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Human papilloma virus (HPV) infection is the major etiological
factor in uterine cervical carcinogenesis.
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Human Papilloma Virus Associated Epidermal
Lesions
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.
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All HPV types
have a common molecular structure, which allows them to be
classified according to DNA sequence.
To date, 78
HPV types have been described together with a small number of
subtypes and numerous variants.
Each genome
can be divided into early (E) or late (L) regions, containing
seven early and late open reading frames (ORFs), and a non-coding
region.
The early
genes control viral replication and are associated, in the case of
oncogenic viruses, with cellular transformation.
Important
genes are: E6
and E7 genes, the E2 gene, and the L1 gene :
The most
important of these, from the point of view of clinical and
biological investigation, are the E6 and E7 genes, the E2 gene,
and the L1 gene.
The E6 and E7
gene products bind to p53 and Rh-1 proteins respectively, thus
leading to removal of tumour suppressor gene function.
E2 is a
transcriptional regulator and is also involved in viral DNA
replication; disruption of this gene by viral integration or
mutation can lead to enhanced transcription of the E6 and E7
genes.
The L1 gene
is frequently used for molecular HPV typing and encodes the common
papillomavirus antigen which is targeted by antibiotics used in
the immunohistochemical detection of HPV infection.
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Low
risk HPV :
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 HPV :
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 HPV
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 HPV infection in cervical
carcinogensis.
When analysed
using sensitive, broad-spectrum HPV detection methods, the vast
majority of cervical carcinomas contain HPV sequences.
Whether truly HPV
negative carcinomas exist is currently a matter of debate as there are
several reasons why tumours may falsely appear HPV negative.
Conversely, the
epidemiological finding that patients with HPV negative CIN have a
different spectrum of risk factors suggests that at least
intra-epithelial disease may arise in the absence of HPV infection.
It has become
clear that most cervical neoplasia, whether intraepithelial or
invasive, is due to HPV infection.
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