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Сочетанная вирусная инфекция при раке мочевого пузыря
Косова И.В., Лоран О.Б., Синякова Л.А. и др. Сочетанная вирусная инфекция при раке мочевого пузыря. Consilium Medicum. 2018; 20 (7): 30–36. DOI: 10.26442/2075-1753_2018.7.30-36
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Kosova I.V., Loran O.B., Sinyakova L.A. et al. Comorbid viral infection in patients with bladder cancer. Consilium Medicum. 2018; 20 (7): 30–36. DOI: 10.26442/2075-1753_2018.7.30-36
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Аннотация
В настоящее время активно обсуждается роль сочетанной вирусной инфекции в генезе различных онкологических заболеваний, таких как рак молочной железы, шейки матки, орофарингеальной локализации опухолевого процесса.
Цель исследования – выявление морфологических, иммуногистохимических особенностей опухоли мочевого пузыря на фоне сочетанной вирусной инфекции.Материалы и методы. В пилотном исследовании проведено обследование и лечение 100 больных (72 мужчин и 28 женщин) в возрасте от 38 до 90 лет (средний возраст 65±10) с диагнозом «рак мочевого пузыря». Дополнительно выполнены молекулярно-генетические, иммуноферментные методы диагностики наличия вирусных инфекций (герпеса – вируса простого герпеса 1 и 2-го типа, цитомегаловируса – ЦМВ), вируса Эпштейна–Барр – ВЭБ, вируса папилломы человека – ВПЧ высокого онкогенного риска), морфологические (оценка лимфоцитарно-плазмоцитарного инфильтрата, активности воспаления, цитопатических изменений), иммуногистохимические исследования (CD31, EGFR, Ki67, p63, p53, CD44, Bcl-2).
Результаты. Экспрессия EGFR у пациентов с наличием вирусных ДНК в опухолевой ткани коррелировала с наличием ВПЧ в опухоли (R=0,354, p=0,115), уровнем экспрессии р63 (R=0,707, p=0,182), p53 (R=0,499, p=0,025), Ki67 (R=0,747, p=0,05), а также уровнем анти-ВЭБ Ig-VCA (R=0,47, p=0,032). У пациентов с наличием ВЭБ в опухолевой ткани уровень экспрессии ростовых факторов коррелировал с уровнем противовирусных антител к ВЭБ анти-ВЭБ Ig-VCA (R=0,577, p=0,049), наличием койлоцитоза (R=0,368, p=0,24) и внутриядерных включений (R=0,485, p=0,11) как проявлений ВПЧ-инфекции. У пациентов с отсутствием вирусных ДНК имела место незначительная степень цитопатических изменений (2 балла: 10,3% vs 28,6%, р=0,046), тогда как при наличии вирусных ДНК степень этих изменений выше (3 балла: 27,6% vs 9,5% соответственно, p=0,06). Такая же тенденция прослеживается и в случае наличия внутриядерных включений (1 балл: 10,7% vs 28,6%, р=0,046; 2–3 балла: по 17,9% vs 9,5% и 11,9% соответственно). Получены высокие корреляционные связи между пролиферативной активностью и наличием ВПЧ высокого онкогенного риска в опухолевой ткани (R=0,706, p=0,05), койлоцитозом и факторами неоангиогенеза (R=0,576, p=0,008), маркерами пролиферации (R=0,408, p=0,316). Умеренные корреляционные связи были выявлены между наличием внутриядерных включений и ВЭБ в опухолевой ткани (R=0,303, p=0,04), койлоцитозом (R=0,411, p=0,005), очаговой гиперплазией (R=0,459, p=0,001), периваскулярной инфильтрацией (R=0,335, p=0,023). Наличие ЦМВ в опухолевой ткани коррелировало с очаговой гиперплазией в виде фолликулов (R=0,362, p=0,012), койлоцитозом (R=0,32, p=0,028), наличием лейкоцитов (R=0,439, p=0,012) и эозинофилов (R=0,439, p=0,012).
Заключение. Признаки сочетанной вирусной инфекции в той или иной степени определяются у пациентов как с наличием, так и отсутствием вирусных ДНК в опухолевой ткани, определенных методом полимеразной цепной реакции. Определяются корреляционные взаимосвязи между морфологическими, молекулярно-генетическими, иммуноферментными показателями наличия вирусной коинфекции у больных раком мочевого пузыря. Повышение пролиферативной активности, экспрессии факторов апоптоза, ростовых факторов у пациентов с наличием вирусных ДНК в опухолевой ткани свидетельствует о неблагоприятном течении опухолевого процесса.
Ключевые слова: рак мочевого пузыря, вирус Эпштейна–Барр, цитомегаловирус, вирусы простого герпеса 1 и 2-го типа, вирус папилломы человека высокого онкогенного риска, коинфекция, CD31, Ki67, EGFR, Bcl-2.
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The role of combined viral infection in the genesis of various cancers, such as breast cancer, cervical cancer, oropharyngeal localization of the tumor process is being actively discussed.
The aim of the study was to identify possible morphological, immunohistochemical features of the bladder tumor against the background of a combined viral infection. 100 patients (72 men and 28 women) aged 38 to 90 years (mean age 65±10) with a diagnosis of bladder cancer were examined and treated. In addition, molecular genetic, serological methods for the diagnosis of viral infections (herpes type 1 and 2, cytomegalovirus – CMV, Epstein–Barr virus – EBV, human papillomavirus – HPV of high oncogenic risk), morphological and immunohistochemical studies were performed. The indicators of proliferative activity, factors of angiogenesis, growth factors depending on the degree of anaplasia and the stage of the process are analyzed.Results. The expression of EGFR in patients with the presence of viral DNA in tumor tissue correlated with the presence of HPV in the tumor (R=0.354, p=0.115), p63 (R=0.707, p=0.182), p53 (R=0.499, p=0.025), Ki67 (R=0.747, p=0.05) and also with the level of anti-EBV Ig-VCA (R=0.47, p=0.032). In patients with the presence of EBV in tumor tissue, expression of growth factors correlated with the level of anti-EBV Ig-VCA (R=0.577, p=0.049), the presence of coylocytosis (R=0.368, p=0.24) and intranuclear inclusions (R=0.485, p=0.11) as manifestations of HPV infection. In patients with no viral DNA there is a slight degree of cytopathic changes (2 points: 10.3% vs. 28.6%, p=0.046), whereas in the presence of viral DNA the degree of these changes is higher (3 points: 27.6% vs. 9.5% respectively, p=0.06). The same situation can be observed in the case of the presence of intra-nuclear inclusions (1 point: 10.7% vs. 28.6%, p=0.046; 2–3 points: 17.9% vs 9.5% and 11.9% respectively). High correlation links between proliferative activity and the presence of high oncogenic risk HPV in tumor tissue were obtained (R=0.706, p=0.05), koilocytosis and factors of angiogenesis (R=0.576, p=0.008) and markers of proliferation (R=0.408, p=0.316). Moderate correlations were found between the presence of intracardiac inclusions and the presence of EBV in tumor tissue (R=0.303, p=0.04), coilocytosis (R=0.411, p=0.005), focal hyperplasia (R=0.459, p=0.001), perivascular infiltration (R=0.335, p=0.023). The presence of CMV in tumor tissue was correlated with focal hyperplasia in the form of follicles (R=0.362, p=0.012), coilocytosis (R=0.32, p=0.028), the presence of leukocytes (R=0.439, p=0.012) and eosinophils (R=0.439, p=0.012).
Conclusion. The signs of a combined viral infection are to be determined both in patients with the presence and absence of viral DNA in the tumor tissue. Correlation interrelations between morphological, molecular genetic, immunoenzyme indicators of presence of virus co-infection in patients with bladder cancer are determined. Increased proliferative activity, expression of apoptosis factors, growth factors in patients with the presence of viral DNA in tumor tissue indicates an unfavorable course of the tumor process.
Key words: bladder cancer, Epstein–Barr virus, cytomegalovirus, herpes simplex viruses 1 and 2 type, human papillomavirus of high oncogenic risk, co-infection, CD31, Ki67, EGFR, Bcl-2.
Полный текст
Список литературы
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________________________________________________
1. Harald zur Hausen. Infections causing human cancer. 2006. Wiley–VCH Verlag GmbH and Co. KGA, Weinheim. p 517.
2. Jalilvand S, Shoja Z, Hamkar R. Human papillomavirus burden in different cancers in Iran: a systematic assessment. Asian Pac J Cancer Prev 2014; 15 (17): 7029–35. [PubMed]
3. Karbalaie Niya HM, Safarnezhad Tameshkel F, Panahi M et al. Human papillomavirus investigation in head and neck squamous cell carcinoma: initial report from the low risk HPV types associations. Asian Pac J Cancer Prev 2017; 18 (9): 2573–9. [PubMed]
4. Yahyapour Y, Shamsi-Shahrabadi M, Mahmoudi M et al. Evaluation of human papilloma virus infection in patients with esophageal squamous cell carcinoma from the Caspian Sea area, north of Iran. Asian Pac J Cancer Prev 2012; 13 (4): 1261–6.[PubMed]
5. Lawson JS, Glenn WK, Whitaker NJ. Breast cancer, human papilloma virus and sexual activities. Br J Cancer 2008; 98: 510–1. DOI: 10.1038/sj.bjc.6604104
6. Isakov V.A., Arhipova E.I., Isakov D.V. Gerpesvirusnye infekcii cheloveka. Rukovodstvo dlya vrachej. Izd. 2-e, pererab. i dop. SPb.: SpecLit, 2013. [in Russian]
7. Richardson AK, Currie MJ, Robinson BA et al. Cytomegalovirus and Epstein-Barr virus in breast cancer. PLoS One 2015; 10 (2): e0118989.
8. Tsao SW, Tsang CM, To KF, Lo KW. The role of Epstein–Barr virus in epithelial malignancies. J Pathol 2015; 235: 323–33. [PubMed]
9. Young LS, Rickinson AB. Epstein–Barr virus: 40 years on. Nat Rev Cancer 2004; 4: 757–68. [PubMed]
10. Rickinson AB. Co‐infections, inflammation and oncogenesis: future directions for EBV research. Semin Cancer Biol 2014; 26: 99–115. [PubMed]
11. Michaelis M, Doerr HW, Cinatl JJr. The story of Human Cytomegalovirus and Cancer Increasing Evidence and Open Questions. Neoplasia 2009; 11 (1): 1–9.
12. Andreeva Yu.Yu. Morfologicheskie i molekulyarno-biologicheskie faktory prognoza raka mochevogo puzyrya. Dis. … d-ra med. nauk. M., 2009. [in Russian]
13. Abol-Enein H. Infection: is it cause of bladder cancer? Scand H Urol Nephrol Suppl 2008; 218: 79–84.
14. Аbe T, Shinohara N, Tada M et al. Infiltration of Epstein–Barr virus-harboring lymphocytes occurs in a large subset of bladder cancers. Int J Urol 2008; 15 (5): 429–34. DOI: 10.1111/j.1442-2042.2008.02030.x
15. Panagiotakis GI, Papadogianni D, Chatziioannou MN et al. Association of human herpes, papilloma and polyoma virus families with bladder cancer. Tumour Biol 2013; 34 (1): 71–9. DOI: 10.1007/s13277-012-0512-2
16. Chuang KL, Pang ST, Liao SK et al. Epstein–Barr virus DNA load in tumour tissues correlates with poor differentiation status in non-muscle invasive urothelial carcinomas. BJU Int 2011; 107 (1): 150–4. DOI: 10.1111/j.1464-410X.2010.09474.x
17. Fioriti D, Pietropaolo V, Dal Forno S et al. Urothelial carcinoma and viral infections: different association with human polyomaviruses and papillomaviruses. Int J Immunopathol Pharmacol 2003; 16 (3): 283–83.
18. Golovina DA, Ermilova VD, Zavalishina LE et al. Loss of Cell Differentiation in HPV-Associated Bladder Cancer. Bull Exp Biol Med 2016; 161 (1): 96–8. DOI: 10.1007/s10517-016-3354-x
19. Naushad W, Surriya O, Sadia H. Prevalence of EBV, HPV and MMTV in Pakistani breast cancer patients: A possible etiological role of viruses in breast cancer. Infect Genet Evol 2017; 54: 230–7. DOI: 10.1016/j.meegid.2017.07.010
20. Jiang R, Ekshyyan O, Moore-Medlin T et al. Association between human papilloma virus/Epstein–Barr virus coinfection and oral carcinogenesis. J Oral Pathol Med 2015; 44 (1): 28–36. DOI: 10.1111/jop.12221
21. McCormick TM, Canedo NH, Furtado YL et al. Association between human papillomavirus and Epstein–Barr virus DNA and gene promoter methylation of RB1 and CDH1 in the cervical lesions: a transversal study. Diagn Pathol 2015; 10: 59. DOI: 10.1186/s13000-015-0283-3
22. James S.Lawson, Brian Salmons, Wendy K.Glenn. Oncogenic Viruses and Breast Cancer: Mouse Mammary Tumor Virus (MMTV), Bovine Leukemia Virus (BLV), Human Papilloma Virus (HPV), and Epstein–Barr Virus (EBV). Front Oncol 2018; 8: 1.
23. Szostek S, Zawilinska B, Kopec J, Kosz-Vnenchak M. Herpesviruses as possible cofactors in HPV-16-related oncogenesis. Acta Biochim Pol 2009; 56 (2): 337–42.
24. James S.Lawson, Wendy K.Glenn. Multiple oncogenic viruses are present in human breast tissues before development of virus associated breast cancer. Infect Agent Cancer 2017; 12: 55.
25. Zhou BP, Hun MC. Dysregulation of cellular signaling by HER2/neu in breast Cancer. Semin Oncol 2003; 30 (5 Suppl. 16): 38–48.
26. Loran O.B., Sinyakova L.A., Gundorova L.V. i dr. Morfologicheskie osobennosti raka mochevogo puzyrya u bolnyh s hronicheskoj gerpes-virusnoj infekciej. Lechashij vrach. 2017; 9: 13–8. [in Russian]
27. Flamand L Romerio F, Reitz MS, Gallo RC. CD4 promoter transactivation by human herpesvirus 6. J Virol 1998; 72 (11): 8797–805.
28. Abudoukadeer A, Niyazi M, Aikula A et al. Association of EBV and HPV co-infection with the development of cervical cancer in ethnic Uyghur women. Eur J Gynaecol Oncol 2015; 36 (5): 546–50.
2. Jalilvand S, Shoja Z, Hamkar R. Human papillomavirus burden in different cancers in Iran: a systematic assessment. Asian Pac J Cancer Prev 2014; 15 (17): 7029–35. [PubMed]
3. Karbalaie Niya HM, Safarnezhad Tameshkel F, Panahi M et al. Human papillomavirus investigation in head and neck squamous cell carcinoma: initial report from the low risk HPV types associations. Asian Pac J Cancer Prev 2017; 18 (9): 2573–9. [PubMed]
4. Yahyapour Y, Shamsi-Shahrabadi M, Mahmoudi M et al. Evaluation of human papilloma virus infection in patients with esophageal squamous cell carcinoma from the Caspian Sea area, north of Iran. Asian Pac J Cancer Prev 2012; 13 (4): 1261–6.[PubMed]
5. Lawson JS, Glenn WK, Whitaker NJ. Breast cancer, human papilloma virus and sexual activities. Br J Cancer 2008; 98: 510–1. DOI: 10.1038/sj.bjc.6604104
6. Isakov V.A., Arhipova E.I., Isakov D.V. Gerpesvirusnye infekcii cheloveka. Rukovodstvo dlya vrachej. Izd. 2-e, pererab. i dop. SPb.: SpecLit, 2013. [in Russian]
7. Richardson AK, Currie MJ, Robinson BA et al. Cytomegalovirus and Epstein-Barr virus in breast cancer. PLoS One 2015; 10 (2): e0118989.
8. Tsao SW, Tsang CM, To KF, Lo KW. The role of Epstein–Barr virus in epithelial malignancies. J Pathol 2015; 235: 323–33. [PubMed]
9. Young LS, Rickinson AB. Epstein–Barr virus: 40 years on. Nat Rev Cancer 2004; 4: 757–68. [PubMed]
10. Rickinson AB. Co‐infections, inflammation and oncogenesis: future directions for EBV research. Semin Cancer Biol 2014; 26: 99–115. [PubMed]
11. Michaelis M, Doerr HW, Cinatl JJr. The story of Human Cytomegalovirus and Cancer Increasing Evidence and Open Questions. Neoplasia 2009; 11 (1): 1–9.
12. Andreeva Yu.Yu. Morfologicheskie i molekulyarno-biologicheskie faktory prognoza raka mochevogo puzyrya. Dis. … d-ra med. nauk. M., 2009. [in Russian]
13. Abol-Enein H. Infection: is it cause of bladder cancer? Scand H Urol Nephrol Suppl 2008; 218: 79–84.
14. Аbe T, Shinohara N, Tada M et al. Infiltration of Epstein–Barr virus-harboring lymphocytes occurs in a large subset of bladder cancers. Int J Urol 2008; 15 (5): 429–34. DOI: 10.1111/j.1442-2042.2008.02030.x
15. Panagiotakis GI, Papadogianni D, Chatziioannou MN et al. Association of human herpes, papilloma and polyoma virus families with bladder cancer. Tumour Biol 2013; 34 (1): 71–9. DOI: 10.1007/s13277-012-0512-2
16. Chuang KL, Pang ST, Liao SK et al. Epstein–Barr virus DNA load in tumour tissues correlates with poor differentiation status in non-muscle invasive urothelial carcinomas. BJU Int 2011; 107 (1): 150–4. DOI: 10.1111/j.1464-410X.2010.09474.x
17. Fioriti D, Pietropaolo V, Dal Forno S et al. Urothelial carcinoma and viral infections: different association with human polyomaviruses and papillomaviruses. Int J Immunopathol Pharmacol 2003; 16 (3): 283–83.
18. Golovina DA, Ermilova VD, Zavalishina LE et al. Loss of Cell Differentiation in HPV-Associated Bladder Cancer. Bull Exp Biol Med 2016; 161 (1): 96–8. DOI: 10.1007/s10517-016-3354-x
19. Naushad W, Surriya O, Sadia H. Prevalence of EBV, HPV and MMTV in Pakistani breast cancer patients: A possible etiological role of viruses in breast cancer. Infect Genet Evol 2017; 54: 230–7. DOI: 10.1016/j.meegid.2017.07.010
20. Jiang R, Ekshyyan O, Moore-Medlin T et al. Association between human papilloma virus/Epstein–Barr virus coinfection and oral carcinogenesis. J Oral Pathol Med 2015; 44 (1): 28–36. DOI: 10.1111/jop.12221
21. McCormick TM, Canedo NH, Furtado YL et al. Association between human papillomavirus and Epstein–Barr virus DNA and gene promoter methylation of RB1 and CDH1 in the cervical lesions: a transversal study. Diagn Pathol 2015; 10: 59. DOI: 10.1186/s13000-015-0283-3
22. James S.Lawson, Brian Salmons, Wendy K.Glenn. Oncogenic Viruses and Breast Cancer: Mouse Mammary Tumor Virus (MMTV), Bovine Leukemia Virus (BLV), Human Papilloma Virus (HPV), and Epstein–Barr Virus (EBV). Front Oncol 2018; 8: 1.
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Авторы
И.В.Косова*1,2, О.Б.Лоран1, Л.А.Синякова1, Л.В.Гундорова2, В.А.Косов3, И.Е.Погодина4, Д.Н.Колбасов2
1 ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России. 125993, Россия, Москва, ул. Баррикадная, д. 2/1;
1 Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation. 125993, Russian Federation, Moscow, ul. Barrikadnaia, d. 2/1;
2 V.P.Demikhov City Clinical Hospital of the Department of Health of Moscow. 109263, Russian Federation, Moscow, ul. Shkuleva, d. 4;
3 Komi Republican Oncology Center. 167904, Russian Federation, Syktyvkar, p. Krasnozatonskij, Nyuvchimskoe sh., d. 46;
4 Vologda Regional Clinical Hospital №2. 162602, Russian Federation, Cherepovets, ul. Danilova, d. 15
*kosovainga@mail.ru
1 ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России. 125993, Россия, Москва, ул. Баррикадная, д. 2/1;
2 ГБУЗ «Городская клиническая больница им. В.П.Демихова» Департамента здравоохранения г. Москвы. 109263, Россия, Москва, ул. Шкулева, д. 4;
3 ГУ «Коми республиканский онкологический диспансер». 167904, Россия, Сыктывкар, п. Краснозатонский, Нювчимское ш., д. 46;
4 БУЗ «Вологодская областная клиническая больница №2». 162602, Россия, Череповец, ул. Данилова, д. 15
*kosovainga@mail.ru
4 БУЗ «Вологодская областная клиническая больница №2». 162602, Россия, Череповец, ул. Данилова, д. 15
*kosovainga@mail.ru
________________________________________________
I.V.Kosova*1,2, O.B.Loran1, L.A.Sinyakova1, L.V.Gundorova2, V.A.Kosov3, I.E.Pogodina4, D.N.Kolbasov2
1 Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation. 125993, Russian Federation, Moscow, ul. Barrikadnaia, d. 2/1;
2 V.P.Demikhov City Clinical Hospital of the Department of Health of Moscow. 109263, Russian Federation, Moscow, ul. Shkuleva, d. 4;
3 Komi Republican Oncology Center. 167904, Russian Federation, Syktyvkar, p. Krasnozatonskij, Nyuvchimskoe sh., d. 46;
4 Vologda Regional Clinical Hospital №2. 162602, Russian Federation, Cherepovets, ul. Danilova, d. 15
*kosovainga@mail.ru
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