Cervical cancer pathophysiology

It is established that human papillomavirus (HPV) is the main cause of development of cervical neoplasia, only high risk strain of HPV can cause cervical cancer among women who are affected. This is because of HPV produced proteins E7 which alters epithelium of cervix mainly at junctional zone between the columnar epithelium of the endocervix and the squamous epithelium of the ectocervix.

High risk strains of HPV, mainly HPV types 16 and 18 had been identified as a potent cause of cancer of cervix. HPV plays main role in pathogenesis of cervical cancer and it is widely related to disrupting cell cycle growth and regulations, summary of these include:^[1]

• The high risk HPV E6 and E7 gene products which are involved in viral replication and oncogenesis bind to p53 and prevents its normal activities which is G1 arrest, apoptosis, and DNA repair.

• HPV enters the host cell which are squamous cells of epithelium in cervix, mainly in the junctional zone, between the columnar epithelium of the endocervix and the squamous epithelium of the ectocervix and that is how viral transcription and replication begins.
• HPV infection of the basal layer of epithelium takes place by attachment via different mechanism of entry, this happens by cell surface heparan sulfate, stabilizing proteoglycans and Integrin.

There are other cofactors that cause progression of cervical neoplasia, some of these include:^[2][3][4]

• HLA type
• Immunosuppression, since response to HPV infection is cell mediated.
• Use of oral contraceptives had been identified to play an important role in
• Smoking which disrupts immune response.
• History of promiscuous sexual activity in male partner
• Early age sexual activities
• Co-infection with herpes simplex virus type 2, cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), and HHV-7, which cause promotion of infection with HPV and plays an initiation role.

• IL-1β, encoded by the IL–1B gene, is an inflammatory cytokine and part of the innate immune system.^[5][6]
• TNF-α, encoded by the TNFA gene, is another potent pro-inflammatory cytokine that has been implicated in the control of HPV infection.
• Polymorphisms within HLA plays a role in pathogenesis of cervical neoplasia.
• Interleukin-12 A and B gene (IL12A and IL12B)
• IFN-γ, encoded by the IFNG gene has defensive role against viruses and induces immune mediated inflammatory responses.
• Interleukin-10: the risk and the progression of cervical cancer have been associated with increased IL-10 serum levels.
• Cytotoxic T-lymphocyte antigen-4
• HPV E6/E7 oncogenes, proteins that interfere with cell cycle growth and tumor supressor genes.
• Primary microRNA-218 (pri–miR–218) and laminin-5 β3 (LAMB3).

Conditions associated with cervical cancer include:^[7]

• Enterovaginal, rectovaginal, and vesico- or ureterovaginal fistulas
• Renal failure and/or uremia
• Stress incontinence
• Loss of libido
• Vaginal atrophy and dryness
• Early menopause
• Malnutrition
• Osteoprosis
• Anemia
• depression

Gross pathological changes can be visualized by colposcopy and biopsy and application of a 3% acetic acid solution on biopsy speciemen and inspection under bright filtered light microscopy with 10 to 15 fold magnification. Findings in gross pathology of patients with cervical cancer include:^[8]

• Acetowhitening
• Characteristic vascular pattern of dysplasia or carcinoma

Microscopic morphology of low‐grade squamous intraepithelial lesions (CIN 1) include:^[9]

• Presence of koilocytosis (perinuclear cytoplasmic clearing with peripheral condensation of the cytoplasm)
• Irregular nuclear contours, either binucleation or/and multinucleation
• Hyperchromasia and/or cellular pleomorphism
• Mild dysplasia

High‐grade dysplasia (CIN 2 and 3) is characterized by the following features:

• Loss of maturation
• Nuclear crowding
• Loss of nuclear polarity
• Prominent cytonuclear atypia, increase in nuclear‐to‐cytoplasmic ratios
• Irregular nuclear contours and coarse chromatin.
• Increased proliferation and mitotic changes in the upper part of the epithelium.
• In CIN2, most cytonuclear abnormalities are seen in the lower and middle third of the epithelium.
• CIN3 characteristic features include:
  • Full‐thickness cytonuclear atypia
  • Minimal to absent maturation
  • Numerous mitotic activities

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