Цель. Изучить клинико-лабораторные характеристики и отдаленные результаты лечения когорты больных с АКТГ-эктопированным синдромом – АКТГ-ЭС (АКТГ – адренокортикотропный гормон). Материалы и методы. Проведено ретроспективное обсервационное одноцентровое одномоментное исследование 130 пациентов с АКТГ-ЭС. Проанализированы демографические сведения о пациентах, данные анамнеза, результаты гормональных и инструментальных исследований на до- и послеоперационном этапах, отдаленные результаты лечения. Результаты. Возраст на момент диагностики заболевания составил от 12 до 74 лет (Ме 40 лет [28; 54]). Длительность заболевания с момента появления симптомов до верификации диагноза – от 2 до 168 мес (Ме 17,5 мес [7; 46]). В 81 (62,3%) случае первичный очаг локализовался в легком, в 9 – в средостении, в 7 – в поджелудочной железе, в 5 – в надпочечнике, по 1 случаю – в слепой кишке и червеобразном отростке, у 1 пациента причиной АКТГ-ЭС оказался медуллярный рак щитовидной железы, в 25 (19,2%) случаях установить локализацию нейроэндокринной опухоли (НЭО) не удалось. Медиана периода наблюдения составила 27 мес [9,75; 61,0], максимально 372 мес. Первичный очаг удален у 82 (63,1%) больных, двусторонняя адреналэктомия по жизненным показаниям выполнена 23 (17,7%) пациентам, из них 16 – с НЭО неустановленной локализации, 7 – с целью контроля тяжелого течения гиперкортицизма после нерадикального хирургического лечения. Метастазы выявлены у 25 (19,2%). На момент последнего наблюдения 59 (72%) пациентов в ремиссии заболевания, у 12 (14,6%) развился рецидив, 26 (20%) умерли от полиорганной недостаточности (n=18), тромбоэмболии легочной артерии (n=4), осложнений хирургического вмешательства (n=2), синдрома диссеминированного внутрисосудистого свертывания (n=1), COVID-19 (n=1). Заключение. Наиболее частым источником АКТГ-ЭС являются НЭО бронхолегочной локализации (62,3%). Радикальное хирургическое лечение в большинстве случаев позволяет добиться стойкой ремиссии заболевания (72%), однако частота летальности (20%) и рецидивов заболевания (14,6%) остается высокой.
Aim. To study the clinical, biochemical characteristics, treatment results and follow-up of patients with ectopic ACTH syndrome – EAS (ACTH – adrenocorticotropic hormone ).
Materials and methods. A retrospective, observational, single-center study of 130 patients with EAS. Demographic information of patients, medical history, results of laboratory and instrumental investigations at the pre- and postoperative stages and follow-up of EAS were analyzed. Results. The mean age at the diagnosis ranged from 12 to 74 years (Me 40 years [28; 54]). The duration of the disease from the onset of symptoms to the verification of the diagnosis varied from 2 to 168 months (Me 17.5 months [7; 46]). Eighty-one (62,3%) patients had bronchopulmonary NET, 9 – thymic carcinoid, 7 – pancreatic NET, 5 – pheochromocytoma, 1– cecum NET, 1– appendix carcinoid tumor, 1 – medullary thyroid cancer and 25 (19.2%) had an occult source of ACTH. The median follow-up period of patients was 27 months [9.75; 61.0] with a maximum follow-up of 372 months. Currently, primary tumor was removed in 82 (63.1%) patients, bilateral adrenalectomy was performed in 23 (18%) patients, in 16 of them there was an occult source of ACTH-producing NET and in 7 patients – in order to control hypercortisolism after non-successful surgical treatment. Regional and distant metastases were revealed in 25 (19.2%) patients. At the time of the last observation 59 (72%) patients were exhibited a full recovery, 12 (14.6%) – had relapse of the disease and 26 (20%) – died from multiple organ failure (n=18), pulmonary embolism (n=4), surgical complications (n=2), disseminated intravascular coagulation syndrome (n=1) or COVID-19 (n=1). Conclusion. In our cohort of patients bronchopulmonary NET are the most frequent cause of EAS (62.3%). Surgical treatment leads to remission of hypercortisolism in 72% cases; the proportion of relapse (14.6%) and fatal outcome (20%) remains frequent in EAS.
1. Feelders R, Sharma S, Nieman L. Cushing’s syndrome: epidemiology and developments in disease management. CLEP. 2015:281. DOI:10.2147/CLEP.S44336
2. Lococo F, Margaritora S, Cardillo G, et al. Bronchopulmonary carcinoids causing Cushing syndrome: results from a multicentric study suggesting a more aggressive behavior. Thorac Cardiovasc Surg. 2016;64(2):172-81. DOI:10.1055/s-0035-1555125
3. Maragliano R, Vanoli A, Albarello L, et al. ACTH-secreting pancreatic neoplasms associated with Cushing syndrome: clinicopathologic study of 11 cases and review of the literature. Am J SurgPathol. 2015;39(3):374-82. DOI:10.1097/PAS.0000000000000340
4. Марова Е.И., Воронкова И.А., Лапшина А.М., и др. Феохромоцитома с эктопической продукцией АКТГ: разбор клинических случаев. Ожирение и метаболизм. 2015;12(3):46-52 [Marova EI, Voronkova IA, Lapshina AM, et al. Adrenocorticotropic hormone-producing pheochromocytoma: analysis of clinical cases. Obesity and metabolism. 2015;12(3):46-52 (in Russian)]. DOI:10.14341/omet2015346-52
5. Воронкова И.А., Арапова С.Д., Марова Е.И., и др. АКТГ-эктопический синдром циклического течения; нейроэндокринная опухоль червеобразного отростка. Проблемы эндокринологии. 2013;59(4):23-7 [Voronkova IA, Arapova SD, Marova EI, et al. ACTH-ectopic syndrome with the cyclic clinical course; the cecal neuroendocrine tumour. Problemy endokrinologii. 2013;59(4):23-7 (in Russian)]. DOI:10.14341/probl201359423-27
6. Chentli F, Terki N, Azzoug S. Ectopic adrenocortical carcinoma located in the ovary. Eur J Endocrinol. 2016;175(4):17-23. DOI:10.1530/EJE-16-0224
7. Alshaikh OM, Al-Mahfouz AA, Al-Hindi H, et al. Unusual cause of ectopic secretion of adrenocorticotropic hormone: Cushing syndrome attributable to small cell prostate cancer. Endocr Pract. 2010;16(2):249-54. DOI:10.4158/EP09243.CR
8. Tutal E, Yılmazer D, Demirci T, et al. A rare case of ectopic ACTH syndrome originating from malignant renal paraganglioma. Arch Endocrinol Metab. 2017;61(3):291-5.
DOI:10.1590/2359-3997000000240
9. Марова Е.И., Рожинская Л.Я., Воронкова И.А., и др. АКТГ-продуцирующий медуллярный рак щитовидной железы. Клинический случай. Проблемы эндокринологии. 2016;62(4):45-9 [Marova EI, Rozhinskaya LYa, Voronkova IA, et al. ACTH-producing medullary thyroid cancer. Clinical case. Problemy endokrinologii. 2016;62(4):45-9 (in Russian)]. DOI:10.14341/probl201662445-49
10. Ilias I, Torpy DJ, Pacak K, et al. Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institutes of Health. J Clin Endocrinol Metab. 2005;90(8):4955-62. DOI:10.1210/jc.2004-2527
11. Дедов И.И., Белая Ж.Е., Ситкин И.И., и др. Значение метода селективного забора крови из нижних каменистых синусов в дифференциальной диагностике АКТГ-зависимого эндогенного гиперкортицизма. Проблемы эндокринологии. 2009;55(6):35-40. [Dedov II, Belaya ZE, Sitkin II, et al. Significance of the method of selective blood collection from the inferior petrosal sinuses for differential diagnosis of ACTH-dependent hypercorticism. Problemy endokrinologii. 2009;55(6):35-40 (in Russian)]. DOI:10.14341/probl200955635-40
12. Aniszewski JP, Young WF, Thompson GB, et al. Cushing syndrome due to ectopic adrenocorticotropic hormone secretion. World J Surg. 2001;25(7):934-40. DOI:10.1007/s00268-001-0032-5
13. Davi MV, Cosaro E, Piacentini S, et al. Prognostic factors in ectopic Cushing’s syndrome due to neuroendocrine tumors: a multicenter study. Eur J Endocrinol. 2017;176(4):453-61. DOI:10.1530/EJE-16-0809
14. Espinosa-de-los-Monteros AL, Ramírez-Rentería C, Mercado M. Clinical heterogeneity of ectopic ACTH syndrome: a long-term follow-up study. Endocrine Practice. 2020;26(12):1435-41. DOI:10.4158/EP-2020-0368
15. Lase I, Strele I, Grönberg M, et al. Multiple hormone secretion may indicate worse prognosis in patients with ectopic Cushing’s syndrome. Hormones (Athens). 2020;19(3):351-60. DOI:10.1007/s42000-019-00163-z
16. Paleń-Tytko JE, Przybylik-Mazurek EM, Rzepka EJ, et al. Ectopic ACTH syndrome of different origin-diagnostic approach and clinical outcome. Experience of one clinical centre. PLoS One. 2020;15(11):e0242679. DOI:10.1371/journal.pone.0242679
17. Isidori AM, Kaltsas GA, Pozza C, et al. The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term follow-up. J Clin Endocrinol Metab. 2006;91(2):371-7. DOI:10.1210/jc.2005-1542
18. Sathyakumar S, Paul TV, Asha HS, et al. Ectopic cushing syndrome: a 10-year experience from a tertiary care center in Southern India. Endocrine Practice. 2017;23(8):907-14. DOI:10.4158/EP161677.OR
19. Salgado LR, Fragoso MCBV, Knoepfelmacher M, et al. Ectopic ACTH syndrome: our experience with 25 cases. Eur j Endocrinol. 2006;155(5):725-33. DOI:10.1530/eje.1.02278
20. Mokhtar A, Arnason T, Gaston D, et al. ACTH-Secreting neuroendocrine carcinoma of the cecum: case report and review of the literature. Clin Colorectal Cancer. 2019;18(1):163-70. DOI:10.1016/j.clcc.2018.07.013
21. Tsirona S, Tzanela M, Botoula E, et al. Clinical presentation and long-term outcome of patients with ectopic ACTH syndrome due to bronchial carcinoid tumors: a one-center experience. Endocr Pract. 2015;21(10):1104-10. DOI:10.4158/EP15647.OR
22. Boddaert G, Grand B, Le Pimpec-Barthes F, et al. Bronchial carcinoid tumors causing Cushing’s syndrome: more aggressive behavior and the need for early diagnosis. Ann Thorac Surg. 2012;94(6):1823-9. DOI:10.1016/j.athoracsur.2012.07.022
23. Neary NM, Lopez-Chavez A, Abel BS, et al. Neuroendocrine ACTH-producing tumor of the thymus--experience with 12 patients over 25 years. J Clin Endocrinol Metab. 2012;97(7):2223-30. DOI:10.1210/jc.2011-3355
________________________________________________
1. Feelders R, Sharma S, Nieman L. Cushing’s syndrome: epidemiology and developments in disease management. CLEP. 2015:281. DOI:10.2147/CLEP.S44336
2. Lococo F, Margaritora S, Cardillo G, et al. Bronchopulmonary carcinoids causing Cushing syndrome: results from a multicentric study suggesting a more aggressive behavior. Thorac Cardiovasc Surg. 2016;64(2):172-81. DOI:10.1055/s-0035-1555125
3. Maragliano R, Vanoli A, Albarello L, et al. ACTH-secreting pancreatic neoplasms associated with Cushing syndrome: clinicopathologic study of 11 cases and review of the literature. Am J SurgPathol. 2015;39(3):374-82. DOI:10.1097/PAS.0000000000000340
4. Marova EI, Voronkova IA, Lapshina AM, et al. Adrenocorticotropic hormone-producing pheochromocytoma: analysis of clinical cases. Obesity and metabolism. 2015;12(3):46-52 (in Russian). DOI:10.14341/omet2015346-52
5. Voronkova IA, Arapova SD, Marova EI, et al. ACTH-ectopic syndrome with the cyclic clinical course; the cecal neuroendocrine tumour. Problemy endokrinologii. 2013;59(4):23-7 (in Russian). DOI:10.14341/probl201359423-27
6. Chentli F, Terki N, Azzoug S. Ectopic adrenocortical carcinoma located in the ovary. Eur J Endocrinol. 2016;175(4):17-23. DOI:10.1530/EJE-16-0224
7. Alshaikh OM, Al-Mahfouz AA, Al-Hindi H, et al. Unusual cause of ectopic secretion of adrenocorticotropic hormone: Cushing syndrome attributable to small cell prostate cancer. Endocr Pract. 2010;16(2):249-54. DOI:10.4158/EP09243.CR
8. Tutal E, Yılmazer D, Demirci T, et al. A rare case of ectopic ACTH syndrome originating from malignant renal paraganglioma. Arch Endocrinol Metab. 2017;61(3):291-5.
DOI:10.1590/2359-3997000000240
9. Marova EI, Rozhinskaya LYa, Voronkova IA, et al. ACTH-producing medullary thyroid cancer. Clinical case. Problemy endokrinologii. 2016;62(4):45-9 (in Russian). DOI:10.14341/probl201662445-49
10. Ilias I, Torpy DJ, Pacak K, et al. Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institutes of Health. J Clin Endocrinol Metab. 2005;90(8):4955-62. DOI:10.1210/jc.2004-2527
11. Dedov II, Belaya ZE, Sitkin II, et al. Significance of the method of selective blood collection from the inferior petrosal sinuses for differential diagnosis of ACTH-dependent hypercorticism. Problemy endokrinologii. 2009;55(6):35-40 (in Russian). DOI:10.14341/probl200955635-40
12. Aniszewski JP, Young WF, Thompson GB, et al. Cushing syndrome due to ectopic adrenocorticotropic hormone secretion. World J Surg. 2001;25(7):934-40. DOI:10.1007/s00268-001-0032-5
13. Davi MV, Cosaro E, Piacentini S, et al. Prognostic factors in ectopic Cushing’s syndrome due to neuroendocrine tumors: a multicenter study. Eur J Endocrinol. 2017;176(4):453-61. DOI:10.1530/EJE-16-0809
14. Espinosa-de-los-Monteros AL, Ramírez-Rentería C, Mercado M. Clinical heterogeneity of ectopic ACTH syndrome: a long-term follow-up study. Endocrine Practice. 2020;26(12):1435-41. DOI:10.4158/EP-2020-0368
15. Lase I, Strele I, Grönberg M, et al. Multiple hormone secretion may indicate worse prognosis in patients with ectopic Cushing’s syndrome. Hormones (Athens). 2020;19(3):351-60. DOI:10.1007/s42000-019-00163-z
16. Paleń-Tytko JE, Przybylik-Mazurek EM, Rzepka EJ, et al. Ectopic ACTH syndrome of different origin-diagnostic approach and clinical outcome. Experience of one clinical centre. PLoS One. 2020;15(11):e0242679. DOI:10.1371/journal.pone.0242679
17. Isidori AM, Kaltsas GA, Pozza C, et al. The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term follow-up. J Clin Endocrinol Metab. 2006;91(2):371-7. DOI:10.1210/jc.2005-1542
18. Sathyakumar S, Paul TV, Asha HS, et al. Ectopic cushing syndrome: a 10-year experience from a tertiary care center in Southern India. Endocrine Practice. 2017;23(8):907-14. DOI:10.4158/EP161677.OR
19. Salgado LR, Fragoso MCBV, Knoepfelmacher M, et al. Ectopic ACTH syndrome: our experience with 25 cases. Eur j Endocrinol. 2006;155(5):725-33. DOI:10.1530/eje.1.02278
20. Mokhtar A, Arnason T, Gaston D, et al. ACTH-Secreting neuroendocrine carcinoma of the cecum: case report and review of the literature. Clin Colorectal Cancer. 2019;18(1):163-70. DOI:10.1016/j.clcc.2018.07.013
21. Tsirona S, Tzanela M, Botoula E, et al. Clinical presentation and long-term outcome of patients with ectopic ACTH syndrome due to bronchial carcinoid tumors: a one-center experience. Endocr Pract. 2015;21(10):1104-10. DOI:10.4158/EP15647.OR
22. Boddaert G, Grand B, Le Pimpec-Barthes F, et al. Bronchial carcinoid tumors causing Cushing’s syndrome: more aggressive behavior and the need for early diagnosis. Ann Thorac Surg. 2012;94(6):1823-9. DOI:10.1016/j.athoracsur.2012.07.022
23. Neary NM, Lopez-Chavez A, Abel BS, et al. Neuroendocrine ACTH-producing tumor of the thymus--experience with 12 patients over 25 years. J Clin Endocrinol Metab. 2012;97(7):2223-30. DOI:10.1210/jc.2011-3355
1 ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия;
2 ФГБУ «Национальный медицинский исследовательский центр эндокринологии» Минздрава России, Москва, Россия;
3 ФГБУ «Национальный медицинский исследовательский центр хирургии им. А.В. Вишневского» Минздрава России, Москва, Россия
*olga.golounina@mail.ru
________________________________________________
Olga O. Golounina*1, Zhanna E. Belaya2, Liudmila Ya. Rozhinskaya2, Evgeniya I. Marova2, Michail Yu. Pikunov3, Patimat M. Khandaeva2, Svetlana D. Arapova2, Larisa K. Dzeranova2, Nikolai S. Kuznetsov2, Valentin V. Fadeev1, Galina A. Melnichenko2, Ivan I. Dedov2
1 Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia;
2 Endocrinology Research Centre, Moscow, Russia;
3 Vishnevsky National Medical Research Center of Surgery, Moscow, Russia
*olga.golounina@mail.ru