HPV – Human Papillomavirus

Cervical cancer is the second most common among female cancers. According to the data of the World Health Organization, 510,000 new cases of cervical cancer were diagnosed all over the world in 2006 and 288,000 women died from cervical cancer, and cervical cancer is a health problem especially seen in underdeveloped countries. Despite the existence of widespread cervical cancer screening programs in developed countries, cervical cancer still remains on the agenda as an important health problem. According to the data of the American Cancer Society, 9710 new cases of cervical cancer were diagnosed in the USA in 2006 and 3700 cases of cervical cancer died.In Turkey, the average incidence of cervical cancer detected in the cancer research study conducted in 8 provinces by the Ministry of Health in 2002 is 3.96 per 100,000. According to GLOBOCAN data, approximately 1500 cervical cancers are seen annually in Turkey. It is now accepted that Human Papillomavirus (HPV) infection causes cervical cancer with the effect of some auxiliary factors. 99.7% of cervical cancers contain HPV DNA. While scientific publications emphasize that the presence of HPV is ‘necessary’ for the development of cancer in the cervix, they agree that it is not ‘sufficient’. Such that, when HPV Type 16 infection occurs, the increase in risk rates (Odds ratio-OR) for the development of cervical cancer is calculated as 434 times. Similarly, the increase in risk ratios (OR) for HPV Type 18 is 248 times.

Among genital infections, the role of HPV is gradually increasing. HPV is the most common sexually transmitted disease in the United States. It is claimed that approximately 15% of the population in the USA is infected with HPV, and the lifetime transmission rate of the virus is reported to be 75%. In addition, between 1966 and 1987 in the USA, the number of cases who sought for medical advise for genital warts increased every year, from 70,000 to 360,000 on average annually. The prevalence of HPV-related genital infections raises a second important issue besides cervical cancer.

Virology

HPV is a non-enveloped DNA virus consisting of 72 capsomeres. There are more than 200 types of this virus detected in the skin and mucous membranes, and 40% of them are seen in the anogenital epithelium. They are classified as high risk (HR) and low risk (LR) for the development of cervical cancer according to their detection rates in cervical cancer samples.

Fifteen anogenital HPV types have been identified as high-risk: 16,18,31,33,35,39,45,51,52,56,58,59,68,73,82.

Three HPV types are considered ‘possible’ high risk: 26,53,66.

Low-risk HPV: 6,11



Transmission

The most important risk factor for HPV transmission is sexual activity. The risk of HPV transmission in men and women increases with the number of sexual partners, and the number of previous partners the man and woman have been with is also an important factor. Especially the group that has started sexual intercourse close to the menarche has the highest risk. The problem here is that immature metaplasia present in the active transformation zone in the young woman is much more susceptible to various factors likely to be transmitted by sexual intercourse.

HPV infection is extremely common (80%) in young sexually active women. The peak incidence of HPV occurs between the ages of 20-25 and most of them regress spontaneously. Viral clearance occurs in 8-14 months for high-risk HPV types and 5-6 months for low-risk HPV types.

Cervical Carcinogenesis

Immature squamous metaplasia in the cervical transformation zone is the most at risk for malignant transformation. The most active periods of transformation zone metaplasia are fetal period, years following puberty and pregnancy period.

The main clinical stages of genital HPV infection are; 1. Latent, 2. Subclinical and 3. clinical periods.

The virus first infects cells in the stratum germinativum close to the basal lamina, which occurs most often in the area of microtrauma related to sexual intercourse. The genome of the virus leaves the protein coat and enters the nucleus of the cell, where it is located episomally (other than the host DNA). Vascular proliferation and basal cell proliferation begin with basal cell division during wound healing, and a basal intermediate cell hyperplasia occurs with virus replication. Initially, HPV DNA is only in the basal epithelial layer, that is, it remains in the latent period. It can usually become apparent within at least six weeks after contact, sometimes remaining undetected for years. This is true for both high-risk and low-risk types. In the latent period, the disease has no cytological, colposcopic or morphological findings, only HPV DNA can be demonstrated by ultrasensitive PCR techniques. In the subclinical period, there are cytological-microscopic changes due to HPV or lesions that can be seen by applying augmentation methods such as colposcopy. CIN and intraepithelial neoplasms are generally examples of this period. The period in which visible lesions and symptoms such as genital condyloma or invasive cancer are present is also called the clinical period.






With the loss of immunological control, the virus genome is replicated, with the effect of growth factors, epithelial proliferation; acanthosis (intermediate cell hyperplasia) and hyperchromasia occur. Normally, CIN is a subclinical infection and capillary and stromal proliferation is not at a level to make a visible condyloma. However, in 30% of the cases, this proliferation is excessive and a visible exophytic condyloma may develop in the cervix. In the upper layers of the epithelial layer, “koilocytosis” with the characteristic finding of HPV occurs (Koilos means space in Greek). Koilocytes are dead or dying stratum granulosum cells that can not show malignant transformation. The koilocyte nucleus is hyperchromatic because it is irregular and filled with virus particles. The vacuole is located just above the nucleus in the cytoplasm. These koilocytes are actually the markers of HPV infections in the low risk group.

Cellular HPV infection can be observed in two different ways. In episomal infection, virally active HPV is located in the cell nucleus, but the viral DNA is separate from human DNA. HPV causing infection can be from high or low risk groups. It can cause clinically abnormal Pap tests and can be seen colposcopically. In integrated infection, the HPV DNA helix is uncoiled and incorporated into human DNA. This situation is observed only with high-risk HPV types. As in episomal diseases, it can cause abnormal Pap tests and is seen colposcopically. It should definitely be treated to prevent cancer that may originate from this infection.

Segments E6 and E7, which play a key role in cell transformation, are responsible for the synthesis of oncogenes in HPV 16 and 18. For cell tumor development, virus DNA often needs to be integrated into the cell DNA. This merger is more common in E1 and E2 regions. As a result, especially the E2 region gene is fragmented and becomes inactive. Losing the function of the E2 section enables the E6 and E7 sections to work actively. This leads to suppression of tumor suppressor genes p53 and pRB, respectively, and ultimately to uncontrolled proliferation and malignant development. In rare cases, it has been reported that HPV DNA may remain episomal without integrating into cell DNA, leading to tumor development.

It is known that approximately 90% of people infected with HPV have viral clearance. No specific time is given for this. However, regression is reported between 4-6 months and 1-2 years. However, 10% of these cases progress to intraepithelial lesion; 1% of these can turn into invasive cancer. It should be considered that all CIN lesions may regress, and patients should be evaluated accordingly during treatment and follow-up.

In the meta-analysis of studies in which cytology was prioritized, it was found that CIN1 cases spontaneously regressed in 57%, persisted in 31%, transformed into CIN 3 in 11% and invasive cancer in 1%. The regression rate for CIN 3 was 32% and the transition to invasion was 12%. It is reported that the transition from CIN 3 to invasive cancer varies between 16-40% by various authors. On the other hand, Nasiell found that the regression from CIN 1 was 62% and the progression to CIN 3 was 16% at the end of the 39-month follow-up. In a more recent meta-analysis, it was shown that LSIL returned to normal in 47%, progressed to HSIL in 21%, and transformed into cancer in 0.15% (25). 50-80% of HSIL lesions were detected in types 16 and 18 . Women infected with HPV 16 and 18 have a higher risk of developing CIN 3 and cancer than other types if they persist.

Permanent infection with high-risk HPV types in all precancerous lesions is a very important risk factor for cervical cancer. Persistence may also be associated with advanced age and immunity (8,21,29). Although long-term viral elimination seems to be a risk factor for carcinogenesis, long-term elimination is not directly related to carcinogenesis. HPV 16 is eliminated in a longer time than other types. A 5-year persistence of HPV 16 infection carries a 40% CIN3 risk. However, HPV 61 is the type that is eliminated in the longest time. However , it is low risk .





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