ПРОГНОСТИЧЕСКОЕ И ДИФФЕРЕНЦИАЛЬНО-ДИАГНОСТИЧЕСКОЕ ЗНАЧЕНИЕ ЭКСПРЕССИИ ЦИТОКЕРАТИНОВ 7 И 19 И ТИРЕОИДНОГО ФАКТОРА ТРАНСКРИПЦИИ-1 В НЕЙРОЭНДОКРИННЫХ ОПУХОЛЯХ ЛЕГКИХ РАЗНОЙ СТЕПЕНИ ЗЛОКАЧЕСТВЕННОСТИ

Статья в Elpub

Альманах клинической медицины. 2016; 44: 613-623

ПРОГНОСТИЧЕСКОЕ И ДИФФЕРЕНЦИАЛЬНО-ДИАГНОСТИЧЕСКОЕ ЗНАЧЕНИЕ ЭКСПРЕССИИ ЦИТОКЕРАТИНОВ 7 И 19 И ТИРЕОИДНОГО ФАКТОРА ТРАНСКРИПЦИИ-1 В НЕЙРОЭНДОКРИННЫХ ОПУХОЛЯХ ЛЕГКИХ РАЗНОЙ СТЕПЕНИ ЗЛОКАЧЕСТВЕННОСТИ

Гуревич Л. Е., Корсакова Н. А., Воронкова И. А., Казанцева И. А., Ашевская В. Е., Титов А. Г., Когония Л. М., Мазурин В. С., Шабаров В. Л.

https://doi.org/10.18786/2072-0505-2016-44-5-613-623

Аннотация

Актуальность. Нейроэндокринные опухоли легких (НЭОЛ) представляют собой целый спектр опухолей, различающихся по степени злокачественности и прогнозу. Несмотря на их распространенность – от 20 до 25% всех случаев рака данной локализации – многие аспекты, определяющие особенности клинического течения НЭОЛ и прогноз, еще недостаточно хорошо изучены. Цель – выявить морфологические и иммунофенотипические особенности разных типов НЭОЛ, которые бы более точно отражали их биологический потенциал и позволяли прогнозировать менее благоприятное клиническое течение. Материал и методы. Проводили иммуногистохимическое исследование диагностических биопсий и операционного материала от 152 пациентов с НЭОЛ в возрасте 53±13 лет. Были диагностированы 49 типичных карциноидов, 32 атипичных карциноида, 60 мелкоклеточных нейроэндокринных карцином/раков и 11 крупноклеточных нейроэндокринных карцином/раков, которые составили 32,2, 21,1, 39,5 и 7,2% соответственно. Использовали маркеры нейроэндокринной дифференцировки – синаптофизин, хромогранин А и CD56, а также цитокератины 7 и 19, тиреоидный фактор транскрипции-1 (TTF-1), Ki67. Pезультаты подвергли статистической обработке с использованием дисперсионного анализа (ANOVA), критерия χ², апостериорных сравнений с поправкой Бонферрони. Результаты. Чаще всего экспрессия цито- кератинов 7 и 19 встречалась в группе крупноклеточной нейроэндокринной карциномы – в 72,7 и 90,9% случаев соответственно, реже в группе атипичного карциноида (50 и 53,3%) и мелкоклеточной нейроэндокринной карциномы (41,7 и 64,6%), редко – типичного карциноида (5,9 и 15,9%). Частота экспрессии цитокератинов 7 и 19 была статистически значимо меньше в группе типичного карциноида по сравнению с атипичным карциноидом, мелкоклеточной и крупноклеточной нейроэндокринными карциномами (р<0,05, χ²,> <0,05, χ², апостериорные сравнения). Экспрессия цитокератина 19 значимо чаще наблюдалась в крупноклеточных нейроэндокринных карциномах, чем в мелкоклеточных нейроэндокринных карциномах и атипичных карциноидах (р <0,05 χ², апостериорные сравнения). Экспрессия TTF-1 в клетках типичных карциноидов выявлялась очень редко – в 6,5% случаев, в атипичных карциноидах значительно чаще – в 61,5%, а в мелкоклеточных и крупноклеточных нейроэндокринных карциномах – в подавляющем большинстве случаев: 82,7 и 77,8% соответственно. Частота экспрессии TTF-1 в типичных карциноидах была значимо меньше, чем в атипичных карциноидах, мелкоклеточных и крупноклеточных нейроэндокринных карциномах (р <0,01, χ², апостериорные сравнения). Средний индекс пролиферации опухолевых клеток Ki67 был самым низким в группе типичного карциноида – 2,6%, в группе атипичного карциноида он достигал 12%, крупноклеточной нейроэндокринной карциномы – 44%, а максимальным оказался при мелкоклеточной нейроэндокринной карциноме – 61%. Имелись статистически значимые различия в величине среднего индекса Ki67 во всех 4 группах НЭОЛ (р <0,001, ANOVA, апостериорные сравнения). Заключение. Экспрессия в нейроэндокринных опухолях легкого TTF-1, цитокератинов 7 и 19 характеризует менее дифференцированный клеточный иммунофенотип и позволяет выделить среди высокодифференцированных типичных и атипичных карциноидов группу риска с менее благоприятным клиническим течением.

Список литературы

1. Travis WD, Brambilla E, Burke AP, Marx A, Nichol-son AG, editors. WHO Classiﬁcation of tumours of the lung, pleura, thymus and heart. 4th ed. Lyon: IARC; 2015. 412 p.

2. Тер-Ованесов МД, Полоцкий БЕ. Карциноидные опухоли торакальной локализации – современное состояние проблемы. Практическая онкология. 2005;6(4):220–6.

3. Gustafsson BI, Kidd M, Chan A, Malfertheiner MV, Modlin IM. Bronchopulmonary neuroendocrine tumors. Cancer. 2008;113(1):5–21. doi: 10.1002/cncr.23542.

4. Caplin ME, Baudin E, Ferolla P, Filosso P, Gar-cia-Yuste M, Lim E, Oberg K, Pelosi G, Perren A, Rossi RE, Travis WD. Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann On-col. 2015;26(8):1604–20. doi: 10.1093/annonc/ mdv041.

5. Granberg D, Eriksson B, Wilander E, Grim-fjard P, Fjallskog ML, Oberg К, Skogseid B. Experience in treatment of metastatic pulmonary car-cinoid tumors. Ann Oncol. 2001;12(10):1383–91.

6. Okereke IC, Taber AM, Griffith RC, Ng TT. Outcomes after surgical resection of pulmonary car-cinoid tumors. J Cardiothorac Surg. 2016;11:35. doi: 10.1186/s13019-016-0424-0.

7. Hamanaka W, Motoi N, Ishikawa S, Ushijima M, Inamura K, Hatano S, Uehara H, Okumura S, Nakagawa K, Nishio M, Horai T, Aburatani H, Matsuura M, Iwasaki A, Ishikawa Y. A subset of small cell lung cancer with low neuroendocrine expression and good prognosis: a comparison study of surgical and inoperable cases with biopsy. Hum Pathol. 2014;45(5):1045–56. doi: 10.1016/j.humpath.2014.01.001.

8. Travis WD, Giroux DJ, Chansky K, Crowley J, Asamura H, Brambilla E, Jett J, Kennedy C, Ra-mi-Porta R, Rusch VW, Goldstraw P; International Staging Committee and Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for the inclusion of broncho-pulmonary carcinoid tumors in the forthcoming (seventh) edition of the TNM Classiﬁcation for Lung Cancer. J Thorac Oncol. 2008;3(11):1213–23. doi: 10.1097/JTO.0b013e31818b06e3.

9. Phan AT, Oberg K, Choi J, Harrison LH Jr, Has-san MM, Strosberg JR, Krenning EP, Kocha W, Woltering EA, Maples WJ; North American Neuroendocrine Tumor Society (NANETS). NA-NETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-diﬀerentiated neuroendocrine tumors of the thorax (includes lung and thymus). Pancreas. 2010;39(6):784–98. doi: 10.1097/ MPA.0b013e3181ec1380.

10. Rindi G, Klersy C, Inzani F, Fellegara G, Ampollini L, Ardizzoni A, Campanini N, Carbognani P, De Pas TM, Galetta D, Granone PL, Righi L, Rusca M, Spaggiari L, Tiseo M, Viale G, Volante M, Papot-ti M, Pelosi G. Grading the neuroendocrine tumors of the lung: an evidence-based proposal. Endocr Relat Cancer. 2013;21(1):1–16. doi: 10.1530/ERC-13-0246.

11. Klimstra D, Modlin IR, Coppola D, Lloyd RV, Suster S. The pathologic classiﬁcation of neuroendocrine tumors a review of nomenclature, grading, and staging systems. Pancreas. 2010;39(6):707–12. doi: 10.1097/ MPA.0b013e3181ec124e.

12. Perez EA, Koniaris LG, Snell SE, Sumner WE 3rd, Lee DJ, Hodgson NC, Livingstone AS, Frances-chi D. 7201 carcinoids: increasing incidence overall and disproportionate mortality in the elderly. World J Surg. 2007;31(5):1022–30. doi: 10.1007/s00268-005-0774-6.

13. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A, Evans DB. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26(18):3063–72. doi: 10.1200/ JCO.2007.15.4377.

14. Lou F, Sarkaria I, Pietanza C, Travis W, Roh MS, Sica G, Healy D, Rusch V, Huang J. Recurrence of pulmonary carcinoid tumors after resection: implications for postoperative surveillance. Ann Thorac Surg. 2013;96(4):1156–62. doi: 10.1016/j. athoracsur.2013.05.047.

15. Wu BS, Hu Y, Sun J, Wang JL, Wang P, Dong WW, Tao HT, Gao WJ. Analysis on the characteristics and prognosis of pulmonary neuro-endocrine tumors. Asian Pac J Cancer Prev. 2014;15(5):2205–10.

16. Walts AE, Ines D, Marchevsky AM. Limited role of Ki-67 proliferative index in predicting overall short-term survival in patients with typical and atypical pulmonary carcinoid tumors. Mod Pathol. 2012;25(9):1258–64. doi: 10.1038/mod-pathol.2012.81.

17. Lau SK, Luthringer DJ, Eisen RN. Thyroid transcription factor-1: a review. Appl Immunohistochem Mol Morphol. 2002;10(2):97–102. doi: 10.1097/00022744-200206000-00001.

18. Nakamura N, Miyagi E, Murata S, Kawaoi A, Katoh R. Expression of thyroid transcription factor-1 in normal and neoplastic lung tissues. Mod Pathol. 2002;15(10):1058–67. doi: 10.1097/01. MP.0000028572.44247.CF.

19. DeLellis RA, Shin SJ, Treaba OD. Chapter 10: Immunohistology of endocrine tumors. In: Dabbs DJ, editor. Diagnostic immunohisto-chemistry: theranostic and genomic applications. 3rd ed. Philadelphia: Saunders Elsevier; 2010. p. 291–329. doi: http://dx.doi.org/10.1016/ B978-1-4160-5766-6.00014-5.

20. Jagirdar J. Application of immunohisto-chemistry to the diagnosis of primary and metastatic carcinoma to the lung. Arch Pathol Lab Med. 2008;132(3):384–96. doi: 10.1043/1543-2165(2008)132[384:AOITTD]2.0. CO;2.

21. Mukhopadhyay S, Katzenstein AL. Subclassiﬁcation of non-small cell lung carcinomas lacking morphologic diﬀerentiation on biopsy specimens: Utility of an immunohistochemical panel containing TTF-1, napsin A, p63, and CK5/6. Am J Surg Pathol. 2011;35(1):15–25. doi: 10.1097/ PAS.0b013e3182036d05.

22. Lin F, Liu H. Immunohistochemistry in undiﬀerentiated neoplasm/tumor of uncertain origin. Arch Pathol Lab Med. 2014;138(12):1583–610. doi: 10.5858/arpa.2014-0061-RA.

23. Govindan R, Page N, Morgensztern D, Read W, Tierney R, Vlahiotis A, Spitznagel EL, Picciril-lo J. Changing epidemiology of small cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol. 2006;24(28):4539–44. doi: 10.1200/ JCO.2005.04.4859.

24. Pelosi G, Rindi G, Travis WD, Papotti M. Ki-67 antigen in lung neuroendocrine tumors: unravelling a role in clinical practice. J Tho-rac Oncol. 2014;9(3):273–84. doi: 10.1097/ JTO.0000000000000092.

25. Ustaalioglu BB, Ulas A, Esbah O, Turan N, Bilici A, Demirci U, Alkıs N, Seker M, Oksuzoglu B, Gumus M, ASMO (Anatolian Society of Medical Oncology). Large cell neuroendocrine carcinoma: retrospective analysis of 24 cases from four oncology centers in Turkey. Thoracic Cancer. 2013;4:161–6. doi: 10.1111/j.1759-7714.2012.00129.x.

26. Folpe AL, Gown AM, Lamps LW, Garcia R, Dail DH, Zarbo RJ, Schmidt RA. Thyroid transcription factor-1: immunohistochemical evaluation in pulmonary neuroendocrine tumors. Mod Pathol. 1999;12(1):5–8.

27. Sturm N, Rossi G, Lantuejoul S, Papotti M, Frachon S, Claraz C, Brichon PY, Brambilla C, Brambilla E. Expression of thyroid transcription factor-1 in the spectrum of neuroendocrine cell lung proliferations with special interest in carcinoids. Hum Pathol. 2002;33(2):175–82. doi: http://dx.doi.org/10.1053/hupa.2002.31299.

28. Fisseler-Eckhoﬀ A, Demes M. Neuroendocrine tumors of the lung. Cancers (Basel). 2012;4(3):777–98. doi: 10.3390/cancers4030777.

29. Rekhtman N. Neuroendocrine tumors of the lung: an update. Arch Pathol Lab Med. 2010;134(11):1628–38. doi: 10.1043/2009-0583-RAR.1.

30. Hiroshima K, Iyoda A, Shida T, Shibuya K, Iizasa T, Kishi H, Tanizawa T, Fujisawa T, Nakatani Y. Distinction of pulmonary large cell neuro-endocrine carcinoma from small cell lung carcinoma: a morphological, immunohisto-chemical, and molecular analysis. Mod Pathol. 2006;19(10):1358–68. doi: 10.1038/mod-pathol.3800659.

31. Zhang H, Liu J, Cagle PT, Allen TC, Laga AC, Zander DS. Distinction of pulmonary small cell carcinoma from poorly diﬀerentiated squamous cell carcinoma: an immunohistochemical approach. Mod Pathol. 2005;18(1):111–8. doi: 10.1038/modpathol.3800251.

32. Agoﬀ SN, Lamps LW, Philip AT, Amin MB, Schmidt RA, True LD, Folpe AL. Thyroid transcription factor-1 is expressed in extrapulmo-nary small cell carcinomas but not in other extrapulmonary neuroendocrine tumors. Mod Pathol. 2000;13(3):238–42. doi: 10.1038/mod-pathol.3880044.

33. Verset L, Arvanitakis M, Loi P, Closset J, Delhaye M, Remmelink M, Demetter P. TTF-1 positive small cell cancers: Don't think they're always primary pulmonary! Worl J Gastrointest Oncol. 2011;3(10):144–7. doi: 10.4251/wjgo. v3.i10.144.

34. Nagashio R, Sato Y, Matsumoto T, Kageyama T, Satoh Y, Ryuge S, Masuda N, Jiang SX, Okayasu I. Signiﬁcant high expression of cytokeratins 7, 8, 18, 19 in pulmonary large cell neuroendocrine carcinomas, compared to small cell lung carcinomas. Pathol Intern. 2010;60(2):71–7. doi: 10.1111/j.1440-1827.2009.02487.x.

35. Naseem N, Reyaz N, Nagi AH, Ashraf M, Sami W. Immunohistochemical expression of cytokeratin-19 in non-small cell lung carcinomas – an experience from a Tertiary Care Hospital in La-hore. Intern J Pathol. 2010;8(2):54–9.

36. Rossi G, Marchioni A, Milani M, Scotti RF, Foroni M, Cesinaro AM, Longo L, Migaldi M, Cavazza A. TTF-1, Cytokeratin 7, 34βE12, and CD56/ NCAM immunostaining in the subclassiﬁcation of large cell carcinomas of the lung. Am J Clin Pathol. 2004;122(6):884–93. doi: http://dx.doi. org/10.1309/9W8D3XCVLRA3858A.

37. Nitadori J, Ishii G, Tsuta K, Yokose T, Murata Y, Kodama T, Nagai K, Kato H, Ochiai A. Immunohistochemical diﬀerential diagnosis between large cell neuroendocrine carcinoma and small cell carcinoma by tissue microarray analysis with a large antibody panel. Am J Clin Pathol. 2006;125(5):682–692. doi: http://dx.doi. org/10.1309/DT6BJ698LDX2NGGX.

38. Aslam BM, Sahasrabudhe N. Cytokeratin (CK7 and CK20) switching in the natural history of pulmonary small cell carcinoma: an interesting but unpublished phenomenon. J Clin Pathol. 2011;64(4):367–8. doi: 10.1136/ jcp.2010.083816.

39. Райхлин НТ, Букаева ИА, Смирнова ЕА, Пономарева МВ, Чекини АК, Павловская АИ, Шабанов МА. Пролиферативная активность, степень злокачественности и прогноз при карциноидных опухолях легких. Вестник РОНЦ им. Н.Н. Блохина РАМН. 2012;23(4): 17–24.

40. Чекини АК, Павловская АИ, Смирнова ЕА. Карциноидные опухоли легких и тимуса. Морфологические особенности. Архив патологии. 2012;74(2):40–1.

41. Grimaldi F, Muser D, Beltrami CA, Machin P, Mo-relli A, Pizzolitto S, Talmassons G, Marciello F, Colao AA, Monaco R, Monaco G, Faggiano A. Partitioning of bronchopulmonary carcinoids in two diﬀerent prognostic categories by Ki-67 score. Front Endocrinol (Lausanne). 2011;2:20. doi: 10.3389/fendo.2011.00020.

Almanac of Clinical Medicine. 2016; 44: 613-623

THE PROGNOSTIC AND DIFFERENTIAL DIAGNOSTIC VALUE OF CYTOKERATIN 7 AND 19, AND THYROID TRANSCRIPTION FACTOR-1 EXPRESSION IN LUNG NEUROENDOCRINE TUMORS OF VARIOUS GRADES

Gurevich L. E., Korsakova N. A., Voronkova I. A., Kazantseva I. A., Ashevskaya V. E., Titov A. G., Kogoniya L. M., Mazurin V. S., Shabarov V. L.

https://doi.org/10.18786/2072-0505-2016-44-5-613-623

Abstract

Background: Neuroendocrine tumors of the lung (NETL) are a wide range of tumors with various malignancy grades and prognosis. Despite their prevalence being 20 to 25% of all lung cancers, many aspects that impact their clinical course and prognosis are not well understood. Aim – to identify morphological and immunophenotypic characteristics of various NETL types would that more accurately reflect their biological potential and allow for prediction of their unfavorable clinical outcomes. Materials and methods: We performed immunohistochemical assessment of the diagnostic biopsies and surgical specimens from 152 patients with NETL aged 53 ± 13 years and identified 49 typical carcinoids, 32 atypical carcinoids, 60 small cell neuroendocrine carcinomas and 11 large cell neuroendocrine carcinomas, which accounted for 32.2, 21.1, 39.5 and 7.2%, respectively. Markers of neuroendocrine differentiation, such as synaptophysin, chromogranin A and CD56, as well as cytokeratins 7 and 19, thyroid transcription factor-1 (TTF-1), and Ki67 were used. The results were analyzed with analysis of variance (ANOVA), chi-square test (χ²), and post-hoc comparisons with the Bonferroni correction. Results: Most often, the expression of cytokeratins 7 and 19 was found in large cell neuroendocrine carcinoma (72.7 and 90.9%, respectively), less frequently, in atypical carcinoids and small cell neuroendocrine carcinomas (50 and 53.3%; 41.7 and 64.6% of cases, respectively), whereas in typical carcinoids it was rare (5.9 and 15.9%, respectively). The rates of cytokeratin 7 and 19 expression were significantly lower in the typical carcinoids, compared to the atypical carcinoids, small cell neuroendocrine carcinomas and large cell neuroendocrine carcinomas (р < 0.05, χ²). The expression of cytokeratin 19 was significantly more common for large cell neuroendocrine carcinomas, than for small cell neuroendocrine carcinomas and atypical carcinoids (р < 0.01, χ²). The expression of TTF-1 was very rare in the typical carcinoid cells (6.5% of cases) and significantly more often in atypical carcinoids (61.5%) and in small cell neuroendocrine carcinomas and large cell neuroendocrine carcinomas (82.7 and 77.8% of cases, respectively). TTF-1 expression was significantly less frequent in typical than in atypical carcinoids, small cell neuroendocrine carcinomas and large cell neuroendocrine carcinomas (р < 0.01, χ²). The mean index of tumor cell proliferation (Ki67) was the lowest in typical carcinoids (2.6%), amounted to 12% in atypical carcinoids, to 44% in large cell neuroendocrine carcinomas and reached the maximum of 61% in small cell neuroendocrine carcinomas. There were significant differences in the mean Ki67 index in the NETL 4 groups (р < 0.001, ANOVA). Conclusion: Expression of TTF-1, cytokeratin 7 and 19 in the neuroendocrine tumors of the lung is characteristic for a less differentiated cell immunophenotype and allows for identification of the risk group with unfavorable clinical outcome among low-grade typical and atypical carcinoids.

References

1. Travis WD, Brambilla E, Burke AP, Marx A, Nichol-son AG, editors. WHO Classiﬁcation of tumours of the lung, pleura, thymus and heart. 4th ed. Lyon: IARC; 2015. 412 p.

2. Ter-Ovanesov MD, Polotskii BE. Kartsinoidnye opukholi torakal'noi lokalizatsii – sovremennoe sostoyanie problemy. Prakticheskaya onkologiya. 2005;6(4):220–6.

3. Gustafsson BI, Kidd M, Chan A, Malfertheiner MV, Modlin IM. Bronchopulmonary neuroendocrine tumors. Cancer. 2008;113(1):5–21. doi: 10.1002/cncr.23542.

5. Granberg D, Eriksson B, Wilander E, Grim-fjard P, Fjallskog ML, Oberg K, Skogseid B. Experience in treatment of metastatic pulmonary car-cinoid tumors. Ann Oncol. 2001;12(10):1383–91.

6. Okereke IC, Taber AM, Griffith RC, Ng TT. Outcomes after surgical resection of pulmonary car-cinoid tumors. J Cardiothorac Surg. 2016;11:35. doi: 10.1186/s13019-016-0424-0.

15. Wu BS, Hu Y, Sun J, Wang JL, Wang P, Dong WW, Tao HT, Gao WJ. Analysis on the characteristics and prognosis of pulmonary neuro-endocrine tumors. Asian Pac J Cancer Prev. 2014;15(5):2205–10.

17. Lau SK, Luthringer DJ, Eisen RN. Thyroid transcription factor-1: a review. Appl Immunohistochem Mol Morphol. 2002;10(2):97–102. doi: 10.1097/00022744-200206000-00001.

22. Lin F, Liu H. Immunohistochemistry in undiﬀerentiated neoplasm/tumor of uncertain origin. Arch Pathol Lab Med. 2014;138(12):1583–610. doi: 10.5858/arpa.2014-0061-RA.

28. Fisseler-Eckhoﬀ A, Demes M. Neuroendocrine tumors of the lung. Cancers (Basel). 2012;4(3):777–98. doi: 10.3390/cancers4030777.

29. Rekhtman N. Neuroendocrine tumors of the lung: an update. Arch Pathol Lab Med. 2010;134(11):1628–38. doi: 10.1043/2009-0583-RAR.1.

39. Raikhlin NT, Bukaeva IA, Smirnova EA, Ponomareva MV, Chekini AK, Pavlovskaya AI, Shabanov MA. Proliferativnaya aktivnost', stepen' zlokachestvennosti i prognoz pri kartsinoidnykh opukholyakh legkikh. Vestnik RONTs im. N.N. Blokhina RAMN. 2012;23(4): 17–24.

40. Chekini AK, Pavlovskaya AI, Smirnova EA. Kartsinoidnye opukholi legkikh i timusa. Morfologicheskie osobennosti. Arkhiv patologii. 2012;74(2):40–1.

Аннотация

THE PROGNOSTIC AND DIFFERENTIAL DIAGNOSTIC VALUE OF CYTOKERATIN 7 AND 19, AND THYROID TRANSCRIPTION FACTOR-1 EXPRESSION IN LUNG NEUROENDOCRINE TUMORS OF VARIOUS GRADES

Abstract

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