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I. ДИАГНОСТИКА И ЛЕЧЕНИЕ
ASPECTS OF ETIOPATHOGENESIS OF BACKGROUND, PRECANCEROUS DISEASES AND CANCER OF THE CERVIX
Amiraslanov A.T., Panahova A.M.
Azerbaijan Medical University, Department of Oncology, Baku, Azerbaijan
МРНТИ 76.29.48
ABOUT THE AUTHORS
AmiraslanovA.T. member of the Academy of Sciences,head of a department of carcinology of Azerbaijan Medical University.
Panakhova A.M. junior research assistant,academic department of carcinology of Azerbaijan Medical University. E-mail aynur.panahova@yahoo.com Telephone +994552113803
Abstract
Contemporary aspects of ethiopathogenesis pre-malignant condition and cervix cancer were presented -
in the article. From the point of view of systematic review of modern literature the most likely etiological fac- Keywords
tors of these diseases were discussed by athours. cervix, cancer, hpv
Жатыр мойыны катерл1 iciriHiœ жэне катерл1 iciK алды ауруларыньщ шыгу этиопатогенетикалык аcпектiлерi
Амирасланов А.Т., Панахова А.М.
Эз1рбайжан Медициналык, Университету Онкология 6eëiMi, Эз1рбайжан, Баку
АВТОРЛАР ТУРАЛЫ
Амирасланов А.Т. - академик, Эз/рбайжан Медицина Университетшщ онкология кафедрасынын менгеруш/с/
Панахова A.M. - k.f.k-, Эз/рбайжан Медицина Университет/шн онкология кафедрасы: E-mail aynur.panahova@yahoo. com тел+994552113803
Ацдатпа
Мацалада жатыр мойны çaTepni iciriHiœ этиопатогенезшщ цазр заман€ы аспектшерi -
Карастырылган. Авторлар осы аурулардь,ц ен ыцтимал ммошмьщ факторларын ^фп замангы Туй1н сездер
9âe6èeTTepâi yнeмi царап шыгу устанымымен талцылады. ЖаШр мойыны, ick, hpv.
Этиопатогенетические аспекты происхождения, предраковых заболеваний и рака шейки матки
Амирасланов А.Т., Панахова А.М.
Азербайджанский медицинский университет, отдел онкологии, Баку, Азербайджан
ОБ АВТОРАХ
Амирасланов А.Т. академик.зав. кафедрой онкологии АМУ. Баку
Панахова А.М. м.н.с. Кафедра онкологии Азербайджанского медицинского Университета
E-mail aynur.panahova@yahoo.com тел+994552113803
Аннотация
В статье представлены современные аспекты этиопатогенеза предраковых заболеваний и рака -
шейки матки. Авторами обсуждены наиболее вероятные этиологические факторы этих заболеваний с КлюЧевые слова
позиции систематического обзора современной литературы. шейка матки, опухоль, HPV
The first investigations devoted to the epidemiology of cervical cancer was published as far back as in nineteenth century. Rigoni-Stern in 1842, he published the results of a study of the causes of death in 1760-1830in Verona. He noted that cervical cancer was more common in married women and widows, while nuns and virgins practically did not occur. This fact allowed to the scientist to come to the conclusion that cervical cancer could be of infectious origin. Later, F. Gagnon (1950), studying medical records in Montreal and Quebec, discovered that nuns almost did not have cervical cancer. F.Gagnon connected this fact with a low level of inflammation of the cervix in nuns (4,8,9,16).
In virgins histopathological proven cervical cancer is extremely rare. A lot of epidemiological studies dedicate to the role in the development of cervical cancer, the early onset of sexual activity, early pregnancy, frequent replacement of sexual partners, infectious diseases transmitted sexually. The patients with cervical cancer compared to the control group begin sexual activity earlier (2, ,7,12).
Frequently change of sexual partners and first childbirth at the young age play negative role in the occurrence of cervical cancer (12,14,16).
The number of epidemiological and clinical-statistical investigations demonstrate the role of a poor socioeconomic status and a low level of education (8,11, 13)On the contrary, other authors believe that the formation of cervical cancer, the level of education and the economic situation do not matter (6,14,15,16).
The carcinogenic effect of abortion conclude in the mechanical trauma of the endocervix with subsequent development of infection (8,14).
Injury of the cervix and its further deformation is the cause of damage to the physiological barrier. Cervical mucus in the canal is not retained, which is accompanied by a decrease in the local immunity and further infection (7,9,10,14)Precancerous lesions, representing a high risk of cervical cancer, is often formed on the background of scar cervical strain and ectropion. To the violation of the innervations, reception and tropism of the cervix leads to birth (abortion) injury (8).
Oral contraception, especially in the presence of cervical infection, correlate with cervical ectopia (6,7,10,11). This is increase risk of adenocarcinoma of the endocervix. In international studies have found that women with similar risk factors for cervical dysplasia often found in those who are infected with human immunodeficiency virus. Injuries of the cervix are in etiological factor in the metaplastic processes of the cervix. Cervical injury, do not by themselves and subsequently occurring chronic infection is the etiological factor carcinomas. 83% of cervical lesions accompanied by inflammatory pro-
cesses in the preparations is found metaplasia. In the pathogenesis of cervical cancer is very important infective process after injury ( 5,6,12).
Appleby P. and others believe that the use of hormonal contraceptives do not affect the development of dysplastic processes and cervical cancer. There is a correlation between hormonal, immunosuppressive therapy and cervical cancer. (13,15,16).
The influence of tobacco smoking the risk of malignant neoplasms have been studied thoroughly. The results of epidemiological and experimental studies are recognized that smoking tobacco is a carcinogenic factor for a person, having thr negative effect on the body, and it is a risk factor for the occurrence of cancer of any location (10).
The dependence of cervical cancer and intraep-ithelial neoplasia with smoking has been revealed. Smoking plays the role of a promoter of carcino-genesis in the epithelium of the cervix, infected with HPV, especially for squamous cell carcinoma (11). Intensive smoking reduces the immune defenses and nicotine plays a co-carcinogenic role in facilitating the implementation of the carcinogenic effects of a viral infection in case of CIN and cervical cancer. In the mucous membrane of the cervix, according to research, nicotine and its derivatives have been discovered, and smoking-related damage to the DNA of the cervical epithelium has been established ( 11,12,14,16) Appleby P. et al. (2006), Gadducci A. et al. (2011) believe that nicotine acts as a co-carcinogenic factor (11,14). In urogenital chlamydiosis occurs desquamation squamous epithelium of the cervix to form a true or pseudo erosion expressed edema, swelling of mucosa abundant blood supply, looseness of tissues, that is, favorable conditions for infection with HPV, associated dysplasia and cervical cancer (1,5,8,9,10). Chl. Trachomatis a obligate intracellular parasite, has a tropism to the cylindrical epithelium, forming a primary lesion in the mucous membrane of the cervix, where it can persist for a long time, causing various pathological changes (10,15).
Urogenital trichomoniasis causes a slow inflammatory process in the mucous membrane of the cervix. The toxic effect of trichomonads on epithelial cells, which provokes the disruption in the maturation of the epithelium, and its partial destruction. Chronic erosions of the cervix of the trichomonas of the etiology in the presence of additional risk factors are capable of malignant transformation (12).
The role of HPV as a carcinogen factor in the intraepithelial neoplastic processes. Viral etiology of neoplasia is the most difficult questions of modern oncology. The most cases, neoplasias cannot be associated with carcinogenic factors. The viral etiology of cervical cancer is closely related to studies
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ВЕСТНИК ХИРУРГИИ КАЗАХСТАНА № 4-2017
of condylomas of different locations. The first time Rigoni-Stern in 1842 suggested a theory of the infectious origin of cervical cancer. In the first time in 1903 Borrel and Bosc advanced the theory of the viral origin of tumors, Rous, Kidd (1938), Friedewald (1941) believe that viruses enhance the effect of carcinogenic factors.
The data of experimental virilology studies obtained for the first time by L.A. Zilber (1945), and then Horsfall (1963) and Southam (1964) suggested that viruses are acting on the gen of normal cells turning cells into cancer cells. The role of viruses in cancertransformation differrent from the role of viruses in the occurrence of infection. After transformation of the normal cells into tumor, viruses do not affect the reproduction and growth of the tumor ( 9, 12,13,16). The central etiological factor of intraepithelial cancer and precancerous neoplastic lesions of the cervix is the HPV with high carcinogenic risk (6,7,8,9). HPV is the group of viruses for which confirm their inducing role in the formation of tumors in humans in vivo (11,16).
For dysplasia and cervical cancer, the genetic material of HPV is detected in 90-95% of the samples. Currently, more than 79 types of HPV are known,have its own specific properties (13,14) More than 30 types can infect the genital tract (11, 12) All HPV types associated with neoplasias can be conditionally divided into 2 groups: "high risk", which is detected in malignant tumors, and "low risk", detected in benign lesions of the cervix and rarely in invasive cancer. High-risk viruses are HPV-16,18,31,33, which increase the risk of developing cervical cancer by 20-150 times, and HPV-6,11 (13,14)and "low-risk".
Persistent HPV-KR-mediated infection increases the risk of developing cervical cancer (cervical cancer) by 10-20 times, and the initiation of severe intraepithelial neoplasia of the cervix is 100 times that of uninfected women (6,8,14,15). A number of studies indicate that in women infected with oncogen types of HPV, the risk of progression of preexisting low-grade intraepithelial dysplasia (LSIL) to severe (HSIL) increases (1,4,6 12,13). According to Guan P. (2012), Daily L.R. (2014), LSIL and HSIL are significant markers of infection with oncogen stamms HPV (5,6,7). At the same time, the validity of the diagnosis of precancer and cervical cancer in HPV-positive patients requires additional extensive examination (10, 11).
The risk of infection with HPV during life varies in the range of 50-90% (9). Infection occurs in the most cases shortly after sexual debut (1) the peak of which is recorded in women under the age of 25 (4)However, with the integration of episomal HPV most of the patients this age happen elimination of virus (7). Progress of persistent infection to
malignant neoplasm through a series of intermediate stages usually takes 10 to 20 years (10,12). The primary role of HPV in the development of cervical neoplasia and the high prevalence of this infection among the population, screening for HPV is an important area of early diagnosis of socially significant diseases of the cervix (8, 9, 10, 13). The wide detection of HPV in the population without regard to the nature of the course of infection leads to over diagnosis and determines the excessively aggressive medical and surgical tactics of the gynecologist and oncologist (4,5).
Of particular importance is the various retro-and prospective research, which aims to identify the importance of, and the correlative relationship of new risk factors affecting the persistence of HPV (2,4,5). According to Afanasyev M.S. (2004), papillomavirus infection in the form of mixed associations occurs in 71% of cases. The most frequently accompanied are bacterial vaginosis (26.6%), vulvovaginal candidiasis (32%), herpes virus (18.4%), mycoplasma (18.1%), and chlamydia (18%) infections affecting to the genital tract causes the background of changes in the vaginal microflora, characterized by a decrease in the frequency of allocation and the number of obligate representatives and excessive growth of opportunistic microorganisms of the vaginal biocenosis (10,12).
For approval the theory "the virus is an etiologi-cal factor" several factors should be together:
1) in tumor cells detected continuously integrated or episomal form DNT virus;
2) in vitro cloned viral genes can be capable of degenerating malignant tumors;
3) in the tumor cells, the regular expression of the viral gene;
4) in nature, similar viruses that cause tumors should also be detected;
5) epidemiological studies need to prove the relationship between the tumor process and the identified genetic material of the virus (1,3,4,5).
In cervical cancer cells is very impartant active of transcription of the viral genome in the cells , and the persistence of the viral genome has an important role in the proliferation of cervical cancer cells (15).
The process of replication of HPV and the subsequent transformation of cells, induced by it, are connected in a certain way with the process of differentiation of the epithelium. Release of cellular growth factor stimulating the expression of E6 and E7 genes and epithelial proliferation. Differentiation and maturation of flat epithelial cells absent due to the suppression of the synthesis of native cellular proteins; The cellular renewal of the epithelial layer disrupted and a dysplasia occurs at the subsequent
stage of the infection, which is based on the proliferation and structural rearrangement of the epithelial cells, at the beginning of the basal and parabasal layers(2,5,9,14). Modern molecular genetic investigations using the PCR method 95-100% of cases of cervical cancer cages are detected by the virus genome (5,6,8,9). Currently it identified more than 100 types of HPV, more than 70 of them studied in detail and described. It was found that some types of HPV virus infect only certain types of epithelium, causing characteristic changes. Many works devoted to the identification of various variants of genotypes of the virus and malignant transformation of cervical warts (2,6).
Of all types of HPV virus, only 34 affect the anogenital zone. HPV affects the basal layer of the squamous epithelium (mainly affects the transition zone of the flat epithelium into the cylindricepithe-lium).
Kurz (1993) and Schiffman (1994), the patho-morphological change to caused by the papilloma virus classify 1) benign atypia; 2) LSIL (Low-grade Squamous Intraepithelial Lesions) or CIN-I (Cervical Intraepithelial Neoplasia) -easy dysplasia of flat epithelium with no signs of coilocytosis; 3) HSIL (High-grade Squamous Intraepithelial Lesions) or CIN-II-medium dysplasia; 4) severe dysplasia or intraepithelial cancer (in situ) - CIN-III (1,5,6,7) Discussions of the classification of dysplastic and preinvasive cancers continue to this day. Dysplasia in terms of severity divide into three degrees and intraepithelial cancers isolate into a separate group [10]. Groups of dysplasias based on virological and pathomorphological criteria are heterogeneous. There is no certainty that different degrees of dysplasia is consecutive stages of carcinogenesis (16).
The oncogenic potential of various different types of HPV in their ability to cause dysplastic processes and cervical cancer HPV types are divided into groups with respect to low and high risk. Depending on the capacity of the transformation of cancer types HPV 6,11, 42, 43, 44 are low, while 16, 18, 48, 56 types of high-risk group. HPV types 6 and 11 contribute to the occurrence of genital warts with mild to moderate dysplasia, is very rarely found in cervical cancer. In cancer of the cervix, HPV types 16 and 18 are mostly detected, with HPV 16 50-70%, HPV18 10-20%, other types of HPV are extremely rare (2,4,6,8) HPV 16 type 21% of cases occurs with CIN-I, 57% of cases with CIN-II-III. HPV 16 and 18 types 67-93% of cases are associated with cervical cancers, type 18 occurs 2 times more often than type 16 (11,13)hPV 18 associated with the occurrence of adenocarcinoma, has a high oncogenic potential, the tumor rapidly progresses and usually the tumor differentiation is low, the prognosis is usually poor (11,13). HPV is widespread and has
a high oncogenic potential (11).A group of authors believe that the only effect of the papilloma virus in the cell is insufficient for the development of cancer. When dependent HPV carcinogenesis requires the presence of additional cofactors. Such factors as immortalization and transformation that ensure cell division and differentiation are also involved in the process of carcinogenesis (1,4,6)A number of authors believe that HPV viruses increase the pro-liferative activity of the cervix, damage the mechanism of apoptosis, change the genetic code of the epithelium and are an additional carcinogen of the carcinogenesis of the cervix (4,7,8)Risk factors are not an etiological factor in the development of cancer, together with a number of other factors increase the risk of cancer. In order for the carcinogenic factor to act, the effects of additional exogenous and endogenous factors are necessary (2,6,7).
Infection with the HPV virus and dysplastic processes of the cervix is interrelated with the sexual life, degree of education and the effectiveness of screening programs (1,11,16). Thus, all risk factors can be divided into two groups - managed and uncontrolled risk factors (9,12).
Controlled risk factors include: early onset of sexual activity (up to 17-18 years), frequently change of sexual partner and multiple sexual partners (3 or more) (4,6)promiscuous sexual relations increase the risk of infection and dysplastic processes, thereby risking the occurrence of cervical cancer increases 5-7.5 times (11,12). Dysplastic processes arise mainly imarried women, especially re-born. Uncontrolled risk factors include genetic changes.
Morphological basis of oncological pathologies of the cervix. Numerous clinical studies confirm that in the transformation of the normal epithelium of the cervix into cancer it is possible to diagnose beforehand with special methods. Only 2-11% of cases of cancer occur in the unchanged epithelium (2, 6, 10).
To understand the essence of the pathological processes of processes, it is necessary to know the normal histological structure of the endo and ecto-cervix.
Normally, the mucous membrane of the cervix consists of a covering epithelium and a stroma. The vaginal part of the cervix of women of reproductive age consists of a non-horny, highly differentiated squamous epithelium with complex functional fea-tures.Multilayer coating cervical squamous epithelium has 4 layers: superficial, intermediate, parabasal and basal (1,5,7).
The cells of the surface layer are polygonal with clear contours. The diameter of the cells is 35-50mkm, the edges of the cytoplasm are sometimes curved.Small size of nucleus are decomposed centrally, with colored cytoplasm. Cells of the surface layer are easily desquamated (7,8).
The cells of the intermediate layer are round and oval in shape, smaller than the surface layer cells (20-35 em), the cytoplasm is, on the contrary, larger than the surface layer cells, more basic than their cells. The nucleus of cells is larger than the surface layer cells. Nuclei is found in the nuclei. Cells are mostly found singly, sometimes in single layers.
Parabasal cells 15-18 mkm in size, with clear boundaries, in cytological preparations are detected in the pre- and postmenopausal period. The cytoplasm of cells as a thin rim of basophilic, intensely stained. The nucleus of cells is located in the center. Cells are mostly located singly, very rarely in groups.
Cells of the basal layer are 15-20 mm in size, mostly rounded sometimes oval shaped cells. Cell nuclei is large, intensely colored, surrounded by a thin border basophilous stained cytoplasm ( 4,5,6,8). The ratio of the cells of the epithelial layer change depending on the age, phase of the menstrual cycle of the woman. The women in pre and postmenopausal periods are mainly found the cells of the intermediate, parabasal and basal layers. In smears can also be found the scraps of the squamous epithelium, erythrocytes, leukocytes and single neutrophils. Occasionally, epithelial cells of the upper parts (endometrium, fallopian tubes) of the genital organ, epithelial cells, various bacterial flora, spermatozoa ( 3,5,8).
References
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In smears obtained from the cervical canal is found the cells of the cylindrical epithelium. In pathocytological smears the cells of the cylindrical epithelium are of rounded shape and are located in complexes. The appearance of the epithelium depends on the projection of the cell in the cytologi-cal smears. Epithelial cells of the cervical canal in the lateral projection of a quadrangular shape with irregular margins. The nuclei of cells are round or oval, basophilic. The cytoplasm of cells in the form of a thin rim is located at the base of the cells. When examining a single-layer formation on top or bottom of the cell closely adjoining each other, resemble a honeycomb. The nucleus of cells is located in the center of cells (6,7,9).
Tipe of the invasive cancer is squamous squa-mous keratinizing cancer, squamous non- kera-tinizing cancer, adenocarcinoma, dimorph squa-mous cell carcinoma and undifferentiated cancer (4,5,7).
Background diseases creating a background for the development of cancer contribute to the development of the process. Precancerous diseases in many, untreated cases turn into cancer (3,5,7).
According to many authors, the process of malignant epithelium of the cervix passes several successive stages-dysplasia, cancer in situ, invasive cancer. In some cases, with dysplasia without progressing to the stage of cancer in situ, invasive cancer develops (3).
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