Цель. Изучить прогностическую ценность определения хромогранина А (ХрА) в диагностике феохромоцитомы (ФХЦ). Материалы и методы. Выполнено сравнительное аналитическое исследование с участием 157 пациентов с подозрением на ФХЦ, проводилась статистическая обработка результатов анализа суточной мочи на метанефрин (МН) и норметанефрин, а также анализа крови на ХрА по группам, которые включали пациентов без ФХЦ, с первичной опухолью или ее рецидивом, подтвержденными по данным мультиспиральной компьютерной томографии, и/или сцинтиграфии с метайодбензилгуанидином, и/или пробы с клонидином. Результаты. Рассчитаны показатели эффективности методов по группам и отмечено, что наиболее низкие цифры чувствительности метода определения ХрА наблюдаются в группе с рецидивом ФХЦ (43,8%). При ее исключении из общей выборки специфичность метода сохранилась на высоком уровне (85,45%), а чувствительность значимо возросла – до 87,1%. Также значимо повысился и показатель чувствительности метода определения МН в суточной моче до 96,8% при специфичности в 98,2%. Получены данные о наличии корреляционной связи между диаметром опухоли и ее секреторной активностью: слабая – с уровнем ХрА [коэффициент корреляции Спирмена (rho) 0,491] и сильная с суммарным уровнем метилированных катехоламинов – МКА (rho 0,765). Ложноположительные результаты чаще отмечались у пациентов с другими нейроэндокринными опухолями (37,5%), а также у принимающих ингибиторы протонной помпы (43,75%). Чувствительность и специфичность метода определения ХрА в группе пациентов с результатами анализа на МН в пределах «серой зоны» оказались 50 и 86,1% соответственно. Заключение. Анализ крови на ХрА можно рекомендовать в качестве подтверждающего теста для диагностики ФХЦ при сомнительных показателях МКА или при подозрении на рецидив ФХЦ. Применение теста в качестве метода 1-го ряда – только при отсутствии возможности исследования МКА. При интерпретации ХрА необходимо учитывать состояния, вызывающие ложноположительные результаты.
Aim. To study the prognostic value of determining Chromogranin A blood level in the diagnosis of PHEO. Materials and methods. We conducted a comparative analytical study of 157 patients with suspected PHEO, statistical analysis of 24-hour urinary metanephrine and normetanephrine excretion test was performed, as well as a blood test for CrA, in groups that included patients without PHEO, with primary tumor or its recurrence, confirmed according to MSCT and/or scintigraphy with MIBG and/or the clonidine suppression test. Results. The parameters of efficiency of these methods were calculated by groups and it was noted that the lowest sensitivity of the CrA determination method was observed in the group with recurrence of PHEO (43.8%), their exclusion from the entire sample didn’t change specificity of the method and it remained at a high level (85.45%), though sensitivity significantly increased up to 87.1%. Sensitivity of determining 24-hour urinary metanephrine excretion also increased significantly up to 96.8%, with 98.2% of specificity. The correlation between diameter of the tumor and its secretory activity was identified: small – with CrA level (rho 0.491) and strong – with total level of methylated catecholamines (rho 0.765). False positive results were more often observed in patients present with other neuroendocrine tumors (37.5%), as well as those taking proton-pump inhibitors (43.75%). The sensitivity and specificity of CrA determining method in the group of patients with methanephrins elevated within “gray zone” appeared to be 50 and 86.1%, respectively. Conclusion. A blood test for CrA can be recommended as a confirmatory test for diagnosing PHEO in cases of questionable methylated catecholamines indicators or in cases of suspected relapse of PHEO. The use of the test as a first-line method is only possible if there is no possibility to study methylated catecholamines. When interpreting CrA level, it is necessary to take into account the conditions that may cause false-positive results.
Keywords: pheochromocytoma, chromogranin A, methanephrine, normetanephrine, catecholamines
Список литературы
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21. Юкина М.Ю., Трошина Е.А,. Бельцевич Д.Г., и др. Феохромоцитома/параганглиома: клинико-генетические аспекты. Проблемы эндокринологии. 2013;3:19-26 [Yukina MY, Troshina EA, Beltsevich DG, et al. Pheochromocytoma/paraganglioma: clinical and genetic aspects. Problemy endokrinologii. 2013;3:19-2 (In Russ.)].
doi: 10.14341/probl201359319-26
22. Ardill JES, O’Dorisio TM. Circulating biomarkers in neuroendocrine tumors of the enteropancreatic tract: application to diagnosis, monitoring disease, and as prognostic indicators. Endocrinol Metab Clin North Am. 2010;39(4):777-90. doi:
10.1016/j.ecl.2010.09.001
23. Martucci VL, Pacak K. Pheochromocytoma and Paraganglioma: Diagnosis, Genetics, Management, and Treatment. Curr Probl Cancer. 2014;38(1):7-41. doi: 10.1038/jid.2014.371
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25. Pregun I, Herszényi L, Juhász M, et al. Effect of proton-pump inhibitor therapy on serum chromogranin A level. Digestion. 2011;84(1):22-8. doi: 10.1159/000321535
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1. Chen H, Sippel RS, O’Dorisio MS, et al. The north american neuroendocrine tumor society consensus guideline for the diagnosis and management of neuroendocrine tumors: Pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas. 2010;39(6):775-83. doi: 10.1097/MPA.0b013e3181ebb4f0
2. Omura M, Saito J, Yamaguchi K, et al. Prospective Study on the Prevalence of Secondary Hypertension among Hypertensive Patients Visiting a General Outpatient Clinic in Japan. Hypertens Res Vol. 2003;27(3):193-202. doi: 10.1291/hypres.27.193
3. Neumann HPH, Young WFJr, Eng C. Pheochromocytoma and Paraganglioma. N Engl J Med. 2019;381(6):552-65. doi: 10.1056/NEJMra1806651
4. Mannelli M, Lenders JWM, Pacak K, et al. Subclinical phaeochromocytoma. Best Pract Res Clin Endocrinol Metab. 2012;26(4):507-15. doi: 10.1016/j.beem.2011.10.008
5. Gimm O, Koch CA, Januszewicz A, et al. The genetic basis of pheochromocytoma. Front Horm Res. 2004;31:45-60. doi: 10.1159/000074657
6. Zuber S, Wesley R, Prodanov T, et al. Clinical utility of chromogranin A in SDHx- related paragangliomas. Eur J Clin Invest. 2014;44(4):365-71. doi: 10.1111/eci.12245
7. Lenders JWM, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: An endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915-42. doi: 10.1210/jc.2014-1498
8. Hsiao RJ, Parmer RJ, Takiyyuddin MA, O’Connor DT. Chromogranin A storage and secretion: sensitivity and specificity for the diagnosis of pheochromocytoma. Medicine (Baltimore). 1991;70(1):33-45. doi: 10.1097/00005792-199101000-00003
9. Bílek R, Ík LŠŘ, Ciprová V, et al. Chromogranin A, a member of neuroendocrine secretory proteins as a selective marker for laboratory diagnosis of pheochromocytoma. Physiol Res. 2008;57:171-9.
10. Bílek R, Zelinka T, Vlček P, et al. Radioimmunoassay of Chromogranin A and Free Metanephrines in Diagnosis of Pheochromocytoma. Physiol Res. 2017;66:397-408. doi: 10.33549/physiolres.933719
11. Bílek R, Zelinka T, Vlček P, et al. Deconjugated Urinary Metanephrine, Normetanephrine and 3-Methoxytyramine in Laboratory Diagnosis of Pheochromocytoma and Paraganglioma. Physiol Res. 2015;64:313-22. doi: 10.33549/physiolres.933109. PMID: 26680494
12. Unger N, Hinrichs J, Deutschbein T, et al. Plasma and Urinary Metanephrines Determined by an Enzyme Immunoassay, but not Serum Chromogranin A for the Diagnosis of Pheochromocytoma in Patients with Adrenal Mass. Exp Clin Endocrinol Diabetes. 2012;120(8):494-500. doi: 10.1055/s-0032-1309007
13. Al-risi ES, Al-essry FS. Chromogranin A as a Biochemical Marker for Neuroendocrine Tumors: A Single Center Experience at Royal Hospital, Oman. Oman Med J. 2017;32(5):365-70. doi: 10.5001/omj.2017.71
14. Yang X, Yang Y, Li Z, et al. Diagnostic value of circulating chromogranin a for neuroendocrine tumors: A systematic review and meta-analysis. PLoS One. 2015;10(4):1-14. doi: 10.1371/journal.pone.0124884
15. Kidd M, Bodei L, Modlin IM. Chromogranin A: any relevance in neuroendocrine tumors? Curr Opin Endocrinol Diabetes Obes. 2016. 2016;23(1):28-37. doi: 10.1097/MED.0000000000000215
16. Cimitan M, Buonadonna A, Cannizzaro R, et al. Somatostatin receptor scintigraphy versus chromogranin A assay in the management of patients with neuroendocrine tumors of different types: Clinical role. Ann Oncol. 2003;14(7):1135-41. doi: 10.1093/annonc/mdg279
17. Zawadzka-Leska SK, Radziszewski M, Malec K, Stadnik AUA. Predictive value of chromogranin a in a diagnosis towards Pheochromocytoma in adrenal incidentaloma. Endocr Care. 2016;12(4):437-42. doi: 10.4183/aeb.2016.437
18. Glinicki P, Jeske W, Bednarek-Papierska L, et al. Chromogranin A (CgA) in adrenal tumours. Endokrynol Pol. 2013;64(5):358-62. doi: 10.5603/ep.2013.0018
19. Giovanella L, Ceriani L, Balerna M, et al. Diagnostic value of serum chromogranin-A combined with MIBG scintigraphy in patients with adrenal incidentalomas. Q J Nucl Med Mol Imaging. 2008;52(1):84-8.
20. De Jong WHA, Eisenhofer G, Post WJ, et al. Dietary influences on plasma and urinary metanephrines: Implications for diagnosis of catecholamine-producing tumors. J Clin Endocrinol Metab. 2009;94(8):2841-9. doi: 10.1210/jc.2009-0303
21. Yukina MY, Troshina EA, Beltsevich DG, et al. Pheochromocytoma/paraganglioma: clinical and genetic aspects. Problemy endokrinologii. 2013;3:19-2 (In Russ.)
doi: 10.14341/probl201359319-26
22. Ardill JES, O’Dorisio TM. Circulating biomarkers in neuroendocrine tumors of the enteropancreatic tract: application to diagnosis, monitoring disease, and as prognostic indicators. Endocrinol Metab Clin North Am. 2010;39(4):777-90. doi:
10.1016/j.ecl.2010.09.001
23. Martucci VL, Pacak K. Pheochromocytoma and Paraganglioma: Diagnosis, Genetics, Management, and Treatment. Curr Probl Cancer. 2014;38(1):7-41. doi: 10.1038/jid.2014.371
24. Herman DS, Lam L, Taylor M, et al. Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma. Endocr Relat Cancer. 2011;18(1):97-111. doi: 10.1038/jid.2014.371
25. Pregun I, Herszényi L, Juhász M, et al. Effect of proton-pump inhibitor therapy on serum chromogranin A level. Digestion. 2011;84(1):22-8. doi: 10.1159/000321535