital, intermenstrual) -> Most common symptom.

  • Vaginal discharge.

  • Invasion of the anterior uterine wall into the bladder blocking the ureters.

    • Hydronephrosis and post-renal failure is a common cause of death in advanced cervical cancer.

Investigations:

  • History & Clinical examination (lymphadenopathy, pelvic exam..)

  • PAP smear (for screening and Diagnosis).

  • Colposcopy.

  • Cervical biopsy.

  • Imaging:

    • CT (modality of choice).

    • MRI (more sensitive than CT for staging used only if CT was inconclusive).

Staging:

  • It is mainly dependent on the clinical & FIGO criteria.

Figure 3: Simplified FIGO Staging

Treatment:

  • Early stages (up to stage IIA) -> surgery:

    • IA - Lympho-vascular space invasion: Cone OR simple hysterectomy • Fertility is conserved.

    •  IA + Lympho-vascular space invasion= Modified radical hysterectomy & Pelvic lymph node dissection (PLND).

    •  IB, IIA = Radical hysterectomy & Pelvic lymph node dissection (PLND)

  • Advanced stages (involvement of parametrium (IIB) and beyond) -> chemotherapy +radiation.

Follow-up & Screening:

  • Every 3 months for 2 years THEN every 6 months for 3 years THEN once/year.

  • Clinical (examination) + radiological (mainly CT).

  • Screening:

    • Pap smear is performed at the age of 21 and repeat the pap smear every 3 years until the age of 65.

Recurrence:

  • Management of recurrence:

    • Pelvic exenteration or pelvic evisceration.

    • Chemotherapy.

    • Radiotherapy.

Ureteral
obstruction
Recurrence
triad
Unilateral
leg edema
Sciatica

Prevention:

  • HPV vaccines (Gardasil, and Cervarix) against 16, 18, 6, 11: reducing the risk of developing persistent HPV infection and type-specific cervical dysplasia.

    • Effective for 5 years.

    • Best to be administered before evidence of sexual exposure to the virus.

References:

  1. Sattar H. Fundamentals of pathology. Chicago: Pathoma.com; 2011.

  2. Cecil R, Goldman L, Ausiello D. Cecil medicine. Philadelphia: Saunders Elsevier; 2008.

  3. Le T, Bhushan V, Singh Bagga H. First aid for the USMLE step 2 CK. New York: McGraw-Hill Medical; 2010.

  4. Le T, Bhushan V, Sochat M, Sylvester P, Mehlman M, Kallianos K. First aid for the® USMLE.

  5. Kumar V, Abbas A, Aster J, Cotran R, Robbins S. Robbins and Cotran Pathologic Basis of Disease.

  6. Dueñas-González A, Lizano M, Candelaria M, Cetina L, Arce C, Cervera E. Molecular Cancer. 2005;4(1):38.

  7. 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/

  8. Burd E. Human Papillomavirus and Cervical Cancer. Clinical Microbiology Reviews. 2003;16(1):1-17.

  9. 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).

  10. 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

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