Clinical and morphological characteristic of ACTH producing tumors of various localization and the ectopic Cushing’s syndrome

Cover Page


Cite item

Full Text

Abstract

Background: Ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome is a type hypercorticism caused by ectopic production of ACTH and/or its precursors by neuroendocrine tumors (NET) of various localization, such as lung and thymus carcinoids, less frequently those of pancreas and gastrointestinal tract, medullary thyroid cancer, pheochromocytoma, small cell lung cancer, as well as some other tumor types. The wide spectrum of tumors associated with the ectopic ACTH syndrome (EAS) makes their diagnosis and treatment a complicated issue.

Materials and methods: The study was done with surgical and diagnostic biopsy samples from 60 patients who had tumors with EAS, 36 (60%) of them being bronchopulmonary carcinoids, 10 (16.7%) thymus carcinoids, 5 (8.3%) pancreatic NETs, 3 (5%) medullary thyroid cancers, 3 (5%) NETs of unknown primary localization, and NET of appendix, cecum and pheochromocytoma (one case of each, i.e. 1.7%, 1.7%, 1.7%). There were 38 female and 22 male patients (1.72:1), with their mean age of 39 ± 14 years (range, 16 to 77 years). We analyzed their clinical data, as well as the results of morphological and immunohistochemical examination of the tumors.

Results: According to the World Health Organization classification (2015), typical carcinoids (TC) of the lung were found in 77.8% (28/36) of the bronchopulmonary tumors. 22.2% (8/36) of the bronchopulmonary tumors and all thymus tumors (100%, n = 10) were classified as atypical carcinoids (ATC). Four pancreatic NETs were classified as Grade 2 (G2), 1 as G3, and NETs of the cecum and appendix as G1 and G2, respectively. At present, 29 (48%) patients are living with no relapse (mean age 39 ± 13.5 years), whereas 22 (37%) of patients developed a relapse (mean age 35 ± 13 years), and 15 (25%) of them died, regardless of the age of the patients The history of the disease was not traced in 4 cases. 5-year relapse-free survival of patients with TC of the lung was 85.7% (24/28), of those with ATC 25% (2/8), with ATC of the thymus and medullary thyroid cancer 0%. Mortality from to TC of the lung for the entire follow-up period was 3.6% (1/28), to ATC 12.5% (1/8), to ATC of the thymus and for medullary thyroid cancer 62.5% and 100%, respectively. The patients with NET of the cecum, appendix and pheochromocytoma are alive without progression for 4, 5 and 6 years, respectively. Therefore, the lowest 5-year survival of patients with EAS was observed in medullary thyroid cancer, pancreatic NET and thymus carcinoids: in 100% (3/3), 75% (3/4), and 57.1% (4/7), respectively.

Conclusion: The most unfavorable prognostic factors in the EAS are the localization of tumors in the thymus, pancreas and thyroid gland. This indicates the necessity of a differentiated treatment approaches to patients with this syndrome.

About the authors

L. E. Gurevich

Moscow Regional Research and Clinical Institute (MONIKI)

Author for correspondence.
Email: larisgur@mail.ru

ScD in Biology, Professor, Leading Research Fellow, Department of Pathological Anatomy

6/2–12 Begovaya ul., Moscow, 125284, Russian Federation. Tel.: +7 (495) 631 74 22

Russian Federation

I. A. Voronkova

Endocrinology Research Center

Email: fake@neicon.ru

MD, PhD, Physician, Parathyroid Glands Pathology Department

11 Dmitriya Ul'yanova ul., Moscow, 117036, Russian Federation

Russian Federation

E. I. Marova

Endocrinology Research Center

Email: fake@neicon.ru

MD, PhD, Professor, Chief Research Fellow, Department of Neuroendocrinology and Bone Disease

11 Dmitriya Ul'yanova ul., Moscow, 117036, Russian Federation

Russian Federation

L. Ya. Rozhinskaya

Endocrinology Research Center

Email: fake@neicon.ru

MD, PhD, Professor, Chief Research Fellow, Department of Neuroendocrinology

11 Dmitriya Ul'yanova ul., Moscow, 117036, Russian Federation

Russian Federation

A. M. Lapshina

Endocrinology Research Center

Email: fake@neicon.ru

MD, PhD, Department of Fundamental Pathomorphology

11 Dmitriya Ul'yanova ul., Moscow, 117036, Russian Federation

Russian Federation

T. A. Britvin

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru

MD, PhD, Head of the Department of Endocrine Surgery

61/2 Shchepkina ul., Moscow, 129110, Russian Federation

Russian Federation

I. V. Komerdus

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru

MD, PhD, Associate Professor, Chair of Endocrinology, Postgraduate Training Faculty

61/2 Shchepkina ul., Moscow, 129110, Russian Federation

Russian Federation

References

  1. Hauso O, Gustafsson BI, Kidd M, Waldum HL, Drozdov I, Chan AK, Modlin IM. Neuroendocrine tumor epidemiology: contrasting Norway and North America. Cancer. 2008;113(10): 2655–64. doi: 10.1002/cncr.23883.
  2. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer. 2003;97(4): 934–59. doi: 10.1002/cncr.11105.
  3. 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.
  4. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO classification of tumours of the lung, pleura, thymus and heart. 4rd ed. Lyon: IARC; 2015. 412 p.
  5. Gustafsson BI, Kidd M, Chan A, Malfertheiner MV, Modlin IM. Bronchopulmonary neuroendocrine tumors. Cancer. 2008;113(1): 5–21. doi: 10.1002/cncr.23542.
  6. Caplin ME, Baudin E, Ferolla P, Filosso P, Garcia-Yuste M, Lim E, Oberg K, Pelosi G, Perren A, Rossi RE, Travis WD; ENETS consensus conference participants. Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol. 2015;26(8): 1604–20. doi: 10.1093/annonc/mdv041.
  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. Brown WH. A case of pluriglandular syndrome. “Diabetes of bearded women”. Lancet. 1928;2:1022–3.
  9. Aniszewski JP, Young WF Jr, Thompson GB, Grant CS, van Heerden JA. Cushing syndrome due to ectopic adrenocorticotropic hormone secretion. World J Surg. 2001;25(7): 934–40. doi: 10.1007/s00268-001-0032-5.
  10. Lindholm J, Juul S, Jørgensen JO, Astrup J, Bjerre P, Feldt-Rasmussen U, Hagen C, Jørgensen J, Kosteljanetz M, Kristensen L, Laurberg P, Schmidt K, Weeke J. Incidence and late prognosis of cushing's syndrome: a population-based study. J Clin Endocrinol Metab. 2001;86(1): 117–23. doi: 10.1210/jcem.86.1.7093.
  11. Fazel P, Ganesa P, Mennel RG, Austin NA. The ectopic adrenocorticotropic hormone syndrome in carcinoid tumors. Proc (Bayl Univ Med Cent). 2008;21(2): 140–3.
  12. Oberg K, Hellman P, Kwekkeboom D, Jelic S; ESMO Guidelines Working Group. Neuroendocrine bronchial and thymic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21 Suppl 5:v220–2. doi: 10.1093/annonc/mdq191.
  13. Марова ЕИ, Кокшарина НВ, Рожинская ЛЯ. АКТГ-продуцирующие нейроэндокринные опухоли грудной клетки. Проблемы эндокринологии. 2010;56(5): 8–14. doi: http://dx.doi.org/10.14341/probl20105658-14.
  14. Кузнецов НС, Марова ЕИ, Ремизов ОВ, Латкина НВ, Воскобойников ВВ, Добрева ЕА, Крылов ВВ, Воронкова ИА. АКТГ-продуцирующая опухоль слепой кишки. Клинический случай. Эндокринная хирургия. 2013;7(2): 39–44. doi: http://dx.doi.org/10.14341/serg2013239-44.
  15. Гуревич ЛЕ, Бессмертная BC, Бритвин ТА, Полякова ГА, Пантелеева ЕИ, Богатырев ОП, Самойлов МА. АКТГ-эктопированный синдром, обусловленный нейроэндокринной опухолью поджелудочной железы (клиническое наблюдение). Анналы хирургии. 2010;(2): 73–5.
  16. Perakakis N, Laubner K, Keck T, Steffl D, Lausch M, Meyer PT, Burger D, Csanadi A, Seufert J. Ectopic ACTH-syndrome due to a neuroendocrine tumour of the appendix. Exp Clin Endocrinol Diabetes. 2011;119(9): 525–9. doi: 10.1055/s-0031-1284368.
  17. Dobnig H, Stepan V, Leb G, Wolf G, Buchfelder M, Krejs GJ. Recovery from severe osteoporosis following cure from ectopic ACTH syndrome caused by an appendix carcinoid. J Intern Med. 1996;239(4): 365–9. doi: 10.1046/j.1365-2796.1996.416763000.x.
  18. Maragliano R, Vanoli A, Albarello L, Milione M, Basturk O, Klimstra DS, Wachtel A, Uccella S, Vicari E, Milesi M, Davì MV, Scarpa A, Sessa F, Capella C, La Rosa S. ACTH-secreting pancreatic neoplasms associated with Cushing syndrome: clinicopathologic study of 11 cases and review of the literature. Am J Surg Pathol. 2015;39(3): 374–82. doi: 10.1097/PAS.0000000000000340.
  19. Uecker JM, Janzow MT. A case of Cushing syndrome secondary to ectopic adrenocorticotropic hormone producing carcinoid of the duodenum. Am Surg. 2005;71(5): 445–6.
  20. Singer J, Werner F, Koch CA, Bartels M, Aigner T, Lincke T, Fasshauer M, Paschke R. Ectopic Cushing's syndrome caused by a well differentiated ACTH-secreting neuroendocrine carcinoma of the ileum. Exp Clin Endocrinol Diabetes. 2010;118(8): 524–9. doi: 10.1055/s-0029-1243634.
  21. Smallridge RC, Bourne K, Pearson BW, Van Heerden JA, Carpenter PC, Young WF. Cushing's syndrome due to medullary thyroid carcinoma: diagnosis by proopiomelanocortin messenger ribonucleic acid in situ hybridization. J Clin Endocrinol Metab. 2003;88(10): 4565–8. doi: 10.1210/jc.2002-021796.
  22. Miehle K, Tannapfel A, Lamesch P, Borte G, Schenker E, Kluge R, Ott RA, Wiechmann V, Koch M, Kassahun W, Paschke R, Koch CA. Pancreatic neuroendocrine tumor with ectopic adrenocorticotropin production upon second recurrence. J Clin Endocrinol Metab. 2004;89(8): 3731–6. doi: 10.1210/jc.2003-032164.
  23. Salgado LR, Fragoso MC, Knoepfelmacher M, Machado MC, Domenice S, Pereira MA, de Mendonça BB. Ectopic ACTH syndrome: our experience with 25 cases. Eur J Endocrinol. 2006;155(5): 725–33. doi: 10.1530/eje.1.02278.
  24. Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK. 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.
  25. Isidori AM, Kaltsas GA, Pozza C, Frajese V, Newell-Price J, Reznek RH, Jenkins PJ, Monson JP, Grossman AB, Besser GM. 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.
  26. O'Brien T, Young WF Jr, Davila DG, Scheithauer BW, Kovacs K, Horvath E, Vale W, van Heerden JA. Cushing's syndrome associated with ectopic production of corticotrophin- releasing hormone, corticotrophin and vasopressin by a phaeochromocytoma. Clin Endocrinol (Oxf ). 1992;37(5): 460–7. doi: 10.1111/j.1365-2265.1992.tb02359.x.
  27. Amouzegar A, Ghanei A, Azizi F. Cushing's syndrome accompanied with adrenal and pancreatic mass: a case report. Int J Endocrinol Metab. 2008;(3): 154–7.
  28. Kasperlik-Zauska AA, Jeske W, Migdalska B. Cushing's syndrome secondary to ectopic ACTH secretion from a primary ovarian carcinoma. Clin Endocrinol (Oxf ). 1997;47(4): 501–2.
  29. Воронкова ИА. Нейроэндокринные опухоли негипофизарной локализации, продуцирующие АКТГ: клинические, морфологические, иммуногистохимические характеристики: дис. … канд. мед. наук. М.; 2013. 158 с.
  30. Комердус ИВ, Чеканова АВ, Древаль АВ. Клинический случай АКТГ- продуцирующей карциномы тимуса. Русский медицинский журнал. 2016;(1): 25–8.
  31. Воронкова ИА, Арапова СА, Марова ЕИ, Кузнецов НС, Абросимов АЮ, Рожинская ЛЯ. АКТГ-эктопический синдром циклического течения; нейроэндокринная опухоль червеобразного отростка. Проблемы эндокринологии. 2013;59(4): 23–7.
  32. Pelosi G, Rindi G, Travis WD, Papotti M. Ki-67 antigen in lung neuroendocrine tumors: unraveling a role in clinical practice. J Thorac Oncol. 2014;9(3): 273–84. doi: 10.1097/JTO.0000000000000092.
  33. 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/modpathol.2012.81.
  34. Ветшев ПС, Мельниченко ГА, Павлова МГ, Рыбин ВК, Полунин ГВ, Гуревич ЛЕ. Клиническое наблюдение АКТГ-эктопированного синдрома. Хирургия. Журнал им. Н.И. Пирогова. 2006;(9): 63–5.
  35. Павлова МГ, Харнас СС, Ипполитов ЛИ, Егоров АВ, Колода ДЕ, Полунин ГВ, Зыкова ПГ, Янкин ПЛ, Гуревич ЛЕ, Волков РЮ, Рабинович ЭЗ. АКТГ-эктопированный синдром (клиническое наблюдение). Клиницист. 2008;(3): 25–9.
  36. Doherty GM. Rare endocrine tumours of the GI tract. Best Pract Res Clin Gastroenterol. 2005;19(5): 807–17. doi: 10.1016/j.bpg.2005.05.004.
  37. Okereke IC, Taber AM, Griffith RC, Ng TT. Outcomes after surgical resection of pulmonary carcinoid tumors. J Cardiothorac Surg. 2016;11:35. doi: 10.1186/s13019-016-0424-0.
  38. Neary NM, Lopez-Chavez A, Abel BS, Boyce AM, Schaub N, Kwong K, Stratakis CA, Moran CA, Giaccone G, Nieman LK. 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.
  39. Granberg D, Eriksson B, Wilander E, Grimfjärd P, Fjällskog ML, Oberg K, Skogseid B. Experience in treatment of metastatic pulmonary carcinoid tumors. Ann Oncol. 2001;12(10): 1383–91. doi: https://doi.org/10.1023/A:1012569909313.
  40. Калинин АП, Казанцева ИА, Бритвин ТА, Гуревич ЛЕ, Котова ИВ. АКТГ- эктопированный синдром, обусловленный бронхиальным карциноидом (клиническое наблюдение). Проблемы эндокринологии. 2002;48(5): 48–50.
  41. Бритвин ТА, Калинин АП. АКТГ-эктопированный синдром. Клиническая медицина. 2003;81(9): 8–13.
  42. 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.
  43. Гуревич ЛЕ, Корсакова НА, Воронкова ИА, Казанцева ИА, Ашевская ВЕ, Титов АГ, Когония ЛМ, Мазурин ВС, Шабаров ВЛ. Прогностическое и дифференциально- диагностическое значение экспрессии цитокератинов 7 и 19 и тиреоидного фактора транскрипции-1 в нейроэндокринных опухолях легких разной степени злокачественности. Альманах клинической медицины. 2016;44(5): 613–23. doi: 10.18786/2072-0505-2016-44-5-613-623.
  44. Kondo T, Matsuyama R, Ashihara H, Matsuo Y, Sasaki K, Goto R, Ono K, Takaki Y, Honda Y, Iyama K, Kawashima J, Motoshima H, Tsuruzoe K, Miyamura N, Araki E. A case of ectopic adrenocorticotropic hormone-producing pancreatic neuroendocrine tumor with multiple liver metastases. Endocr J. 2010;57(3): 229–36. doi: http://doi.org/10.1507/endocrj.K09E-179.
  45. Vaduganathan M, Nagarur A, Kerr DA, Lauter KB, Padmanabhan A, Raghavan S, Pallais JC, Fenves AZ. Metastatic pancreatic neuroendocrine tumor with ectopic adrenocorticotropic hormone production. Proc (Bayl Univ Med Cent). 2015;28(1): 46–9.
  46. Chrisoulidou A, Pazaitou-Panayiotou K, Georgiou E, Boudina M, Kontogeorgos G, Iakovou I, Efstratiou I, Patakiouta F, Vainas I. Ectopic Cushing's syndrome due to CRH secreting liver metastasis in a patient with medullary thyroid carcinoma. Hormones (Athens). 2008;7(3): 259–62.
  47. Марова ЕИ, Воронкова ИА, Лапшина АМ, Арапова СД, Кузнецов НС, Рожинская ЛЯ, Животов ВА, Жарков ОБ, Гуревич ЛЕ, Полякова ГА. Феохромоцитома с эктопической продукцией АКТГ: разбор клинических случаев. Ожирение и метаболизм. 2015;12(3): 46–52. doi: http://dx.doi.org/10.14341/omet2015346-52.
  48. Tsuchiya K, Minami I, Tateno T, Izumiyama H, Doi M, Nemoto T, Mae S, Kasuga T, Osamura RY, Oki Y, Hirata Y. Malignant gastric carcinoid causing ectopic ACTH syndrome: discrepancy of plasma ACTH levels measured by different immunoradiometric assays. Endocr J. 2005;52(6): 743–50. doi: http://doi.org/10.1507/endocrj.52.743.
  49. Meinardi JR, Wolffenbuttel BH, Dullaart RP. Cyclic Cushing's syndrome: a clinical challenge. Eur J Endocrinol. 2007;157(3): 245–54. doi: 10.1530/EJE-07-0262.
  50. Bi YF, Liu RX, Ye L, Fang H, Li XY, Wang WQ, Zhang J, Wang KK, Jiang L, Su TW, Chen ZY, Ning G. Gene expression profiles of thymic neuroendocrine tumors (carcinoids) with ectopic ACTH syndrome reveal novel molecular mechanism. Endocr Relat Cancer. 2009;16(4): 1273–82. doi: 10.1677/ERC-08-0325.
  51. Rieker RJ, Aulmann S, Penzel R, Schnabel PA, Blaeker H, Esposito I, Morresi-Hauf A, Otto HF, Hecker E, Dienemann H, Schirmacher P, Mechtersheimer G. Chromosomal imbalances in sporadic neuroendocrine tumours of the thymus. Cancer Lett. 2005;223(1): 169–74. doi: 10.1016/j.canlet.2004.10.027.
  52. Teh BT, Zedenius J, Kytölä S, Skogseid B, Trotter J, Choplin H, Twigg S, Farnebo F, Giraud S, Cameron D, Robinson B, Calender A, Larsson C, Salmela P. Thymic carcinoids in multiple endocrine neoplasia type 1. Ann Surg. 1998;228(1): 99–105.
  53. Leotlela PD, Jauch A, Holtgreve-Grez H, Thakker RV. Genetics of neuroendocrine and carcinoid tumours. Endocr Relat Cancer. 2003;10(4): 437–50. doi: 10.1677/erc.0.0100437.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2017 Gurevich L.E., Voronkova I.A., Marova E.I., Rozhinskaya L.Y., Lapshina A.M., Britvin T.A., Komerdus I.V.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies