Etiopathogenesis of cervical carcinoma

ETIOPATHOGENESIS OF CERVICAL CARCINOMA

Human Papilloma virus is currently considered to be the most important agent in cervical oncogenesis.
50% of virus after infection is cleared with in 8 months and 90% with in 2 years
Clearance depends upon HPV type and immune status
Increased persistence of virus is associated with risk of developing malignancy
Risk factors for cervical neoplasia

    – Early age at first intercourse

    – Multiple sexual partners

    – Increased parity

    – A male partners with multiple previous sexual partners

    – The presence of cancer associated HPV

    – Certain HLA & viral subtypes

    – Exposure to oral contraceptives & nicotine.
HPV cannot infect mature squamous epithelium covering ectocervix, vaginal mucosa and vulva
Establishment of HPV infection requires damage to the surface epithelium, which allows the virus access to the immature cells in the basal layer epithelium.
Immature metaplastic squamous epithelium is also vulnerable to HPV infection.
Although HPV infects immature squamous cells, viral replication occurs in maturing squamous cells
Ability of HPV to act as carcinogen depends upon the viral protein E6 and E7 which interferes with the activity of tumor suppressor proteins that regulate cell growth and survival
Viral E7 protein
- binds the hypophosphorylated (active) form of RB and promotes its degradation via the proteasome pathway
- binds and inhibits p21 and p27, two important cyclin dependent kinase inhibitors
- Removal of these controls not only enhances cell cycle progression, but also impairs the ability of cells to repair DNA damage.
Viral E6 protein
- Binds to tumor suppressor protein p53 and promote its degradation by the proteosome
- This causes defect in DNA repair
- It upregulates the expression of telomerase which leads to cellular immortalization
Viral protein E5 is responsible for koilocytic change i,e. perinuclear halo
Types of HPV
- Low risk HPV (6,11, 42, 44) – These viruses leads to lesions like Warts and condyloma accuminata. they rarely lead to invasive carcinoma
- High risk HPV (16, 18, 31 33, 35) – These viruses leads to carcinomas
The physical state of virus differs in different lesions
- In cancers viral DNA is integrated with host DNA. This configuration increases the expression of E6 and E7 genes, and may also dysregulate oncogenes near the sites of viral insertion
- In precancerous conditions like Condylomata viral DNA is present in episomal form (extrachromosomal form).

HPV infection may clear or may progress to intraepithelial lesion. This lesion may exist in the non-invasive stage for as long as 20 years & shed abnormal cells that can be detected on cytologic examination by Papanicolaou smear screening

Reference

Lora Hedrick Ellenson, Edyta C pirog. The Female genital tract. In:Robbins and Cotran Pathologic basis of disease.2015. 9 edition. volume II.pg 991-1042

ETIOPATHOGENESIS OF CERVICAL CARCINOMA

Human Papilloma virus is currently considered to be the most important agent in cervical oncogenesis.

50% of virus after infection is cleared with in 8 months and 90% with in 2 years

Clearance depends upon HPV type and immune status

Increased persistence of virus is associated with risk of developing malignancy

Risk factors for cervical neoplasia

– Early age at first intercourse

– Multiple sexual partners

– Increased parity

– A male partners with multiple previous sexual partners

– The presence of cancer associated HPV

– Certain HLA & viral subtypes

– Exposure to oral contraceptives & nicotine.

HPV cannot infect mature squamous epithelium covering ectocervix, vaginal mucosa and vulva

Establishment of HPV infection requires damage to the surface epithelium, which allows the virus access to the immature cells in the basal layer epithelium.

Immature metaplastic squamous epithelium is also vulnerable to HPV infection.

Although HPV infects immature squamous cells, viral replication occurs in maturing squamous cells

Ability of HPV to act as carcinogen depends upon the viral protein E6 and E7 which interferes with the activity of tumor suppressor proteins that regulate cell growth and survival

Viral E7 protein

binds the hypophosphorylated (active) form of RB and promotes its degradation via the proteasome pathway

binds and inhibits p21 and p27, two important cyclin dependent kinase inhibitors

Removal of these controls not only enhances cell cycle progression, but also impairs the ability of cells to repair DNA damage.

Viral E6 protein

Binds to tumor suppressor protein p53 and promote its degradation by the proteosome

This causes defect in DNA repair

It upregulates the expression of telomerase which leads to cellular immortalization

Viral protein E5 is responsible for koilocytic change i,e. perinuclear halo

Types of HPV

Low risk HPV (6,11, 42, 44) – These viruses leads to lesions like Warts and condyloma accuminata. they rarely lead to invasive carcinoma

High risk HPV (16, 18, 31 33, 35) – These viruses leads to carcinomas

The physical state of virus differs in different lesions

In cancers viral DNA is integrated with host DNA. This configuration increases the expression of E6 and E7 genes, and may also dysregulate oncogenes near the sites of viral insertion

In precancerous conditions like Condylomata viral DNA is present in episomal form (extrachromosomal form).

HPV infection may clear or may progress to intraepithelial lesion. This lesion may exist in the non-invasive stage for as long as 20 years & shed abnormal cells that can be detected on cytologic examination by Papanicolaou smear screening

Reference

Lora Hedrick Ellenson, Edyta C pirog. The Female genital tract. In:Robbins and Cotran Pathologic basis of disease.2015. 9 edition. volume II.pg 991-1042