Infectious Disease Online
Role of Human Papillomavirus in Cervical Cancer
Human papilloma virus (HPV) infection is the major etiological
factor in uterine cervical carcinogenesis.
Epidemiological evidence indicates that the majority of cervical neoplasia is due to HPV infections.
Many HPV infections regress and not all non-invasive cervical lesions progress to the full malignant phenotype, suggesting that other co-factors may be required for full neoplastic transformation.
Papillomaviruses are small DNA viruses comprising viral capsid proteins L1 and L2) enclosing a circular double stranded DNA genome.
Low risk Human papilloma virus :
Low risk HPV types (HPV 6, 11, 40, 42, 43, 44) are usually associated with benign exophytic genital warts.
They are also associated with a minority of low grade cervical lesions (‘flat’ condylomas and CIN 1) but are only rarely found in high grade lesions (CIN 2 and 3) and invasive carcinomas.
High risk Human papilloma virus :
By contrast, high risk HPV types are found in the majority of ‘flat’ condylomas, in all grades of CIN and in all grades of CIN and in invasive carcinoma, HPV 16 being the most commonly found HPV type in squamous carcinomas, while HPV 18 is often associated with adenocarcinoma.
The concept of high and low risk HPV is supported by many epidemiological case controlled studies.
These have collectively shown a consistent association between high risk HPV and cervical cancer, and have also led to the distinction between high risk HPVs (HPV 16, 18, 45, 56) and intermediate risk HPVs (HPV 31, 33, 35, 39, 51, 52, 58), based on the relative risk association of these viral types across the spectrum of cervical neoplasia.
Permissive HPV infection occurs when viral infection leads to completion of the vegetative viral replication cycle with production of intact, infectious viral particles.
This process is closely linked to keratinocyte differentiation, with late gene expression and hence capsid protein production occurring in association with terminal differentiation in superficial squamous cells.
If viral replication and production of intact viral particles does not occur, viral DNA may persist as either an extra-chromosomal element or by integration into host DNA.
The later often causes disruption of the of the viral E2 or E1 gene (s) in a manner that results in loss of function of these genes.
This form of infection may be seen also in glandular epithelial cells where vegetative viral production does not proceed as squamous differentiation.
Indeed, there is increasing evidence that glandular neoplasia of the cervix is also Human papilloma virus associated, particularly when it occurs in conjunction with squamous neoplasia.
Recent evidence suggests that viral genes, particularly E2, E6 and E7 are also capable of altering mitotic control, leading to DNA re-replication without intervening mitosis: this is likely to predispose to the development of gross genetic changes involving whole chromosomes (chromosomal instability) and is consistent with the observation that chromosomal aneusomy is common in cervical carcinomas.
There is evidence that a variety of co-factors, including the effects of cigarette smoking, other infectious agents, hormones, immune status, cytokines and growth factors interact with Human papilloma virus infection in cervical carcinogenesis.
When analysed using sensitive, broad-spectrum Human papilloma virus detection methods, the vast majority of cervical carcinomas contain Human papilloma virus sequences.
Whether truly Human papilloma virus negative carcinomas exist is currently a matter of debate as there are several reasons why tumours may falsely appear Human papilloma virus negative.
Conversely, the epidemiological finding that patients with Human papilloma virus negative CIN have a different spectrum of risk factors suggests that at least intra-epithelial disease may arise in the absence of Human papilloma virus infection.
It has become clear that most cervical neoplasia, whether intraepithelial or invasive, is due to Human papilloma virus infection.
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