**2. Epidemiology of HPV-associated pathology in Russia and KhMAO-Ugra**

Every year, more than 600,000 new cases of HPV-associated cancer are registered in the world, approximately 90% of which is cervical cancer. According to the statistics of the Russian Center for Information Technology and Epidemiological Research in Oncology of the Herzen Institute (branch of the Federal State Institute "National Medical Research Center of Radiology" of the Ministry of Health of the Russian Federation), in the structure of the incidence of malignant neoplasms of the population of the Russian Federation in 2015, cancers associated with HPV infection accounted for about 10% of the total incidence of cancer, and their total number was about 32,000 cases [6].

In the structure of female cancer incidence, cancers of the anogenital region are presented in different ways. Thus, cervical cancer in the Russian Federation occupies the 5th place (5.2%); cancer of the rectum, rectosigmoid junction, and anus, 6th place (4.6%); vulvar cancer, 20th place (0.6%); pharyngeal cancer (0.2%) and vaginal cancer (0.2%), 25–26th place; and laryngeal cancer—28th place (0.1%) [6].

However, if we consider the structure of oncological diseases of the female reproductive system, cervical cancer takes the second place in prevalence among malignant neoplasms of women under 45 years and the first in the number of lost years of life (the life expectancy of sick women is reduced by 26 years on average). The incidence of cervical cancer is steadily increasing and has increased by 28% on average over the past 10 years [7].

Only in 10 years, the incidence of cervical cancer in Russia has increased by an order of magnitude: from 7.9 per 100,000 of the female population in 2002 to 17.2 in 2012 [7]. In 2018, 17,000 new cases of cervical cancer and 6.6 thousand deaths were registered in the Russian Federation. In 2018, the incidence rate fell slightly to 15.76. Important markers characterizing the neglect of cervical cancer and the quality of treatment are the proportion of patients with advanced tumor process (3–4 stages), as well as the mortality of patients within a year from the moment of diagnosis, which in the Russian Federation in 2018 remained at a fairly high level: 34.6 and 13.8%, respectively. In the structure of disability, 83% of cases in oncogynecology are cervical cancer [8]. The frequent incidence of cervical cancer, the tendency to rejuvenate this pathology, a high percentage of neglected cases, and, as a consequence, the growth of disability among women of working age are a world problem, involving the most active, socially significant part of the female population. The occurrence of cervical cancer in young women is a serious social problem, causing deterioration in health, disability, and reduced fertility.

As for cancers of other localizations, annually in the Russian Federation, about 4000 cases of laryngeal cancer and 3000 deaths, for this reason, are registered. Morbidity and mortality from cancer of the vulva, vagina, anus, and penis in the Russian Federation are not registered, which is obviously due to low diagnosis and underreporting of cases. There are about 100,000 new cases of cancer of these locations in the world every year, and two-thirds of the incidence falls on women [8].

**3**

*The Importance of the Problem of HPV-Associated Diseases in KhMAO-Ugra: Vaccination…*

of the disease, significantly reducing the quality of life of these patients [9].

Cervical cancer in our region occupies the second place in the structure of tumors of the reproductive system of women and the first place in the age category up to 30 years. Precancerous lesions of the cervix are detected more than 6000 cases

The clinical burden of cancer (cervical cancer, vulvar and vaginal cancer, anal cancer) among the female population in our region is up to 300 cases per year, which is relevant within the workload of cancer beds and rationalization of health-care costs. In KhMAO-Ugra, according to the state registration, the incidence of cervical cancer does not tend to decrease: in 2018, it was 14.7 per 100 thousand population and in Russia 15.76. The number of registered women diagnosed with cervical cancer is steadily increasing. Annually in Ugra, about 160–170 cases of cervical cancer are registered for the first time. Among the newly identified cases, every second patient (50.8%) is under the reproductive age of 45 years and every third woman (33.2%) had an advanced stage 3–4 of the disease. About 12–15% of patients with cervical cancer die in the first year of diagnosis. Mortality from this disease in Ugra in 2018 was 6.0 per 100,000 population; in

The standard screening procedure in KhMAO-Ugra, as well as in the world, is the PAP test, the effectiveness of which does not exceed 30–40%. Despite the introduction of modern methods and some progress in diagnosis and treatment,

**3. Study of the expression of oncoprotein E7 in the diagnosis of cervical** 

Infection caused by human papillomavirus occurs in 50–80% of the population and in 99.7% of cases of confirmed cervical cancer and therefore is an important problem of modern health care. First of all, this applies to the pathology of the cervix, which is the most important organ of the reproductive system of a woman. Thus, recent data indicate a fourfold increase in cases of cervical cancer among women under 35 years. The incidence of papillomavirus infection in general has also increased, which occurs in 44% of women who have seen a gynecologist. Against the background of persistent HPV of the urogenital tract, most cervical intraepithelial neoplasms develop, which in 15–20% of cases can end in oncological

Given the high prevalence of papillomavirus infection, the uncertainty of its outcome, it is important to determine the phase of interaction of HPV with the cell. During the reproduction of HPV in the body, there is a persistence of its genome in the episomal form with the production of viral particles. In this phase of reproduc-

**diseases associated with human papillomavirus**

pathology (carcinoma in situ and invasive cancer) [3, 6, 9].

tion, there is a high probability of spontaneous remission [2, 9].

1,659,436 people, of which 851,588 are women and 805,848 are men.

The average annual population of Khanty-Mansiysk Autonomous Region-Ugra is

Anogenital (venereal) warts are the most common clinical manifestation of HPV infection, more than 90% of which are caused by HPV types 6 and 11. In Russia, this pathology is among the five leaders among sexually transmitted infections. It should be emphasized that the level of official registration is significantly different from the true prevalence and the possible true figure of the prevalence of anogenital warts, according to ongoing studies to assess the prevalence, can be more than 1,000,000 cases, which will bring this nosology to the first place in frequency among all recorded genital infections. The lack of specific antiviral therapy, as well as frequent relapses after the use of destructive methods, complicates the treatment

*DOI: http://dx.doi.org/10.5772/intechopen.90668*

per year [10].

2018 54 women died [10].

cancer prevention is still crucial.

### *The Importance of the Problem of HPV-Associated Diseases in KhMAO-Ugra: Vaccination… DOI: http://dx.doi.org/10.5772/intechopen.90668*

Anogenital (venereal) warts are the most common clinical manifestation of HPV infection, more than 90% of which are caused by HPV types 6 and 11. In Russia, this pathology is among the five leaders among sexually transmitted infections. It should be emphasized that the level of official registration is significantly different from the true prevalence and the possible true figure of the prevalence of anogenital warts, according to ongoing studies to assess the prevalence, can be more than 1,000,000 cases, which will bring this nosology to the first place in frequency among all recorded genital infections. The lack of specific antiviral therapy, as well as frequent relapses after the use of destructive methods, complicates the treatment of the disease, significantly reducing the quality of life of these patients [9].

The average annual population of Khanty-Mansiysk Autonomous Region-Ugra is 1,659,436 people, of which 851,588 are women and 805,848 are men.

Cervical cancer in our region occupies the second place in the structure of tumors of the reproductive system of women and the first place in the age category up to 30 years. Precancerous lesions of the cervix are detected more than 6000 cases per year [10].

The clinical burden of cancer (cervical cancer, vulvar and vaginal cancer, anal cancer) among the female population in our region is up to 300 cases per year, which is relevant within the workload of cancer beds and rationalization of health-care costs. In KhMAO-Ugra, according to the state registration, the incidence of cervical cancer does not tend to decrease: in 2018, it was 14.7 per 100 thousand population and in Russia 15.76. The number of registered women diagnosed with cervical cancer is steadily increasing. Annually in Ugra, about 160–170 cases of cervical cancer are registered for the first time. Among the newly identified cases, every second patient (50.8%) is under the reproductive age of 45 years and every third woman (33.2%) had an advanced stage 3–4 of the disease. About 12–15% of patients with cervical cancer die in the first year of diagnosis. Mortality from this disease in Ugra in 2018 was 6.0 per 100,000 population; in 2018 54 women died [10].

The standard screening procedure in KhMAO-Ugra, as well as in the world, is the PAP test, the effectiveness of which does not exceed 30–40%. Despite the introduction of modern methods and some progress in diagnosis and treatment, cancer prevention is still crucial.

### **3. Study of the expression of oncoprotein E7 in the diagnosis of cervical diseases associated with human papillomavirus**

Infection caused by human papillomavirus occurs in 50–80% of the population and in 99.7% of cases of confirmed cervical cancer and therefore is an important problem of modern health care. First of all, this applies to the pathology of the cervix, which is the most important organ of the reproductive system of a woman. Thus, recent data indicate a fourfold increase in cases of cervical cancer among women under 35 years. The incidence of papillomavirus infection in general has also increased, which occurs in 44% of women who have seen a gynecologist. Against the background of persistent HPV of the urogenital tract, most cervical intraepithelial neoplasms develop, which in 15–20% of cases can end in oncological pathology (carcinoma in situ and invasive cancer) [3, 6, 9].

Given the high prevalence of papillomavirus infection, the uncertainty of its outcome, it is important to determine the phase of interaction of HPV with the cell. During the reproduction of HPV in the body, there is a persistence of its genome in the episomal form with the production of viral particles. In this phase of reproduction, there is a high probability of spontaneous remission [2, 9].

*Human Papillomavirus*

**KhMAO-Ugra**

place (0.1%) [6].

number was about 32,000 cases [6].

average over the past 10 years [7].

births.

cesarean sections, and the risk of developing laryngeal papillomatosis of the larynx of the newborn, increasing the risk of infant mortality and the number of surgical interventions on the cervix for severe dysplasia in young women with risk of complications for subsequent pregnancies—spontaneous abortions and premature

Every year, more than 600,000 new cases of HPV-associated cancer are registered in the world, approximately 90% of which is cervical cancer. According to the statistics of the Russian Center for Information Technology and Epidemiological Research in Oncology of the Herzen Institute (branch of the Federal State Institute "National Medical Research Center of Radiology" of the Ministry of Health of the Russian Federation), in the structure of the incidence of malignant neoplasms of the population of the Russian Federation in 2015, cancers associated with HPV infection accounted for about 10% of the total incidence of cancer, and their total

In the structure of female cancer incidence, cancers of the anogenital region are presented in different ways. Thus, cervical cancer in the Russian Federation occupies the 5th place (5.2%); cancer of the rectum, rectosigmoid junction, and anus, 6th place (4.6%); vulvar cancer, 20th place (0.6%); pharyngeal cancer (0.2%) and vaginal cancer (0.2%), 25–26th place; and laryngeal cancer—28th

However, if we consider the structure of oncological diseases of the female reproductive system, cervical cancer takes the second place in prevalence among malignant neoplasms of women under 45 years and the first in the number of lost years of life (the life expectancy of sick women is reduced by 26 years on average). The incidence of cervical cancer is steadily increasing and has increased by 28% on

Only in 10 years, the incidence of cervical cancer in Russia has increased by an order of magnitude: from 7.9 per 100,000 of the female population in 2002 to 17.2 in 2012 [7]. In 2018, 17,000 new cases of cervical cancer and 6.6 thousand deaths were registered in the Russian Federation. In 2018, the incidence rate fell slightly to 15.76. Important markers characterizing the neglect of cervical cancer and the quality of treatment are the proportion of patients with advanced tumor process (3–4 stages), as well as the mortality of patients within a year from the moment of diagnosis, which in the Russian Federation in 2018 remained at a fairly high level: 34.6 and 13.8%, respectively. In the structure of disability, 83% of cases in oncogynecology are cervical cancer [8]. The frequent incidence of cervical cancer, the tendency to rejuvenate this pathology, a high percentage of neglected cases, and, as a consequence, the growth of disability among women of working age are a world problem, involving the most active, socially significant part of the female population. The occurrence of cervical cancer in young women is a serious social problem,

causing deterioration in health, disability, and reduced fertility.

As for cancers of other localizations, annually in the Russian Federation, about 4000 cases of laryngeal cancer and 3000 deaths, for this reason, are registered. Morbidity and mortality from cancer of the vulva, vagina, anus, and penis in the Russian Federation are not registered, which is obviously due to low diagnosis and underreporting of cases. There are about 100,000 new cases of cancer of these locations in the world every year, and two-thirds of the incidence

**2. Epidemiology of HPV-associated pathology in Russia and** 

**2**

falls on women [8].

The integrative phase is characterized by the embedding of HPV DNA sequences of the 16th and 18th serotypes into the chromosome of the infected cell, which is accompanied by the synthesis of oncoprotein E7. Viral particles are not produced. Expression of oncoprotein E7 is a factor that significantly increases the risk of oncogenic transformation of the cervical epithelium. Increased synthesis of oncoprotein E7, a product of the viral genome, indicates an integrative phase of HPV-cell interaction in which the probability of spontaneous remission is low. However, this pattern is not absolute, as some cases in malignant tumors identified episomal form of HPV DNA or a combination of episomal and integrated forms [11, 12].

The insufficient number of clinical studies on the content of oncoprotein E7 in HPV does not yet allow for widespread use of this indicator in practical health care.

The aim of the study was to study the level of expression of cancer protein E7 in patients with cervical pathology with positive and negative HPV tests [11, 12].

Materials and methods: We conducted a continuous randomized prospective study. According to the results of HPV testing by polymerase chain reaction (PCR), all patients with cervical pathology (95 women) were divided into two groups: the 1 group ( control group) (HPV-negative, n = 57) and the 2 group ( main group)(HPVpositive, n = 38). Group 1 (control group), consisting of 57 women with cervical pathology (HPV-negative test) was divided into two subgroups by analysis for the presence of oncoprotein E7 expression. In first subgroup, 13 women had a positive result which is 1 E7-positive subgroup, and 44 women had a negative result which is 1 E7-negative subgroup. Group 2 (main group) consisting of 38 women with cervical pathology, were infected with human papillomavirus of high carcinogenic risk. Group 2 (main group) was divided into two subgroups: subgroup of 11 women is 2 E7-positive subgroup, who tested positive for oncoprotein E7, and of 27 women, whose E7 was not detected—a negative result is 2 E7-negative subgroup.

Clinical observation and bacteriological, bacterioscopic, cytological, endoscopic (colposcopy), and histomorphological methods were used during the examination. All women were tested for papillomavirus infection. Verification of the diagnosis of papillomavirus infection was carried out by polymerase chain reaction. Quantitative determination of oncoprotein E7 in cervical samples was carried out using the enzyme immunoassay system NPF "Mirax-Pharma" (Moscow). Purified recombinant type 16 protein E7 was titrated as standard. The optical density, which is critical for each formulation, was determined. The test result of the sample was considered positive if the optical density was greater than or equal to the critical. The result of the sample study was considered negative if the optical density was less than the critical one. A survey card was filled in for each patient.

The comparison was carried out on the basis of sample averages (M), medians (Me), and standard deviation (Q25–Q75). Statistical analysis was performed using the nonparametric Mann–Whitney criterion (U) for independent groups. The reliability of the differences between the percentages of the two samples was estimated by the value of the Fisher angular distribution criterion (φ). The values at p < 0.05 were considered reliable.

### **4. Results and discussion**

The average age of the patients, the onset of menstrual function, the duration of their residence in the North, and the onset of sexual life were comparable in all groups and had no statistical significance (p > 0.05). The number of sexual partners had statistical significance in 1 E7-negative subgroup of the control group compared with the main group—2.00 (2.00–3.00), 2.00 (1.00–3.00), 3.00 (2.00–7.00), and

**5**

**Table 1.**

*φ \*\*p < 0,01; φ \*p < 0,05.*

*The results of the PAP test.*

*The Importance of the Problem of HPV-Associated Diseases in KhMAO-Ugra: Vaccination…*

comparison with 1 E7-negative subgroup (\*p < 0.05), respectively.

oncological history was revealed in 45.45% of cases.

100.00, and 81.42%.

with the control group (3,4–1,2\*\*p < 0.01).

**Group mark Control group**

**1 Е7-positive (n = 13)1**

cervical intraepithelial neoplasia in the presence of HPV.

**HPV (−)**

3.00 (2.00–5.00), respectively (2–3,4\*p < 0.05). In the study of obstetric history, the number of births and abortions in all groups had no statistical significance (p > 0.05). In the study of somatic history in 2 E7-positive subgroup, kidney disease accounted for 27.3% and endocrine disease 27.3% and had statistical significance in

In the study of hereditary oncological history, oncological diseases were found

In the study of gynecological history, we paid attention to diseases that could serve as additional factors in the development of neoplasia and cervical cancer. Among gynecological pathology, inflammatory diseases of the female genital organs in the 2 E7-positive subgroup were significantly more common, such as endometritis (27.27%) (3–2\*p < 0.05), vulvovaginitis (90.90%) (\*p < 0.05), and salpingo-oophoritis (36.36%) (3–4\*p < 0.05); inflammatory diseases can reduce immunity and stimulate the tumor process. Infection of the genitourinary organs by pathogens of sexually transmissible infections according to the anamnesis also prevailed in the 2 E7-positive subgroup, such as *Ureaplasma* (27.27%), *Mycoplasma* (18.18%), and *Chlamydia* infection (18.18%) (4–2\*p < 0.05), which required an

Attention is drawn to a large number of cervical pathology in history. Cervical diseases in the history of patients in subgroups had, respectively, 84.62, 88.64,

When cytological examination of patients for atypical cells is performed, signs of cervical intraepithelial neoplasia (CIN) were found in 45,5, 61,54, 77,3, 81,81, and 66.66% (1–3\* \* p < 0.01; 1–4. 5\*p < 0.05) in subgroups, respectively (**Table 1**). A HPV effect was observed in patients only in 1 E7-negative (in 4.5% of cases) and 2 E7-positive (in 18.2% of cases); the reliability was confirmed in comparison

In recent years, the impact of sexually transmitted infections on the likelihood of developing dysplasia and cervical cancer has been considered. The structure of chronic inflammatory diseases of the cervical canal and cervix is currently dominated by cervicitis caused by *Chlamydia trachomatis* in combination with human papillomavirus. In these conditions, CIN and possibly cervical cancer often develop. Many researchers note that *Chlamydia* infection is a cofactor in the occurrence of

*Chlamydia* infection was found only in 2 E7-positive subgroup (9.1%); *Ureaplasma* infection also prevailed in this subgroup (27.3%) (3–2\*p < 0.05). *Mycoplasma* infection prevailed in the 2 E7-positive subgroup (14.8%) (4–1\*\*p < 0.01) (**Table 2**).

> **1 Е7-negative (n = 44)2**

NILM 38,46% (5) 25,00% (11) 18,18% (2) 33,33% (9) LSIL 61,54% (8) 77,27% (34) 81,81% (9) 66,66% (18) HSIL 7,69% (1) 4,54% (2) 18,18% (2) 14,81% (4) HPV effect 0,00% (0)\*3 2,27% (1)\*3 18,18% (2)\*\*4 0,00% (0)

**Main group HPV (+)**

> **2 Е7-negative (n = 27)4**

**2 Е7-positive (n = 11)3**

in relatives, 15.38, 40.91, 45.45, and 22.22% in subgroups, respectively (21–2, 3\*p < 0.05; 2–4\*p < 0.05), where in the 2 E7-positive subgroup, a burdened family

in-depth study of the anamnesis and examination of the sexual partner.

*DOI: http://dx.doi.org/10.5772/intechopen.90668*

### *The Importance of the Problem of HPV-Associated Diseases in KhMAO-Ugra: Vaccination… DOI: http://dx.doi.org/10.5772/intechopen.90668*

3.00 (2.00–5.00), respectively (2–3,4\*p < 0.05). In the study of obstetric history, the number of births and abortions in all groups had no statistical significance (p > 0.05).

In the study of somatic history in 2 E7-positive subgroup, kidney disease accounted for 27.3% and endocrine disease 27.3% and had statistical significance in comparison with 1 E7-negative subgroup (\*p < 0.05), respectively.

In the study of hereditary oncological history, oncological diseases were found in relatives, 15.38, 40.91, 45.45, and 22.22% in subgroups, respectively (21–2, 3\*p < 0.05; 2–4\*p < 0.05), where in the 2 E7-positive subgroup, a burdened family oncological history was revealed in 45.45% of cases.

In the study of gynecological history, we paid attention to diseases that could serve as additional factors in the development of neoplasia and cervical cancer. Among gynecological pathology, inflammatory diseases of the female genital organs in the 2 E7-positive subgroup were significantly more common, such as endometritis (27.27%) (3–2\*p < 0.05), vulvovaginitis (90.90%) (\*p < 0.05), and salpingo-oophoritis (36.36%) (3–4\*p < 0.05); inflammatory diseases can reduce immunity and stimulate the tumor process. Infection of the genitourinary organs by pathogens of sexually transmissible infections according to the anamnesis also prevailed in the 2 E7-positive subgroup, such as *Ureaplasma* (27.27%), *Mycoplasma* (18.18%), and *Chlamydia* infection (18.18%) (4–2\*p < 0.05), which required an in-depth study of the anamnesis and examination of the sexual partner.

Attention is drawn to a large number of cervical pathology in history. Cervical diseases in the history of patients in subgroups had, respectively, 84.62, 88.64, 100.00, and 81.42%.

When cytological examination of patients for atypical cells is performed, signs of cervical intraepithelial neoplasia (CIN) were found in 45,5, 61,54, 77,3, 81,81, and 66.66% (1–3\* \* p < 0.01; 1–4. 5\*p < 0.05) in subgroups, respectively (**Table 1**).

A HPV effect was observed in patients only in 1 E7-negative (in 4.5% of cases) and 2 E7-positive (in 18.2% of cases); the reliability was confirmed in comparison with the control group (3,4–1,2\*\*p < 0.01).

In recent years, the impact of sexually transmitted infections on the likelihood of developing dysplasia and cervical cancer has been considered. The structure of chronic inflammatory diseases of the cervical canal and cervix is currently dominated by cervicitis caused by *Chlamydia trachomatis* in combination with human papillomavirus. In these conditions, CIN and possibly cervical cancer often develop. Many researchers note that *Chlamydia* infection is a cofactor in the occurrence of cervical intraepithelial neoplasia in the presence of HPV.

*Chlamydia* infection was found only in 2 E7-positive subgroup (9.1%); *Ureaplasma* infection also prevailed in this subgroup (27.3%) (3–2\*p < 0.05). *Mycoplasma* infection prevailed in the 2 E7-positive subgroup (14.8%) (4–1\*\*p < 0.01) (**Table 2**).


### **Table 1.** *The results of the PAP test.*

*Human Papillomavirus*

The integrative phase is characterized by the embedding of HPV DNA sequences of the 16th and 18th serotypes into the chromosome of the infected cell, which is accompanied by the synthesis of oncoprotein E7. Viral particles are not produced. Expression of oncoprotein E7 is a factor that significantly increases the risk of oncogenic transformation of the cervical epithelium. Increased synthesis of oncoprotein E7, a product of the viral genome, indicates an integrative phase of HPV-cell interaction in which the probability of spontaneous remission is low. However, this pattern is not absolute, as some cases in malignant tumors identified episomal form

The insufficient number of clinical studies on the content of oncoprotein E7 in HPV does not yet allow for widespread use of this indicator in practical health care. The aim of the study was to study the level of expression of cancer protein E7 in

of HPV DNA or a combination of episomal and integrated forms [11, 12].

whose E7 was not detected—a negative result is 2 E7-negative subgroup.

Clinical observation and bacteriological, bacterioscopic, cytological, endoscopic (colposcopy), and histomorphological methods were used during the examination. All women were tested for papillomavirus infection. Verification of the diagnosis of papillomavirus infection was carried out by polymerase chain reaction. Quantitative determination of oncoprotein E7 in cervical samples was carried out using the enzyme immunoassay system NPF "Mirax-Pharma" (Moscow). Purified recombinant type 16 protein E7 was titrated as standard. The optical density, which is critical for each formulation, was determined. The test result of the sample was considered positive if the optical density was greater than or equal to the critical. The result of the sample study was considered negative if the optical density was less than the critical one. A survey card was filled in for

The comparison was carried out on the basis of sample averages (M), medians (Me), and standard deviation (Q25–Q75). Statistical analysis was performed using the nonparametric Mann–Whitney criterion (U) for independent groups. The reliability of the differences between the percentages of the two samples was estimated by the value of the Fisher angular distribution criterion (φ). The values at p < 0.05

The average age of the patients, the onset of menstrual function, the duration of their residence in the North, and the onset of sexual life were comparable in all groups and had no statistical significance (p > 0.05). The number of sexual partners had statistical significance in 1 E7-negative subgroup of the control group compared with the main group—2.00 (2.00–3.00), 2.00 (1.00–3.00), 3.00 (2.00–7.00), and

patients with cervical pathology with positive and negative HPV tests [11, 12]. Materials and methods: We conducted a continuous randomized prospective study. According to the results of HPV testing by polymerase chain reaction (PCR), all patients with cervical pathology (95 women) were divided into two groups: the 1 group ( control group) (HPV-negative, n = 57) and the 2 group ( main group)(HPVpositive, n = 38). Group 1 (control group), consisting of 57 women with cervical pathology (HPV-negative test) was divided into two subgroups by analysis for the presence of oncoprotein E7 expression. In first subgroup, 13 women had a positive result which is 1 E7-positive subgroup, and 44 women had a negative result which is 1 E7-negative subgroup. Group 2 (main group) consisting of 38 women with cervical pathology, were infected with human papillomavirus of high carcinogenic risk. Group 2 (main group) was divided into two subgroups: subgroup of 11 women is 2 E7-positive subgroup, who tested positive for oncoprotein E7, and of 27 women,

**4**

each patient.

were considered reliable.

**4. Results and discussion**

Infection with human papillomavirus in women with cervical pathology was confirmed in 40% of patients. In the main group, a positive test for HPV type 16 was detected in 68.4% (26 women) and HPV type 18 in 42.1% (16 women). The combination of HPV 16 and 18 genotypes was found in 10.5% (4 women). HPV type 16 infection in the main group was found in subgroups 54.54 and 74.07%, respectively, and HPV type 18 was found in subgroups 54.54 and 37.04%, respectively.

Thus, HPV infection alone is not enough to induce tumor growth and confirms the role of mixed infection as a cofactor in HPV-dependent carcinogenesis.

During colposcopy (**Table 3**), the condition of the cervix and vagina was assessed, the localization and boundaries of the lesion were determined, benign changes were differentiated from suspected malignancies, and cytological smears and biopsies were taken from suspicious areas of the cervix. Among the results of a colposcopic view, 2 E7-positive and 2 E7-negative subgroups prevailed of CIN (45.45%) (3-2\* p < 0.05). Atypical vessels were determined in 63.63% (3–2\*\* p < 0.01; 3–1\*p < 0.05) and 59.26% (4–2\*\*p < 0.01; 4–1\*p < 0.05), respectively; the mosaic in the subgroups was 54.54% (3–2\*\* p < 0.01; 3–1\*p < 0.05) and 44.44% (4–2\*\*p < 0.01; 4–1\*p < 0.05), respectively.

In the group of HPV-positive women, abnormal colposcopic views (iodinenegative epithelium, punctuation, mosaic, aceto-white epithelium, atypical vessels) were much more common, which confirms the damaging effect of the human


### **Table 2.**

*Results of examination for sexually transmitted infections.*


**7**

**Table 4.**

*\*\*p < 0,01; \*p < 0,05.*

*Results of histological examination.*

cancer.

*The Importance of the Problem of HPV-Associated Diseases in KhMAO-Ugra: Vaccination…*

indications for biopsy. Tissue for biopsy was taken by radio-wave loop.

papillomavirus on the state of the cervical epithelium and complicates the course of pathological processes toward carcinogenesis. All abnormal colposcopic views were

Histological examination revealed the following results (**Table 4**). Signs of chronic inflammatory process prevailed in the control group and amounted to 61.54% and 56.82%, respectively (2–1, 3–1\* \* p < 0.01). Signs of stationary endocervicosis were found in the control group (30.77 and 38.63%, respectively) and in the main group (18.18 and 33.33%, respectively). This had no statistical significance (p > 0.05). Epidermizing endocervicosis prevailed in 2 E7-positive, and its detec-

CIN I, II, and III prevailed in women with HPV (+) in the main group, and according to the results of histological conclusion, CIN I was found in subgroup 2 E7-positive in 36.36% of cases (4–1\* \* p < 0.01; 4–2\*p < 0.05) and in subgroup 2

CIN II was diagnosed in the main group in 27.27% (4-1\*\*p < 0.01) and in 29.63% of cases (5-1\*\*p < 0.01; 5-3\*p < 0.05), respectively, subgroups. CIN III was observed in women with HPV (+) of the main group in 27.27% (4–1,3\*\*p < 0.01) and in 22.22% of cases (4–1,3\*\*p < 0.01), respectively. Cancer in situ was diagnosed in the main group in 9.09% (4-3\*p < 0.05) and 7.40% of cases (5-1,3\*p < 0.05), respectively, subgroups, indicating the role of HPV in the carcinogenesis of cervical

Signs of koilocytosis were determined in subgroups 0, 7,69, 2,27, 54,54, and 51.85%, respectively. In women with HPV (+) of the main group, these indicators were maximum and had statistical significance (4,5–1,2,3\*\*p < 0.01). It should be noted that the maximum of abnormal colposcopic species were women in sub-

Thus, in the group of HPV-positive women, according to the results of histological examination, cervical intraepithelial neoplasia of medium and severe degree and cervical cancer were more common. Moreover, koilocytic transformation of the epithelium, CIN III, and cervical cancer was diagnosed more often in subgroup

**HPV (−)**

No evidence 0,00% (0) 0,00% (0) 0,00% (0) 0,00% (0) Chronic cervicitis 61,54% (8) 56,82% (25) 45,45% (5) 55,55% (15) Stationary endocervicosis 30,77% (4) 38,63% (17) 18,18% (2) 33,33% (9) Epidermizing endocervicosis 38,46% (5) 38,63% (17)\*4 45,45% (5)\*4 18,52% (5) Leukoplakia 23,08% (3) 9,09% (4) 18,18% (2) 18,52% (5)

CIN II 15,38% (2) 9,09% (4)\*4 27,27% (3) 29,63% (8) CIN III 7,69% (1)\*2 0,00% (0)\*\*3,4 27,27% (3) 22,22% (6) Cervical cancer 0,00% (0) 0,00% (0)\*4 9,09% (1) 7,40% (2) Koilocytes 7,69% (1)\*\*3,4 2,27% (1)\*\*3,4 54,54% (6) 51,85% (14)

**1 Е7-negative (n = 44)2**

**1 Е7-positive (n = 13)1**

**Main group HPV (+)**

> **2 Е7-negative (n = 27)4**

**2 Е7-positive (n = 11)3**

\*\*4 22,72% (10) 36,36%(4) 40,74%(11)

*DOI: http://dx.doi.org/10.5772/intechopen.90668*

tion rate was 45.45% (4–1\* \* p < 0.01; 4–5\*p < 0.05).

E7-negative in 40.74% of cases (5–1,2\*\*p < 0.01).

groups with increased expression of oncoprotein E7.

**Group mark Control group**

CIN I 7,69% (1)\*3

### **Table 3.**

*Extended colposcopy results.*

*The Importance of the Problem of HPV-Associated Diseases in KhMAO-Ugra: Vaccination… DOI: http://dx.doi.org/10.5772/intechopen.90668*

papillomavirus on the state of the cervical epithelium and complicates the course of pathological processes toward carcinogenesis. All abnormal colposcopic views were indications for biopsy. Tissue for biopsy was taken by radio-wave loop.

Histological examination revealed the following results (**Table 4**). Signs of chronic inflammatory process prevailed in the control group and amounted to 61.54% and 56.82%, respectively (2–1, 3–1\* \* p < 0.01). Signs of stationary endocervicosis were found in the control group (30.77 and 38.63%, respectively) and in the main group (18.18 and 33.33%, respectively). This had no statistical significance (p > 0.05). Epidermizing endocervicosis prevailed in 2 E7-positive, and its detection rate was 45.45% (4–1\* \* p < 0.01; 4–5\*p < 0.05).

CIN I, II, and III prevailed in women with HPV (+) in the main group, and according to the results of histological conclusion, CIN I was found in subgroup 2 E7-positive in 36.36% of cases (4–1\* \* p < 0.01; 4–2\*p < 0.05) and in subgroup 2 E7-negative in 40.74% of cases (5–1,2\*\*p < 0.01).

CIN II was diagnosed in the main group in 27.27% (4-1\*\*p < 0.01) and in 29.63% of cases (5-1\*\*p < 0.01; 5-3\*p < 0.05), respectively, subgroups. CIN III was observed in women with HPV (+) of the main group in 27.27% (4–1,3\*\*p < 0.01) and in 22.22% of cases (4–1,3\*\*p < 0.01), respectively. Cancer in situ was diagnosed in the main group in 9.09% (4-3\*p < 0.05) and 7.40% of cases (5-1,3\*p < 0.05), respectively, subgroups, indicating the role of HPV in the carcinogenesis of cervical cancer.

Signs of koilocytosis were determined in subgroups 0, 7,69, 2,27, 54,54, and 51.85%, respectively. In women with HPV (+) of the main group, these indicators were maximum and had statistical significance (4,5–1,2,3\*\*p < 0.01). It should be noted that the maximum of abnormal colposcopic species were women in subgroups with increased expression of oncoprotein E7.

Thus, in the group of HPV-positive women, according to the results of histological examination, cervical intraepithelial neoplasia of medium and severe degree and cervical cancer were more common. Moreover, koilocytic transformation of the epithelium, CIN III, and cervical cancer was diagnosed more often in subgroup


### **Table 4.**

*Results of histological examination.*

*Human Papillomavirus*

respectively.

Infection with human papillomavirus in women with cervical pathology was confirmed in 40% of patients. In the main group, a positive test for HPV type 16 was detected in 68.4% (26 women) and HPV type 18 in 42.1% (16 women). The combination of HPV 16 and 18 genotypes was found in 10.5% (4 women). HPV type 16 infection in the main group was found in subgroups 54.54 and 74.07%, respectively, and HPV type 18 was found in subgroups 54.54 and 37.04%,

Thus, HPV infection alone is not enough to induce tumor growth and confirms

In the group of HPV-positive women, abnormal colposcopic views (iodinenegative epithelium, punctuation, mosaic, aceto-white epithelium, atypical vessels) were much more common, which confirms the damaging effect of the human

**HPV (−)**

*Chlamydia trachomatis* 0,00% (0) 0,00% (0)\*3 9,09% (1)\*4 0,00% (0) *Ureaplasma* spp. 15,38% (2) 6,82% (3)\*3 27,27% (3) 11,11% (3)

HPV 16 0,00% (0)\*\*3,4 0,00% (0)\*\*3,4 54,54% (6) 74,07% (20) HPV 18 0,00% (0)\*\*3,4 0,00% (0)\*\*3,4 54,54% (6) 37,04% (10)

**1 Е7-negative (n = 44)2**

**1 Е7-positive (n = 13)1**

**HPV (−)**

Normal 0,00% (0) 0,00% (0) 0,00% (0) 0,00% (0)

CIS 0,00% (0) 0,00% (0)\*3 9,09% (1) 3,70% (1) Atypical vessels 23,08% (3)\*3,4 18,18% (8)\*\*3,4 63,63% (7) 59,26% (16) Mosaic 15,38% (2)\*3,4 11,36% (5)\*\*3,4 54,54% (6) 44,44% (12) Punctuation 0,00% (0) 4,54% (2) 9,09% (1) 7,40% (2)

**1 Е7-negative (n = 44)2**

**Main group HPV (+)**

**Main group HPV (+)**

**2 Е7-positive (n = 11)3**

\*\*4 9,09% (4) 9,09% (1) 14,81% (4)

**2 Е7-negative (n = 27)4**

**2 Е7-negative (n = 27)4**

**2 Е7-positive (n = 11)3**

\*\*4 45,45% (5) 55,55% (15)

the role of mixed infection as a cofactor in HPV-dependent carcinogenesis. During colposcopy (**Table 3**), the condition of the cervix and vagina was assessed, the localization and boundaries of the lesion were determined, benign changes were differentiated from suspected malignancies, and cytological smears and biopsies were taken from suspicious areas of the cervix. Among the results of a colposcopic view, 2 E7-positive and 2 E7-negative subgroups prevailed of CIN (45.45%) (3-2\* p < 0.05). Atypical vessels were determined in 63.63% (3–2\*\* p < 0.01; 3–1\*p < 0.05) and 59.26% (4–2\*\*p < 0.01; 4–1\*p < 0.05), respectively; the mosaic in the subgroups was 54.54% (3–2\*\* p < 0.01; 3–1\*p < 0.05) and 44.44%

(4–2\*\*p < 0.01; 4–1\*p < 0.05), respectively.

**Group mark Control group**

*Mycoplasma* spp. 0,00% (0)\*2

*φ \*\*p < 0,01; \*p < 0,05; φ \*р < 0,05.*

**Group mark Control group**

*Results of examination for sexually transmitted infections.*

**1 Е7-positive (n = 13)1**

Aceto-white epithelium 23,08% (3)\*4 13,64% (6)\*3

**6**

**Table 3.**

**Table 2.**

*φ \*\*p < 0,01; \*p < 0,05; φ \*p < 0,05.*

*Extended colposcopy results.*

2 E7-positive than in subgroup 2 E7-negative, according to the conclusion of morphologists.

The results of the study of the level of expression of cancer protein E7 are presented in **Table 5**. Indicators were distributed according to subgroups: 0,087 (0,07–0,12); 0,190 (0,18–0,39); 0,074 (0,06–0,10); 0,200 (0,17–0,31); and 0.081 (0.07–0.10) (\*\*p < 0.01). We found a significant increase in the indicator in the main group (2 E7-positive), compared with the control group 1 E7-negative and 2 E7-negative (\*\*p < 0.01). In the main group (subgroup 1 E7-positive), this indicator also had statistical significance in comparison with subgroups 1 E7-negative and 2 E7-negative (\*\*p < 0.01).

The increased expression of oncoprotein E7 in the main group (2 E7-positive) was maximal in comparison with subgroups 1 E7-negative and 2 E7-negative (\*\*p < 0.01), which is an indicator of the aggressiveness of the incipient tumor process and a criterion for an unfavorable prognosis. In subgroup 1 E7-positive, increased expression of oncoprotein E7 was also detected in comparison with the control 1 E7-negative subgroup and the main 2 E7-negative subgroup (\*\*p < 0.01).

As a result of studying the level of expression of oncoprotein E7 in HPV-positive and HPV-negative women, we made the following conclusions:



**9**

*The Importance of the Problem of HPV-Associated Diseases in KhMAO-Ugra: Vaccination…*

**5. Teenagers are a risk group: reproductive behavior and adolescent** 

Biological susceptibility to HPV and structural immaturity of the cervix in adolescence, high frequency of ectopia of the cylindrical epithelium, and activation of squamous metaplasia processes create optimal conditions for the introduction and replication of human papillomavirus, which makes the adolescent population

Features of reproductive behavior of adolescents determine the risks that contribute to the development of diseases of the reproductive system. These are the early beginning of sexual life, frequent change of sexual partners due to the absence of persistent lasting relations in paired unlike adults, who create families and in most adhere to monogamous relations. As a result of adolescents' neglect of barrier contraception, they have a high incidence of sexually transmitted infections. Early sexual life and especially sexual behavior of adolescents contribute to the spread of sexual infections among them, which often remain undiagnosed and

Physiological features of the anatomy of the cervix in adolescent girls' anatomy create prerequisites for the persistence of HPV in the epithelial cells of the cervix of the girl; long-term persistence of the virus can lead to the development of precancerous lesions and cervical cancer. *Chlamydia* and *Mycoplasma* infections associated with HPV are cofactors that exacerbate the situation. Age-related physiological ectopia of the cylindrical epithelium, characteristic of adolescence, and defective hormonal homeostasis lead to a violation of the physiological barriers of the genitals. The cylindrical epithelium is an ideal environment for papillomavirus invasion due to the availability of reserve cells and the large area of the transformation zone [14]. Promiscuity and unsettled partnerships are of primary importance in early HPV infection and increased risk of CIN against the background of high infection rates

In sexually active girls, genital inflammation is detected three times more often (45.2%) than in their peers who do not live a sexual life—in 15.1% of girls. Pathology of the cervix at the age of 18 is detected in 33.4% of girls. According to the results of the survey of sexually active adolescents for genital infections, sexually transmissible infections were detected in 77.8%, including *Mycoplasma genitalium*, 18.4%; *Chlamydia trachomatis*, 6.2%; and HPV, 52.7% (including highly oncogenic types—34.7%), and mixed infections in 51.4%. In KhMAO-Ugra, the HPV infection rate of girls aged 14–16 is 40%, and among girls aged 17–18, the

We conducted an anonymous survey of schoolchildren in Surgut, which was attended by 389 high school students, including 201 girls and 188 boys aged from 14 to 18. The median age was 16.9 years. Among them, 24% have experience of sexual contact. About 50% of sexually active adolescents indicated that they had a sexual

3.Laboratory test evaluation of oncogenic transformation of the cervical epithelium requires further study, as it allows in conjunction with other diagnostic methods to determine the group of increased oncogenic risk among patients with gynecological diseases. The proven relationship between elevated levels of expression of oncoprotein E7 and the presence of CIN allows us to recommend the definition of oncoprotein E7 for inclusion in the diagnostic program for HPV-positive women with changes in the cervix and pathological cervical

*DOI: http://dx.doi.org/10.5772/intechopen.90668*

smears.

**reproductive health**

not treated in time [13].

extremely vulnerable to the development of CIN.

among adolescents with sexually transmitted infections.

infection rate increases to 60% [13].

### **Table 5.**

*The results of the study of the level of expression of the oncoprotein E7.*

*The Importance of the Problem of HPV-Associated Diseases in KhMAO-Ugra: Vaccination… DOI: http://dx.doi.org/10.5772/intechopen.90668*

3.Laboratory test evaluation of oncogenic transformation of the cervical epithelium requires further study, as it allows in conjunction with other diagnostic methods to determine the group of increased oncogenic risk among patients with gynecological diseases. The proven relationship between elevated levels of expression of oncoprotein E7 and the presence of CIN allows us to recommend the definition of oncoprotein E7 for inclusion in the diagnostic program for HPV-positive women with changes in the cervix and pathological cervical smears.

### **5. Teenagers are a risk group: reproductive behavior and adolescent reproductive health**

Biological susceptibility to HPV and structural immaturity of the cervix in adolescence, high frequency of ectopia of the cylindrical epithelium, and activation of squamous metaplasia processes create optimal conditions for the introduction and replication of human papillomavirus, which makes the adolescent population extremely vulnerable to the development of CIN.

Features of reproductive behavior of adolescents determine the risks that contribute to the development of diseases of the reproductive system. These are the early beginning of sexual life, frequent change of sexual partners due to the absence of persistent lasting relations in paired unlike adults, who create families and in most adhere to monogamous relations. As a result of adolescents' neglect of barrier contraception, they have a high incidence of sexually transmitted infections. Early sexual life and especially sexual behavior of adolescents contribute to the spread of sexual infections among them, which often remain undiagnosed and not treated in time [13].

Physiological features of the anatomy of the cervix in adolescent girls' anatomy create prerequisites for the persistence of HPV in the epithelial cells of the cervix of the girl; long-term persistence of the virus can lead to the development of precancerous lesions and cervical cancer. *Chlamydia* and *Mycoplasma* infections associated with HPV are cofactors that exacerbate the situation. Age-related physiological ectopia of the cylindrical epithelium, characteristic of adolescence, and defective hormonal homeostasis lead to a violation of the physiological barriers of the genitals. The cylindrical epithelium is an ideal environment for papillomavirus invasion due to the availability of reserve cells and the large area of the transformation zone [14].

Promiscuity and unsettled partnerships are of primary importance in early HPV infection and increased risk of CIN against the background of high infection rates among adolescents with sexually transmitted infections.

In sexually active girls, genital inflammation is detected three times more often (45.2%) than in their peers who do not live a sexual life—in 15.1% of girls. Pathology of the cervix at the age of 18 is detected in 33.4% of girls. According to the results of the survey of sexually active adolescents for genital infections, sexually transmissible infections were detected in 77.8%, including *Mycoplasma genitalium*, 18.4%; *Chlamydia trachomatis*, 6.2%; and HPV, 52.7% (including highly oncogenic types—34.7%), and mixed infections in 51.4%. In KhMAO-Ugra, the HPV infection rate of girls aged 14–16 is 40%, and among girls aged 17–18, the infection rate increases to 60% [13].

We conducted an anonymous survey of schoolchildren in Surgut, which was attended by 389 high school students, including 201 girls and 188 boys aged from 14 to 18. The median age was 16.9 years. Among them, 24% have experience of sexual contact. About 50% of sexually active adolescents indicated that they had a sexual

*Human Papillomavirus*

E7-negative (\*\*p < 0.01).

morphologists.

2 E7-positive than in subgroup 2 E7-negative, according to the conclusion of

The results of the study of the level of expression of cancer protein E7 are presented in **Table 5**. Indicators were distributed according to subgroups: 0,087 (0,07–0,12); 0,190 (0,18–0,39); 0,074 (0,06–0,10); 0,200 (0,17–0,31); and 0.081 (0.07–0.10) (\*\*p < 0.01). We found a significant increase in the indicator in the main group (2 E7-positive), compared with the control group 1 E7-negative and 2 E7-negative (\*\*p < 0.01). In the main group (subgroup 1 E7-positive), this indicator also had statistical significance in comparison with subgroups 1 E7-negative and 2

The increased expression of oncoprotein E7 in the main group (2 E7-positive)

1.In the group of women with cervical pathology associated with human papillomavirus infection, an increased frequency of abnormal colposcopic views, mosaic (3.5 times higher, p <0.01), acetone-white epithelium (2.4 times higher, p < 0.05), atypical vessels (3.5 times higher, p <0.01), punctuation (2.3 times more often, p <0.05), as well as cytological examination, LSIL signs (2.4 times higher), HSIL was found only in the HPV group (p <0.01), and histological examination of CIN I found is 4.7 times higher (p < 0.05), CIN II is 3.2 times more likely (p < 0.05), CIN III is 22.3 times more often (p < 0.01), and cervical cancer is 7.89%. This confirms the damaging effect of the human papillomavirus on the cervical epithelium and complicates the course of pathological

2.The results of the study showed that in cervical pathology caused by HPV of high carcinogenic risk, the increased content of cancer protein E7 is detected 2.5 times (p < 0.01) more often than in women that are HPV (−). The level of E7 indicates an aggressive process of carcinogenesis and can be considered as

> **Main group HPV (+)**

> > **1 Е7-negative (n = 44)2**

> > > **Me (Q25–Q75)**

0,081 (0,07–0,10)

0,145 (0,145–0,196)

**1 Е7-positive (n = 13)1**

> **Me (Q25–Q75)**

0,200 (0,17–0,31) U\*\*4

0,145 (0,145–0,196)

**Statistic parameters**

**Kruskall-Wallis**

**χ2**

33,116 p < 0,001

was maximal in comparison with subgroups 1 E7-negative and 2 E7-negative (\*\*p < 0.01), which is an indicator of the aggressiveness of the incipient tumor process and a criterion for an unfavorable prognosis. In subgroup 1 E7-positive, increased expression of oncoprotein E7 was also detected in comparison with the control 1 E7-negative subgroup and the main 2 E7-negative subgroup (\*\*p < 0.01). As a result of studying the level of expression of oncoprotein E7 in HPV-positive

and HPV-negative women, we made the following conclusions:

processes toward carcinogenesis.

an unfavorable prognostic sign.

**1 Е7-positive (n = 13)1**

> **Me (Q25–Q75)**

(0,18–0,39) U\*\*2,4

0,145 (0,145–0,196)

**Е7** 0,190

**Control group HPV (−)**

> **1 Е7-negative (n = 44)2**

> > **Me (Q25–Q75)**

0,074 (0,06–0,10) U\*\*2,4

0,145 (0,145–0,196)

*Kruskall-Wallis: χ2; р (\*\*p < 0,01; \*p < 0,05); Mann–Whitney (U) U \*\*p < 0.*

*The results of the study of the level of expression of the oncoprotein E7.*

**8**

**Table 5.**

**Group mark**

> **ОП крит**

### *Human Papillomavirus*

debut at the age of 16 and younger. About 14.6% of them had the first sexual contact at the age of 15, 10.4% from 13 to 14 years old, 31.2% from 17 years old, and 16.7% from 18 years old. About 66.7% of them had 1 sexual partner; every third (33.3%) sexually active teenager under the age of 18 had 2 or more sexual partners. For contraception, 57% of respondents use a condom, 29%—combined oral contraceptives. Only 23.5% of adolescents are regularly protected from sexual infections, 27% never use barrier contraception.
