Persistent or recurrent Cushing’s disease: Surgical adrenalectomy
- Lynnette K Nieman, MD
Lynnette K Nieman, MD
- Section Editor — Adrenal Disease
- Senior Investigator
- Bethesda, MD
The treatment of choice for patients with Cushing's disease (corticotropin [ACTH]-secreting pituitary tumor) is transsphenoidal surgery and resection of the pituitary tumor. However, for patients with persistent or recurrent Cushing's disease, adrenalectomy, which can be achieved either surgically or medically (with mitotane), is sometimes recommended for definitive cure.
Surgical adrenalectomy for persistent or recurrent Cushing’s disease is reviewed here. An overview of the treatment of Cushing’s syndrome, medical therapy of hypercortisolism, and primary therapy for Cushing’s disease are reviewed separately. (See "Overview of the treatment of Cushing's syndrome" and "Medical therapy of hypercortisolism (Cushing's syndrome)" and "Primary therapy of Cushing's disease: Transsphenoidal surgery and pituitary irradiation".)
GENERAL APPROACH TO CUSHING'S DISEASE
Cushing's disease is caused by pituitary corticotropin (ACTH)-secreting tumors. These corticotroph tumors are almost always benign and are usually microadenomas (ie, <10 mm in diameter). The progressive stages of treatment that may be required to cure a patient of Cushing's disease are shown in the algorithm (algorithm 1); this approach is consistent with a 2008 consensus statement on the treatment of ACTH-dependent Cushing's syndrome .
Transsphenoidal microadenomectomy is currently the treatment of choice for Cushing's disease. A neurosurgeon with expertise in transsphenoidal surgery for Cushing's patients can achieve an initial cure rate of 80 to 90 percent with microadenomas, but less than 60 percent with macroadenomas. A meta-analysis of 18 reports since 1995 showed an overall initial cure rate for micro- and macroadenomas combined of 79 percent . It is important to recognize that patients who are initially “cured” should be considered to be in remission rather than cured, as some will recur. Overall, remission from centers with less experience may be much lower, approaching only 50 percent long-term cure . (See "Primary therapy of Cushing's disease: Transsphenoidal surgery and pituitary irradiation", section on 'Transsphenoidal surgery'.)
For patients with clear persistent disease after transsphenoidal surgery, there are five therapeutic options:
- Biller BM, Grossman AB, Stewart PM, et al. Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab 2008; 93:2454.
- Kelly DF. Transsphenoidal surgery for Cushing's disease: a review of success rates, remission predictors, management of failed surgery, and Nelson's Syndrome. Neurosurg Focus 2007; 23:E5.
- Alwani RA, de Herder WW, van Aken MO, et al. Biochemical predictors of outcome of pituitary surgery for Cushing's disease. Neuroendocrinology 2010; 91:169.
- Orth DN, Liddle GW. Results of treatment in 108 patients with Cushing's syndrome. N Engl J Med 1971; 285:243.
- Moore TJ, Dluhy RG, Williams GH, Cain JP. Nelson's syndrome: frequency, prognosis, and effect of prior pituitary irradiation. Ann Intern Med 1976; 85:731.
- Kelly WF, MacFarlane IA, Longson D, et al. Cushing's disease treated by total adrenalectomy: long-term observations of 43 patients. Q J Med 1983; 52:224.
- Aron DC, Schnall AM, Sheeler LR. Cushing's syndrome and pregnancy. Am J Obstet Gynecol 1990; 162:244.
- Thompson SK, Hayman AV, Ludlam WH, et al. Improved quality of life after bilateral laparoscopic adrenalectomy for Cushing's disease: a 10-year experience. Ann Surg 2007; 245:790.
- Hardy JD. Surgical management of Cushing's syndrome with emphasis on adrenal autotransplantation. Ann Surg 1978; 188:290.
- Young WF Jr, Thompson GB. Laparoscopic adrenalectomy for patients who have Cushing's syndrome. Endocrinol Metab Clin North Am 2005; 34:489.
- Smith PW, Turza KC, Carter CO, et al. Bilateral adrenalectomy for refractory Cushing disease: a safe and definitive therapy. J Am Coll Surg 2009; 208:1059.
- Vella A, Thompson GB, Grant CS, et al. Laparoscopic adrenalectomy for adrenocorticotropin-dependent Cushing's syndrome. J Clin Endocrinol Metab 2001; 86:1596.
- Chalmers RA, Mashiter K, Joplin GF. Residual adrenocortical function after bilateral "total" adrenalectomy for Cushing's disease. Lancet 1981; 2:1196.
- Oßwald A, Plomer E, Dimopoulou C, et al. Favorable long-term outcomes of bilateral adrenalectomy in Cushing's disease. Eur J Endocrinol 2014; 171:209.
- Kemink SA, Frijns JT, Hermus AR, et al. Body composition determined by six different methods in women bilaterally adrenalectomized for treatment of Cushing's disease. J Clin Endocrinol Metab 1999; 84:3991.
- Peacey SR, Guo CY, Robinson AM, et al. Glucocorticoid replacement therapy: are patients over treated and does it matter? Clin Endocrinol (Oxf) 1997; 46:255.
- Howlett TA. An assessment of optimal hydrocortisone replacement therapy. Clin Endocrinol (Oxf) 1997; 46:263.
- Assié G, Bahurel H, Coste J, et al. Corticotroph tumor progression after adrenalectomy in Cushing's Disease: A reappraisal of Nelson's Syndrome. J Clin Endocrinol Metab 2007; 92:172.
- Mountjoy KG. The human melanocyte stimulating hormone receptor has evolved to become "super-sensitive" to melanocortin peptides. Mol Cell Endocrinol 1994; 102:R7.
- Barber TM, Adams E, Ansorge O, et al. Nelson's syndrome. Eur J Endocrinol 2010; 163:495.
- Hopwood NJ, Kenny FM. Incidence of Nelson's syndrome after adrenalectomy for Cushing's disease in children: results of a nationwide survey. Am J Dis Child 1977; 131:1353.
- Cohen KL, Noth RH, Pechinski T. Incidence of pituitary tumors following adrenalectomy. A long-term follow-up study of patients treated for Cushing's disease. Arch Intern Med 1978; 138:575.
- McArthur RG, Hayles AB, Salassa RM. Childhood Cushing disease: results of bilateral adrenalectomy. J Pediatr 1979; 95:214.
- Wilson CB, Tyrrell JB, Fitzgerald PA, Pitts LH. Cushing's disease and Nelson's syndrome. Clin Neurosurg 1980; 27:19.
- Pereira MA, Halpern A, Salgado LR, et al. A study of patients with Nelson's syndrome. Clin Endocrinol (Oxf) 1998; 49:533.
- Assié G, Bahurel H, Bertherat J, et al. The Nelson's syndrome... revisited. Pituitary 2004; 7:209.
- Luton JP, Mahoudeau JA, Bouchard P, et al. Treatment of Cushing's disease by O,p'DDD. Survey of 62 cases. N Engl J Med 1979; 300:459.
- Schteingart DE, Tsao HS, Taylor CI, et al. Sustained remission of Cushing's disease with mitotane and pituitary irradiation. Ann Intern Med 1980; 92:613.
- Kemink, SA, Smals, AG, Hermus, AR, et al. Nelson's syndrome: a review. Endocrinologist 1997; 7:5.
- Ray DW, Gibson S, Crosby SR, et al. Elevated levels of adrenocorticotropin (ACTH) precursors in post-adrenalectomy Cushing's disease and their regulation by glucocorticoids. J Clin Endocrinol Metab 1995; 80:2430.
- Karl M, Von Wichert G, Kempter E, et al. Nelson's syndrome associated with a somatic frame shift mutation in the glucocorticoid receptor gene. J Clin Endocrinol Metab 1996; 81:124.
- Nagesser SK, van Seters AP, Kievit J, et al. Long-term results of total adrenalectomy for Cushing's disease. World J Surg 2000; 24:108.
- Jenkins PJ, Trainer PJ, Plowman PN, et al. The long-term outcome after adrenalectomy and prophylactic pituitary radiotherapy in adrenocorticotropin-dependent Cushing's syndrome. J Clin Endocrinol Metab 1995; 80:165.
- Gil-Cárdenas A, Herrera MF, Díaz-Polanco A, et al. Nelson's syndrome after bilateral adrenalectomy for Cushing's disease. Surgery 2007; 141:147.
- Pinto EM, Siqueira SA, Cukier P, et al. Possible role of a radiation-induced p53 mutation in a Nelson's syndrome patient with a fatal outcome. Pituitary 2011; 14:400.
- Kasperlik-Załuska AA, Nielubowicz J, Wisławski J, et al. Nelson's syndrome: incidence and prognosis. Clin Endocrinol (Oxf) 1983; 19:693.
- Kasperlik-Zaluska A, Walecki J, Brzeziński J, et al. MRI versus CT in the diagnosis of Nelson's syndrome. Eur Radiol 1997; 7:106.
- Kemink SA, Grotenhuis JA, De Vries J, et al. Management of Nelson's syndrome: observations in fifteen patients. Clin Endocrinol (Oxf) 2001; 54:45.
- Kasperlik-Załuska AA, Bonicki W, Jeske W, et al. Nelson's syndrome -- 46 years later: clinical experience with 37 patients. Zentralbl Neurochir 2006; 67:14.
- De Tommasi C, Vance ML, Okonkwo DO, et al. Surgical management of adrenocorticotropic hormone-secreting macroadenomas: outcome and challenges in patients with Cushing's disease or Nelson's syndrome. J Neurosurg 2005; 103:825.
- Kelly PA, Samandouras G, Grossman AB, et al. Neurosurgical treatment of Nelson's syndrome. J Clin Endocrinol Metab 2002; 87:5465.
- Howlett TA, Plowman PN, Wass JA, et al. Megavoltage pituitary irradiation in the management of Cushing's disease and Nelson's syndrome: long-term follow-up. Clin Endocrinol (Oxf) 1989; 31:309.
- Jane JA Jr, Vance ML, Woodburn CJ, Laws ER Jr. Stereotactic radiosurgery for hypersecreting pituitary tumors: part of a multimodality approach. Neurosurg Focus 2003; 14:e12.
- Vik-Mo EO, Øksnes M, Pedersen PH, et al. Gamma knife stereotactic radiosurgery of Nelson syndrome. Eur J Endocrinol 2009; 160:143.
- Mauermann WJ, Sheehan JP, Chernavvsky DR, et al. Gamma Knife surgery for adrenocorticotropic hormone-producing pituitary adenomas after bilateral adrenalectomy. J Neurosurg 2007; 106:988.
- Aronin N, Krieger DT. Sustained remission of Nelson's syndrome after stopping cyproheptadine treatment. N Engl J Med 1980; 302:453.
- Mercado-Asis LB, Yanovski JA, Tracer HL, et al. Acute effects of bromocriptine, cyproheptadine, and valproic acid on plasma adrenocorticotropin secretion in Nelson's syndrome. J Clin Endocrinol Metab 1997; 82:514.
- Casulari LA, Naves LA, Mello PA, et al. Nelson's syndrome: complete remission with cabergoline but not with bromocriptine or cyproheptadine treatment. Horm Res 2004; 62:300.
- Pivonello R, Faggiano A, Di Salle F, et al. Complete remission of Nelson's syndrome after 1-year treatment with cabergoline. J Endocrinol Invest 1999; 22:860.
- Andreassen M, Kristensen LØ. Rosiglitazone for prevention or adjuvant treatment of Nelson's syndrome after bilateral adrenalectomy. Eur J Endocrinol 2005; 153:503.
- Munir A, Song F, Ince P, et al. Ineffectiveness of rosiglitazone therapy in Nelson's syndrome. J Clin Endocrinol Metab 2007; 92:1758.
- Mullan KR, Leslie H, McCance DR, et al. The PPAR-gamma activator rosiglitazone fails to lower plasma ACTH levels in patients with Nelson's syndrome. Clin Endocrinol (Oxf) 2006; 64:519.
- Kreutzer J, Jeske I, Hofmann B, et al. No effect of the PPAR-gamma agonist rosiglitazone on ACTH or cortisol secretion in Nelson's syndrome and Cushing's disease in vitro and in vivo. Clin Neuropathol 2009; 28:430.
- Raverot G, Sturm N, de Fraipont F, et al. Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas: a French multicenter experience. J Clin Endocrinol Metab 2010; 95:4592.