HPV and Cervical Cancer
Despite the introduction of screening methods that were developed and integrated in 1970s, cervical cancer (CC) is one of the most common types of cancer. 500,000 new cases of cervical cancer are diagnosed, and about 300,000 women die from the disease worldwide each year. In Europe, cervical cancer constantly takes the 2nd place among the most common types of cancer among women aged 15-49 years, and the first place among women aged 15-29 years. Moreover, mild dysplasia dominates in 20-30 years old women, moderate and severe dysplasia dominates at the age of 30-40 years, while invasive cancer dominates in those who are 40-60 years old.
HPV as an Etiological Factor for Cervical Cancer
“The human papillomavirus (HPV) is sexually transmitted virus. There are currently over one hundred known strains of HPV. About thirty of these strains affect both male and female genitalia, causing conditions like genital warts and more seriously, cancer” (Fayed, 2009). Research in the past decade has clearly demonstrated the role of specific types of human papilloma virus (Human papillomavirus) in the etiology of cervical cancer. This is the result of molecular biological studies that have shown the presence of cervical cancer sequences HPV in the tumor tissue, identified nearly 100% using the polymerase chain reaction. Etiological role is also indicated by the results of serological studies, in which the detection of antibodies to various antigens of the virus was associated with an increased risk of this type of cancer. Epidemiological studies have shown that HPV increase the risk of cervical cancer up to 10 or more (up to 100) times. Moreover, populations with a high incidence of cervical cancer have significantly higher HPV infection rate of women compared to the population with a low incidence of the disease. Currently, more than 200 types of human papilloma virus are identified. About 40 types cause various pathologies of the urogenital area. Two thirds of them, including the highly oncogenic HPV 16 and HPV 18 are allocated to the so-called high risk on the basis of their proven etiological role in the occurrence of cervical cancer. “HPV types 16 and 18 have also been found to cause close to half of vaginal, vulvar, and penile cancers” (Watson, Saraiya, Ahmed, 2008). It is shown that HPV 16 and HPV 18 are responsible for 65%-75% of cases of cervical cancer, and HPV types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 or 66 – for the 18% -20% of cases. Emergence of the remaining cases of cervical cancer is apparently caused by infection with other types of the virus. It should be noted that in most countries, 50-60% of cases of cervical cancer is associated with 16th type, in 10-15% with the 18th type, and 4-5% of the cases occur with the 31th and 45th type (each). HPV-6 and HPV-11 are involved in the appearance of warts and genital warts. They exhibit the same rate of about 1% of sexually active men and women. Over the past 30 years, the incidence of warts and genital warts increased by 5 times.
Methods of Infection
Infection with HPV is primarily sexually transmitted and most often is transmitted through the damaged epithelium. Perinatal and oral transmission are not excluded. In infected epithelial viral DNA synthesis prevails in the granular layer, while the expression of late genes and the maturation of virus particles are the most active in the upper layer of the stratum. Virus could live in the genital long enough, causing a particular disease. Within 3 months after the initial infection, pathological changes in the cervix can be observed, but it may take 10-20 years for the emergence of invasive cancer. It is proved that majority of men and women are infected with the virus in the first few years of sexual activity, and the percentage of infected individuals substantially grows over the years.
Infection with the Main High-risk Papilloma Viruses (HPV-16 and HPV-18) is the Main Key of the Development of Cervical Cancer
It should be noted, however, that only a small percentage of infected women have an invasive form of cancer. Although HPV infection is often enough and reaches a high level (75%) for sexually active people, infection is of temporary character in 90%, and after a year, the virus itself disappears under the influence of the immune system. However, about 65% of infected women can detect initial pathological changes in the cervix, which will eventually regress. If the virus can overcome immunological protection and infection is constant, then there are lesions in the cervix of varying severity, including invasive cancer. Particularly, about 10% of infected women have intraepithelial dysplasia (CIN) of the I, II and III degree, the latter is also called carcinoma in situ, which implies that the tumor is limited and does not germinate in the tissue.
Rather high part of population has HPV infection, and relatively rare cases of cervical cancer suggest that this virus is not the only factor required for the development of malignant disease. Other so-called risk factors are also involved in the process of carcinogenesis and its components are important. These are behavioral, social, cultural, and economic factors. In particular, early sexual activity and multiple partners increase the possibility of HPV infection and other sexually transmitted infections. Sexual behavior of men, who are sexual partners of women, is also important from the point of view of women’s risk of contracting the virus. Other factor that may be mentioned is tobacco smoking. It was shown that nicotine and other products of combustion of cigarettes damage cervical mucus, leading to suppression of immune activity of Langerhans cells (dendritic cells). In principle, any impacts, including HIV infection, leading to a weakening of the immune system facilitate the process of infection with HPV, promote activation of previously acquired infection, and, eventually, lead to the appearance of tumors. Chronic use of corticosteroids (e.g., asthma) and combined oral contraceptives can also play an important role in the development of tumors in the cervix.
More and more of actively proliferating cells in woman’s body infected with HPV lead to the changes in a layer of cervical squamous epithelium that could be revealed by cytological examination. This is initially “koylos atypia”, in which nucleus of infected cells are shifted to the side (located eccentrically) coated with perinuclear cytoplasm. In the progression of the disease, squamous epithelium cells begin to change in size and shape, and sometimes changes occur in the nucleus. About 60% of these cases may be subject to regression, 20-35% of cases remain unchanged, and in the remaining 10-15% of cases, there is intraepithelial carcinoma with marked cellular changes. Because the entire epithelium of the stratum corneum is replaced by genetically modified cells, there is a degree of intraepithelial dysplasia III (CIN III) or carcinoma in situ. Breeding complexes squamous cell first penetrate beyond the basement membrane and with the increase of the number of these cells – the true massive infestation can occur. Most often determined by CIN III in women aged 25-29 years, after about 4-7 years after the maximum development of CIN I. In white representatives, invasive cancer occurs about 15 years after the peak of the manifestations of CIN III and is usually diagnosed between the ages of 40-45 years.
Testing for HPV DNA
At present, two tests are developed for the detection of DNA HPV. These are polymerase chain reaction (PCR) and Hybrid Capture II test (HC II), recently approved in the US for the control of the Office of Food and Drug Administration. This test, when used in a screening program carried out in the US for the early detection of cervical cancer, showed a high sensitivity (80-90%) and specificity (57-89%). In recent years, testing for viral DNA is recommended for certain groups of women whose Pap smear test (common method of cytological diagnosis of cervical pathology) gave a positive result. It is believed that the use of the test for viral DNA as part of screening program of cervical cancer in industrialized countries can be justified by longer intervals between screenings. “Getting the HPV test with the Pap test at the same time can safely increase screening intervals up to 5 years for women who do not have HPV and have a normal Pap test result even if they have new sexual partners” (CDC, n. d.). In addition, testing for viral DNA helps refine data cytology, which improves the diagnosis of doubtful cases and identifies asymptomatic patients at high risk of cervical cancer.
Cervical cancer is one of the most common cancers among women. Years of studies have shown that the occurrence of cervical cancer is caused by HPV, the vast majority of the 16th and 18th types. Tumor detection of viral origin scientists has set the next task – to create anti-virus vaccines for the prevention and treatment of cervical cancer. Currently, a series of trials of vaccines are created and various stages of clinical trials as well. The effectiveness of preventive vaccines will become clear, however, only after a few decades, when vaccinated young women (girls) will reach the age of 40-45 years. The deciding factors were: number of sexual partners, and early sexual activity. For the women who had more than 10 partners the risk of cervical cancer was almost three times higher than for women with one constant partner. Early onset of sexual activity (under 16 years) increased the risk by more than 2-fold compared with women who are having sex at age 22 or later. Even then, researchers have suggested that the basis of these factors is infective. Hypothesis of infectious transmission of squamous cell carcinoma of the cervix was confirmed as the data on the effect of sexual behavior of husbands to the risk of cervical cancer for wives. Low incidences of women who support strict monogamy indirectly support this hypothesis. For now, there is no doubt that the key contributor to development of cervical cancer is infection of HPV.