Human Papillomaviruses And Cervical Cancer - hsmedlife



Human papillomaviruses (HPV) cause various epithelial cell cancers, in particular cancers of the lower genital tract. This editorial will concentrate on genital cancers, but the mechanisms of induction of cancer at other epithelial sites by the viruses are probably very similar. 

It is over a decade since molecular detection techniques such as Southern blotting ande of premalignant, i.e., cervical intraepithelial neoplasia (CIN) 1-111, and malignant lesions. However, as very sensitive methods of detection such as the polymerase chain reaction (PCR) became available, it appeared that HPV infection was more widespread than previously thought and this led many to doubt the aetiological role of HPV in genital cancers.  

 

A brief review of the sequence of events of HPV testing may clarify some of the misconceptions generated in the early days of HPV clinical research. The detection of HPV infection had to be done by molecular methods so that infection was determined by detection of the viral genome in tissue or cells taken from the lesion, rather than by serology (which allows detection of infection in any area of the body by examination of easily obtainable body fluid) or by the culture of the virus. With molecular techniques like Southern blotting, it was possible to test only biopsy material, which was limited in size, from a few individuals. 

The small amounts of material meant that detection of viral DNA and frequency of infection were under-estimated because the virus tends to propagate at low levels in the epithelium and only a few areas of the vaginal vault can be tested. Furthermore, this was the first time that detection of a viral infection was determined solely by molecular methods and there were several unforeseen complications that led to considerable variability from center to center: specimens varied in size; the conditions of transport to the laboratories performing the tests varied; and storage conditions were never the same.

 

The molecular tests were not standardized in any way and test systems with different levels of specificity were used with variable controls. Another problem was that few HPV types had been cloned and studies were carried out with only HPV 6 and HPV 16. At least 29 genital HPV types are now known, of which types 16, 11, 42-44, 53-55, and 66 are considered low risk (not associated with malignancies), and types 18, 26, 31-35, 51, 52, 56, 58, 59, 61, 67-70 and 73, are intermediate or high-risk types (associated with malignancies). 

In each category, types 6 and 11, and 16 and 18, respectively, are the most common viruses detected. In addition, HPV DNA was detected in what was grossly determined to be normal tissue, although the fi-frequency was low compared to tissue from clinical lesions. 

The result of all this early testing was that while most laboratories showed a good association between the presence of the virus and disease, some did not and so the first doubts about the etiology were born.

 

The technique most commonly used at this time was Southern blotting. This method is very specific, but detects only relatively high levels of viral DNA in tissue specimens; cross-contamination between specimens in the clinic or laboratory is not a problem. With the advent of PCR, the situation changed dramatically and additional. problems arose. PCR is very sensitive and can be specific or non-specific depending on the primers used. 

The sensitivity comes from the fact that very small amounts of viral DNA can be amplified: after 30 PCR cycles, lo9 molecules are produced from one molecule of HPV DNA. This translates to 7 ng of HPV DNA - sufficient to detect by Southern blotting and even enough to clone the genome. 

Cross-contamination of specimens in the clinic or laboratory is a major problem if PCR is used to detect HPV DNA, as the transfer of a small amount of DNA from one specimen to another would be readily amplified. PCR is, nevertheless, invaluable in the right hands, as it can be used on a large number of specimens and is very sensitive and specific. A hybrid capture method

[l] (Diagene Diagnostics, MD, USA) is also very specific. Although it is not as sensitive as PCR

 

[2] it does not have the problems of cross-contamination as it does not rely on amplification of the signal.

 

HPV infection and cervical cancer

 

Cervical cancer is by far the most common genital cancer and is the major cancer-related cause of death among women in developing countries. Results of standardized tests in several countries, including the USA, Brazil, and Costa Rica, have shown a causal association between HPV and cervical cancer

 

These studies, with either PCR or hybrid capture methods, have shown that HPV infection is the single most important risk factor for premalignant and malignant disease of the cervix. However, several other important observations have also been made. A large percentage (up to 40% in one study

 

of young women (18-30 years) are infected. In a separate study

 

in which 26% of 393 women were HPV positive, the persistence of the viral DNA in cytologically normal women was associated with age: 65% of women >30 years and 42% of women <24 years had an infection that persisted for >14 months. In the older age group, there was also a higher level of persistence of oncogenic HPV types.

 

This indicates that low-grade disease will regress in >50% of women within 3-4 years, but that persistence of low-grade lesions (CIN I) increases with age. In addition, as women with the persistent low-grade disease are more likely to progress, some young women, specifically those >30 years, may be at greater risk of disease progression.

 

diagnosed as ASCUS to undergo a colposcopy, thus reducing significantly the load on the colposcopy clinic. A new cytological technique, the ThinPrep method (Cytyc, Boxborough, MA, USA) allows HPV testing and cytology to be performed on the same smear [8]. Cells are collected from the cervix and transported to the laboratory in a liquid medium.

 

A portion of the cells is placed on a slide, stained by a modified Papanicolaou stain, and read. Because only a fraction of the cells is used for cytology the residual cells can be stored and used for other tests, including HPV typing, once a diagnosis of ASCUS has been made. 

The method has been approved by the Food and Drug Administration in the USA for clinical use. What remains to be determined is whether the testing of ASCUS smears for HPV is a cost-effective way of managing this group of patients.

 

 

 

 

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