Síndrome de Cushing ectópico: revisión de la literatura

  • Johnayro Gutiérrez-Restrepo Hospital Pablo Tobón Uribe
  • Alejandro Román-González Hospital Universitario San Vicente Fundación
Palabras clave: Síndrome de Cushing, Tumores neuroendocrinos, Carcinoides, Síndrome paraneoplásicos endocrinos, Síndrome de ACTH ectópico

Resumen

El síndrome de Cushing es una enfermedad muy rara pero asociada a una morbimortalidad significativa. Se clasifica como dependiente de la hormona adrenocorticotrópica (ACTH: tumores hipofisiarios y ectópicos) o independiente de ACTH (lesiones de origen adrenal). En la mayoría de los casos, las lesiones responsables del síndrome corresponden a tumores hipofisiarios, seguida de lesiones adrenales y por último de tumores ectópicos (5-15% de todos los casos).
En este artículo se hará una revisión de los aspectos epidemiológicos, clínicos, diagnósticos y terapéuticos más importantes de los tumores ectópicos causantes del síndrome de Cushing.

 

Biografía del autor/a

Johnayro Gutiérrez-Restrepo, Hospital Pablo Tobón Uribe

Servicio de Medicina Interna, Hospital Pablo Tobón Uribe, Servicio de Endocrinología y Metabolismo, Universidad de Antioquia, Medellín, Colombia

Alejandro Román-González, Hospital Universitario San Vicente Fundación

Unidad de Medicina Interna, Hospital Universitario San Vicente Fundación, Medellín, Colombia

Referencias

AbdelMannan D, Selman WR, Arafah BM. Peri-operative management of Cushing's disease. Rev Endocr Metab Disord. 2010;11:127-34.

https://doi.org/10.1007/s11154-010-9140-6

Hatipoglu BA. Cushing's syndrome. J Surg Oncol. 2012;106:565-71.

https://doi.org/10.1002/jso.23197

Alexandraki KI, Grossman AB. The ectopic ACTH syndrome. Rev Endocr Metab Disord. 2010;11:117-26.

https://doi.org/10.1007/s11154-010-9139-z

Ferone D, Albertelli M. Ectopic Cushing and other paraneoplastic syndromes in thoracic neuroendocrine tumors. Thorac Surg Clin. 2014;24:277-83.

https://doi.org/10.1016/j.thorsurg.2014.05.002

Gutiérrez-Restrepo J, Builes-Barrera CA, Toro-Escobar JM, Gómez-Corrales JD, Toro-Lugo C, Uribe-Londo˜no F, et al. Características clínicas y epidemiológicas del síndrome de Cushing. Medellín, 1986-2010. Medicina y Laboratorio. 2013;19:473-85.

Montoya-Escobar J, Builes-Monta˜no C, Gutiérrez-Restrepo J, Campuzano-Maya G. Muestreo de senos petrosos inferiores en el diagnóstico de pacientes con síndrome de Cushing dependiente de hormona adrenocorticotrópica. Medicina & Laboratorio. 2013;19:411-50.

Gutiérrez-Restrepo J, Latorre-Sierra G, Campuzano-Maya G. Síndrome de Cushing. Medicina & Laboratorio. 2009;15:411-30.

Gutiérrez-Restrepo J, Castro-Martínez DC, Vélez-Hoyos A, Pérez-Cadavid JC. Síndrome de Cushing secundario a carcinoma medular de tiroides: descripción de un caso y revisión de la literatura. Iatreia. 2014;27:90-8.

Valenzuela A, Zuñiga E. Ectopic Cushing diagnosis and hybrid SPECT/CT Octreotide-In111 images. Acta Med Colomb. 2006;31:47.

Isidori AM, Kaltsas GA, Pozza C, Frajese V, Newell-Price J, Reznek RH, et al. The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term follow-up. J Clin Endocrinol Metab. 2006;91:371-7.

https://doi.org/10.1210/jc.2005-1542

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;90:4955-62.

https://doi.org/10.1210/jc.2004-2527

Ejaz S, Vassilopoulou-Sellin R, Busaidy NL, Hu MI, Waguespack SG, Jimenez C, et al. Cushing syndrome secondary to ectopic adrenocorticotropic hormone secretion: the University of Texas MD Anderson Cancer Center Experience. Cancer. 2011;117:4381-9.

https://doi.org/10.1002/cncr.26029

Wajchenberg BL, Mendonc¸a B, Liberman B, Adelaide M, Pereira A, Kirschner MA. Ectopic ACTH syndrome. J Steroid Biochem Mol Biol. 1995;53:139-51.

https://doi.org/10.1016/0960-0760(95)00044-Z

Barbosa SL, Rodien P, Leboulleux S, Niccoli-Sire P, Kraimps JL, Caron P, et al. Ectopic adrenocorticotropic hormone-syndrome in medullary carcinoma of the thyroid: a retrospective analysis and review of the literature. Thyroid. 2005;15:618-23.

https://doi.org/10.1089/thy.2005.15.618

Aniszewski JP, Young WF, Thompson GB, Grant CS, van Heerden JA. Cushing syndrome due to ectopic adrenocorticotropic hormone secretion. World J Surg. 2001;25:934-40.

https://doi.org/10.1007/s00268-001-0032-5

Isidori AM, Kaltsas GA, Grossman AB. Ectopic ACTH syndrome. Front Horm Res. 2006;35:143-56.

https://doi.org/10.1159/000094323

Silye R, Rieger R, Topakian R, Dunzinger A, Aigner RM, Pichler R. Cushing syndrome due to ectopic adrenocorticotropin secretion by oncocytic thyroid nodule. J Clin Endocrinol Metab. 2012;97:39-40.

https://doi.org/10.1210/jc.2011-2258

Isidori AM, Lenzi A. Ectopic ACTH syndrome. Arq Bras Endocrinol Metabol. 2007;51:1217-25.

https://doi.org/10.1590/S0004-27302007000800007

Asa SL, Kovacs K, Vale W, Petrusz P, Vecsei P. Immunohistologic localization of corticotrophin-releasing hormone in human tumors. Am J Clin Pathol. 1987;87:327-33.

https://doi.org/10.1093/ajcp/87.3.327

Schalin-Jäntti C, Asa SL, Arola J, Sane T. Recurrent acute-onset Cushing's syndrome 6 years after removal of a thymic neuroendocrine carcinoma: from ectopic ACTH to CRH. Endocr Pathol. 2013;24:25-9.

https://doi.org/10.1007/s12022-012-9228-5

Salvatori R. Ectopic Cushing's syndrome: some facts. Indian J Med Res. 2009;129:4-6.

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;88:4565-8.

https://doi.org/10.1210/jc.2002-021796

Pivonello R, De Martino MC, De Leo M, Lombardi G, Colao A. Cushing's Syndrome Endocrinol Metab Clin North Am. 2008;37:135-49, ix.

https://doi.org/10.1016/j.ecl.2007.10.010

Van Zaane B, Nur E, Squizzato A, Dekkers OM, Twickler MT, Fliers E, et al. Hypercoagulable state in Cushing's syndrome: a systematic review. J Clin Endocrinol Metab. 2009;94: 2743-50.

https://doi.org/10.1210/jc.2009-0290

Kakade HR, Kasaliwal R, Jagtap VS, Bukan A, Budyal SR, Khare S, et al. Ectopic ACTH-secreting syndrome: a single-center experience. Endocr Pract. 2013;19:1007-14.

https://doi.org/10.4158/EP13171.OR

Newell-Price J, Morris DG, Drake WM, Korbonits M, Monson JP, Besser GM, et al. Optimal response criteria for the human CRH test in the differential diagnosis of ACTH-dependent Cushing's syndrome. J Clin Endocrinol Metab. 2002;87:1640-5.

https://doi.org/10.1210/jcem.87.4.8357

Invitti C, Pecori Giraldi F, de Martin M, Cavagnini F. Diagnosis and management of Cushing's syndrome: results of an Italian multicentre study. Study Group of the Italian Society of Endocrinology on the Pathophysiology of the Hypothalamic-Pituitary-Adrenal Axis. J Clin Endocrinol Metab. 1999;84:440-8.

Doi M, Sugiyama T, Izumiyama H, Yoshimoto T, Hirata Y. Clinical features and management of ectopic ACTH syndrome at a single institute in Japan. Endocr J. 2010;57:1061-9.

https://doi.org/10.1507/endocrj.K10E-265

Kola B, Grossman AB. Dynamic testing in Cushing's syndrome. Pituitary. 2008;11:155-62.

https://doi.org/10.1007/s11102-007-0079-x

Kaltsas GA, Giannulis MG, Newell-Price JD, Dacie JE, Thakkar C, Afshar F, et al. A critical analysis of the value of simultaneous inferior petrosal sinus sampling in Cushing's disease and the occult ectopic adrenocorticotropin syndrome. J Clin Endocrinol Metab. 1999;84:487-92.

https://doi.org/10.1210/jcem.84.2.5437

Utz A, Biller BM. The role of bilateral inferior petrosal sinus sampling in the diagnosis of Cushing's syndrome. Arq Bras Endocrinol Metabol. 2007;51:1329-38.

https://doi.org/10.1590/S0004-27302007000800019

Colao A, Faggiano A, Pivonello R, Pecori Giraldi F, Cavagnini F, Lombardi G, et al. Inferior petrosal sinus sampling in the differential diagnosis of Cushing's syndrome: results of an Italian multicenter study. Eur J Endocrinol. 2001;144:499-507.

https://doi.org/10.1530/eje.0.1440499

Oldfield EH, Doppman JL, Nieman LK, Chrousos GP, Miller DL, Katz DA, et al. Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing's syndrome. N Engl J Med. 1991;325:897-905.

https://doi.org/10.1056/NEJM199109263251301

Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008;93:1526-40.

https://doi.org/10.1210/jc.2008-0125

Castinetti F, Morange I, Dufour H, Jaquet P, Conte-Devolx B, Girard N, et al. Desmopressin test during petrosal sinus sampling: a valuable tool to discriminate pituitary or ectopic ACTH-dependent Cushing's syndrome. Eur J Endocrinol. 2007;157:271-7.

https://doi.org/10.1530/EJE-07-0215

Tsagarakis S, Christoforaki M, Giannopoulou H, Rondogianni F, Housianakou I, Malagari C, et al. A reappraisal of the utility of somatostatin receptor scintigraphy in patients with ectopic adrenocorticotropin Cushing's syndrome. J Clin Endocrinol Metab. 2003;88:4754-8.

https://doi.org/10.1210/jc.2003-030525

Tabarin A, Valli N, Chanson P, Bachelot Y, Rohmer V, Bex- Bachellerie V, et al. Usefulness of somatostatin receptor scintigraphy in patients with occult ectopic adrenocorticotropin syndrome. J Clin Endocrinol Metab. 1999;84:1193-202.

https://doi.org/10.1210/jcem.84.4.5583

Venkitaraman B, Karunanithi S, Kumar A, Bal C, Ammini AC, Kumar R. 68Ga-DOTATOC PET-CT in the localization of source of ectopic ACTH in patients with ectopic ACTH-dependent Cushing's syndrome. Clin Imaging. 2014;38:208-11.

https://doi.org/10.1016/j.clinimag.2013.10.007

Kayani I, Bomanji JB, Groves A, Conway G, Gacinovic S, Win T, et al. Functional imaging of neuroendocrine tumors with combined PET/CT using 68Ga-DOTATATE (DOTA-DPhe1,Tyr3- octreotate) and 18F-FDG. Cancer. 2008;112:2447-55.

https://doi.org/10.1002/cncr.23469

Bodei L, Cremonesi M, Kidd M, Grana CM, Severi S, Modlin IM, et al. Peptide receptor radionuclide therapy for advanced neuroendocrine tumors. Thorac Surg Clin. 2014;24:333-49.

https://doi.org/10.1016/j.thorsurg.2014.04.005

Kauhanen S, Seppänen M, Ovaska J, Minn H, Bergman J, Korsoff P, et al. The clinical value of [18F] fluorodihydroxyphenylalanine positron emission tomography in primary diagnosis, staging, and restaging of neuroendocrine tumors. Endocr Relat Cancer. 2009;16:255-65.

https://doi.org/10.1677/ERC-08-0229

Isidori AM, Sbardella E, Zatelli MC, Boschetti M, Vitale G, Colao A, et al. Conventional and nuclear medicine imaging in ectopic cushing's syndrome: A systematic review. J Clin Endocrinol Metab. 2015:JC20151589.

Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19:565-612.

https://doi.org/10.1089/thy.2008.0403

Teves DA. Clinical approach of Cushing syndrome resulting from ACTH-producing metastatic neuroendocrine tumor. The Endocrinologist. 2005;15:401-4.

https://doi.org/10.1097/01.ten.0000188475.05398.09

Salameh JR, Borman KR, Varkarakis GM. Laparoscopic bilateral adrenalectomy for occult ectopic ACTH syndrome. J Laparoendosc Adv Surg Tech A. 2008;18:52-5.

https://doi.org/10.1089/lap.2007.0016

McCance DR, Russell CF, Kennedy TL, Hadden DR, Kennedy L, Atkinson AB. Bilateral adrenalectomy: low mortality and morbidity in Cushing's disease. Clin Endocrinol (Oxf). 1993;39:315-21.

https://doi.org/10.1111/j.1365-2265.1993.tb02371.x

Li H, Yan W, Mao Q, Lu Z, Zeng Z. Role of adrenalectomy in ectopic ACTH syndrome. Endocr J. 2005;52:721-6.

https://doi.org/10.1507/endocrj.52.721

Ritzel K, Beuschlein F, Mickisch A, Osswald A, Schneider HJ, Schopohl J, et al. Clinical review: Outcome of bilateral adrenalectomy in Cushing's syndrome: a systematic review. J Clin Endocrinol Metab. 2013;98:3939-8.

https://doi.org/10.1210/jc.2013-1470

Oßwald A, Plomer E, Dimopoulou C, Milian M, Blaser R, Ritzel K, et al. Favorable long-term outcomes of bilateral adrenalectomy in Cushing's disease. Eur J Endocrinol. 2014;171:209-15.

https://doi.org/10.1530/EJE-14-0214

Amikura K, Alexander HR, Norton JA, Doppman JL, Jensen RT, Nieman L, et al. Role of surgery in management of adrenocorticotropic hormone-producing islet cell tumors of the pancreas. Surgery. 1995;118:1125-30.

https://doi.org/10.1016/S0039-6060(05)80123-0

Fleseriu M, Petersenn S. Medical therapy for Cushing's disease: adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers. Pituitary. 2015.

https://doi.org/10.1007/s11102-014-0627-0

Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, et al. Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100:2807-31.

https://doi.org/10.1210/jc.2015-1818

Tabarin A, Navarranne A, Guérin J, Corcuff JB, Parneix M, Roger P. Use of ketoconazole in the treatment of Cushing's disease and ectopic ACTH syndrome. Clin Endocrinol (Oxf). 1991;34:63-9.

https://doi.org/10.1111/j.1365-2265.1991.tb01737.x

Farwell AP, Devlin JT, Stewart JA. Total suppression of cortisol excretion by ketoconazole in the therapy of the ectopic adrenocorticotropic hormone syndrome. Am J Med. 1988;84:1063-6.

https://doi.org/10.1016/0002-9343(88)90312-9

Sharma ST, Nieman LK. Prolonged remission after long-term treatment with steroidogenesis inhibitors in Cushing's syndrome caused by ectopic ACTH secretion. Eur J Endocrinol. 2012;166:531-6.

https://doi.org/10.1530/EJE-11-0949

Corcuff JB, Young J, Masquefa-Giraud P, Chanson P, Baudin E, Tabarin A. Rapid control of severe neoplastic hypercortisolism with metyrapone and ketoconazole. Eur J Endocrinol. 2015;172:473-81.

https://doi.org/10.1530/EJE-14-0913

Valassi E, Crespo I, Gich I, Rodríguez J, Webb SM. A reappraisal of the medical therapy with steroidogenesis inhibitors in Cushing's syndrome. Clin Endocrinol (Oxf). 2012;77: 735-42.

https://doi.org/10.1111/j.1365-2265.2012.04424.x

Bertagna X, Favrod-Coune C, Escourolle H, Beuzeboc P, Christoforov B, Girard F, et al. Suppression of ectopic adrenocorticotropin secretion by the long-acting somatostatin analog octreotide. J Clin Endocrinol Metab. 1989;68:988-91.

https://doi.org/10.1210/jcem-68-5-988

von Werder K, Muller OA, Stalla GK. Somatostatin analogs in ectopic corticotropin production. Metabolism. 1996;45:129-31.

https://doi.org/10.1016/S0026-0495(96)90107-9

Pivonello R, Ferone D, Lamberts SW, Colao A. Cabergoline plus lanreotide for ectopic Cushing's syndrome. N Engl J Med. 2005;352:2457-8.

https://doi.org/10.1056/NEJM200506093522322

Gatto F, Hofland LJ. The role of somatostatin and dopamine D2 receptors in endocrine tumors. Endocr Relat Cancer. 2011;18:R233-51.

https://doi.org/10.1530/ERC-10-0334

de Bruin C, Feelders RA, Lamberts SW, Hofland LJ. Somatostatin and dopamine receptors as targets for medical treatment of Cushing's Syndrome. Rev Endocr Metab Disord. 2009;10:91-102.

https://doi.org/10.1007/s11154-008-9082-4

Rajeev SP, McDougall S, Terlizzo M, Palmer D, Daousi C, Cuthbertson DJ. Evolution in functionality of a metastatic pancreatic neuroendocrine tumour (pNET) causing Cushing's syndrome: treatment response with chemotherapy. BMC Endocr Disord. 2014;14:70.

https://doi.org/10.1186/1472-6823-14-70

van der ZwanWA, Bodei L, Mueller-Brand J, de HerderWW, Kvols LK, Kwekkeboom DJ. GEPNETs update: Radionuclide therapy in neuroendocrine tumors. Eur J Endocrinol. 2015;172:R1-8.

https://doi.org/10.1530/EJE-14-0488

Gómez K, Varghese J, Jiménez C. Medullary thyroid carcinoma: molecular signaling pathways and emerging therapies. J Thyroid Res. 2011;2011:815826.

https://doi.org/10.4061/2011/815826

Cabanillas ME, Hu MI, Jimenez C. Medullary thyroid cancer in the era of tyrosine kinase inhibitors: to treat or not to treat- and with which drug-those are the questions. J Clin Endocrinol Metab. 2014;99:4390-6.

https://doi.org/10.1210/jc.2014-2811

Barroso-Sousa R, Lerario AM, Evangelista J, Papadia C, Lourenc¸o DM, Lin CS, et al. Complete resolution of hypercortisolism with sorafenib in a patient with advanced medullary thyroid carcinoma and ectopic ACTH (adrenocorticotropic hormone) syndrome. Thyroid. 2014;24:1062-6.

https://doi.org/10.1089/thy.2013.0571

Baudry C, Paepegaey AC, Groussin L. Reversal of Cushing's syndrome by vandetanib in medullary thyroid carcinoma. N Engl J Med. 2013;369:584-6.

https://doi.org/10.1056/NEJMc1301428

Pitoia F, Bueno F, Schmidt A, Lucas S, Cross G. Rapid response of hypercortisolism to vandetanib treatment in a patient with advanced medullary thyroid cancer and ectopic Cushing syndrome. Arch Endocrinol Metab. 2015;59:352-5.

https://doi.org/10.1590/2359-3997000000057

Publicado
2016-12-01
Sección
Artículos de revisión