Pathogenesis of Papillomaviruses Infection
1. Clinical Manifestations
2. Association with Cervical Cancer
The association between certain strains of HPV and cervical cancer is well known. In the West, cervical cancer is the fourth most common cancer in women. In developing countries though, it is the most common cancer, with 1/2 million new cases per year. Overall, it is the most common virus associated cancer worldwide, followed by hepatocellular carcinoma, NPC and Burkitt's Lymphoma. There is now compelling evidence for an aetiological role of HPV in cervical and other cancers.
a. Epidemiological Evidence ;- it has been known for a long time that the incidence of cervical Ca. is related to sexual activity. Promiscuous women are far more likely to develop cervical Ca. Nuns rarely get cervical Ca. Several sexually transmitted agents have been implicated including Herpes Simplex. It is now fair to say that evidence of a role for HSV is very slim and now very much discounted.
b. Virological Evidence ;-
It must be borne in mind that other factors are involved in the tumourigenesis of cervical Ca ;-
3. Association with tumours in immunocompromised individuals
10% of the general population have warts at any one time but warts and skin cancers are much more common and of a greater problem in immunocompromised patients, in particular renal transplants and people with AIDs. The actual number of people undergoing renal transplant operations have increased gradually in the last 20 years. As survival times increased, it became apparent that many of them are developing serious problems with warts and skin cancers. The problem seems to be related to the maintenance immunosuppressive therapy, which is prescribed to patients as long-term therapy after their operation. Prednisolone and Azothiaprine are the 2 most common immunosuppressants given.
Many renal transplant patients appeared with horrific intractable warts in all parts of the body. The warts could not be controlled by any methods but may respond to the withdrawal of the immunosuppressive therapy. Some of these patients with warts progressed onwards to malignancy in many parts of the body at once. Several factors are known to contribute to malignancy ;-
- Diminished immunosurveillance
- UV exposure
- Oncogenic effects of the drugs given
- Chronic antigenic stimulation
The longer the graft survives, the more likely that patient will develop warts and skin cancers.
|< 5 years||35%||15%||2%|
|> 5 years||83%||36%||13%|
The widespread appearance of warts in renal transplant patients resembles those found in the condition Epidermaldysplasia Verruciformis (EV). EV is a rare autosomal recessive condition characterized by the appearance of widespread warts on the surface of the body and 30% of the development of squamous cell carcinomas (SCC). Over 20 types of HPV are associated with EV and the HPV DNA exists mainly in the episomal form in the lesions of these patients. In renal graft survivors the ratio of basal cell carcinoma to SCC is 1:15 compared to a ratio of 1:5 for a normal population. The female renal transplant patients are also at a much higher risk of developing cervical Ca., CIN and VIN than the normal population. The precise role of HPV in the causation of skin cancers in the renal-transplant patients is not known. The skin lesions do resemble those of EV on appearance and the DNA of HPV 5 and 8 ( the HPV strains commonly isolated from patients with EV ) are found in 50% of SCC of the renal transplant patients. HPV 5 and 8 may act as inducing agents for the development of skin tumours. In a recent study, it was claimed that the prevalence of anti-HPV 8 Ab is increased in patients with skin tumours ;-
|Basal Cell Carcinoma||40%|
|Squamous Cell Carcinoma||80%|
If the above can be substantiated, then HPV may have a far more sinister role in human cancers than previously thought. It may have a role in inducing the development of skin and other epithelial cancers. It is not clear whether a withdrawal of immunosuppressive therapy will have a beneficial effect on skin cancers. Although some patients with intractable cancer problems have been offered a withdrawal of immunosuppressive therapy. There have been no cases of metastasis from a SCC arising in an ex-renal transplant patient to date.
4. Persistence of HPV infection
There is circumstantial evidence that HPVs may persist in the
squamous epithelium, without producing recognizable lesions, in a
fashion similar to the persistence of polyomaviruses in the
kidney. Up to 42% of allograft recipients develops cutaneous
lesions within a year after transplant. This suggests that
transplanted patients experience either new infections or
reactivation of latent virus. HPV DNA sequences have been found
in biopsies of normal areas of the larynx of individuals who have
had recurrent episodes of laryngeal papillomas.
D. Laboratory Diagnosis
The appearance of warts vary from the scaly flat lesions on the epithelium of individuals with EV, to the aceto-white flat CIN lesion of the cervix. It may be hard to distinguish wart lesions from other lesions such as molluscum. The methods which are in routine use are:
DNA-DNA hybridization and PCR techniques have been developed in research laboratories. The Southern blot is the most sensitive and specific hybridization technique but is labor-intensive and time-consuming. Dot-blot is available in commercial kits and is as sensitive as Southern blot but not as specific, being unable to distinguish between cross-reacting closely related viruses. RNA probes are more sensitive than DNA probes because of the stability of the RNA-RNA or RNA-DNA hybrids compared to DNA-DNA hybrids. Commercial high sensitivity hybridization assays such as the Digene hybrid capture will detect HPV types that are associated with cervical cancers from biopsies of genital lesions. However, the usefulness of these tests in a histopathological setting remains controversial and more research is required.
E. Management and Prevention
Although they are a cosmetic nuisance in most cases, warts are notoriously difficult to treat. The treatments which could be used include cryotherapy with liquid nitrogen, podophyllin (an antimitotic agent), lasers (for mucosal lesions such as CIN), electrodiathermy, and surgery. Interferon has been used successfully to treat recurrent laryngeal warts and CIN. However, the cost of the treatment may prove to be prohibitive. Precancerous CIN-2 and CIN-3 lesions should be treated by lasers, electrodiathermy, or surgery. In the case of immunocompromised patients with intractable warts, improvement is often seen. There are mass screening programs for CIN and cervical cancers in a number of countries. Being one of the most common cancers in women, a vaccine against HPV types associated with cervical cancers would be desirable and research is being carried out in this area.