Without treatment, hypercortisolism persists and in many patients worsens. Untreated disease carries a dismal survival rate of 50% at 5 years.[113]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 Nov;103(5):825-30.
http://www.ncbi.nlm.nih.gov/pubmed/16304985?tool=bestpractice.com
This leads to worsening of the Cushing phenotype and increased mortality, mainly from cardiovascular disease. With therapy to normalise cortisol levels, patients have a mortality rate similar to the general population.[66]Nieman LK, Biller BM, Findling JW, et al. Treatment of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015 Aug;100(8):2807-31.
https://academic.oup.com/jcem/article/100/8/2807/2836065
http://www.ncbi.nlm.nih.gov/pubmed/26222757?tool=bestpractice.com
[67]Swearingen B, Biller BM, Barker FG 2nd, et al. Long-term mortality after transsphenoidal surgery for Cushing disease. Ann Intern Med. 1999 May 18;130(10):821-4.
http://www.ncbi.nlm.nih.gov/pubmed/10366371?tool=bestpractice.com
Within the first year of effective therapy, many of the characteristic features such as facial plethora, striae, and supraclavicular fat pads will resolve or show marked improvement. Patients lose a significant amount of weight with improved control or resolution of diabetes and hypertension. Bone density steadily improves after hypercortisolism resolves. Despite improvement of complications in most patients, cardiovascular risk, hypertension, obesity, and decreased quality of life may persist in some patients even after biochemical cure.[11]Hakami OA, Ahmed S, Karavitaki N. Epidemiology and mortality of Cushing's syndrome. Best Pract Res Clin Endocrinol Metab. 2021 Jan;35(1):101521.
http://www.ncbi.nlm.nih.gov/pubmed/33766428?tool=bestpractice.com
[114]Faggiano A, Pivonello R, Spiezia S, et al. Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing's disease during active disease and 1 year after disease remission. J Clin Endocrinol Metab. 2003 Jun;88(6):2527-33.
https://academic.oup.com/jcem/article/88/6/2527/2845327
http://www.ncbi.nlm.nih.gov/pubmed/12788849?tool=bestpractice.com
[115]Van der Klaauw AA, Kars M, Biermasz NR, et al. Disease-specific impairments in quality of life during long-term follow-up of patients with different pituitary adenomas. Clin Endocrinol (Oxf). 2008 Nov;69(5):775-84.
http://www.ncbi.nlm.nih.gov/pubmed/18462264?tool=bestpractice.com
Patient-reported outcomes are scarce, but they show that decreased quality of life persists even in patients with biochemical normalisation and they are worse in Cushing's disease compared with Cushing syndrome.[116]Knoble N, Nayroles G, Cheng C, et al. Illustration of patient-reported outcome challenges and solutions in rare diseases: a systematic review in Cushing's syndrome. Orphanet J Rare Dis. 2018 Dec 19;13(1):228.
https://ojrd.biomedcentral.com/articles/10.1186/s13023-018-0958-4
http://www.ncbi.nlm.nih.gov/pubmed/30567582?tool=bestpractice.com
Pituitary adenomectomy
Outcomes are largely based on the size of the initial tumour in patients with Cushing's disease. Micro-adenomas (size <1 cm) have superior outcomes with remission rates quoted as 48% to 100% of patients. An average of approximately 32% of Cushing's disease patients, and up to 75% of Cushing's disease patients initially submitted to pituitary surgery, will require a second-line treatment during the disease course. The long-term failure of pituitary surgery is evidently higher in patients with macro-adenomas (range, 0 to 71.4; mean, 48.8; median, 52.2) than in patients with micro-adenomas (range, 0 to 55.5; mean, 25; median, 21.2).[69]Pivonello R, De Leo M, Cozzolino A, et al. The treatment of Cushing's disease. Endocr Rev. 2015 Aug;36(4):385-486.
https://academic.oup.com/edrv/article/36/4/385/2354703
http://www.ncbi.nlm.nih.gov/pubmed/26067718?tool=bestpractice.com
[73]Fleseriu M, Hamrahian AH, Hoffman AR, et al; AACE Neuroendocrine and Pituitary Scientific Committee. American Association of Clinical Endocrinologists and American College of Endocrinology Disease State Clinical Review: diagnosis of recurrence in Cushing disease. Endocr Pract. 2016 Dec;22(12):1436-48.
http://www.ncbi.nlm.nih.gov/pubmed/27643842?tool=bestpractice.com
[117]Petersenn S, Beckers A, Ferone D, et al. Therapy of endocrine disease: outcomes in patients with Cushing's disease undergoing transsphenoidal surgery: systematic review assessing criteria used to define remission and recurrence. Eur J Endocrinol. 2015 June;172(6):R227-39.
https://eje.bioscientifica.com/view/journals/eje/172/6/R227.xml
http://www.ncbi.nlm.nih.gov/pubmed/25599709?tool=bestpractice.com
Patients with macro-adenomas (size >1 cm) have remission rates <65% after surgery and show recurrence rates of 12% to 45% at about 16 months.[67]Swearingen B, Biller BM, Barker FG 2nd, et al. Long-term mortality after transsphenoidal surgery for Cushing disease. Ann Intern Med. 1999 May 18;130(10):821-4.
http://www.ncbi.nlm.nih.gov/pubmed/10366371?tool=bestpractice.com
[113]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 Nov;103(5):825-30.
http://www.ncbi.nlm.nih.gov/pubmed/16304985?tool=bestpractice.com
[118]Blevins LS Jr, Christy JH, Khajavi M, et al. Outcomes of therapy for Cushing's disease due to adrenocorticotropin-secreting pituitary macroadenomas. J Clin Endocrinol Metab. 1998 Jan;83(1):63-7.
https://academic.oup.com/jcem/article/83/1/63/2865075
http://www.ncbi.nlm.nih.gov/pubmed/9435417?tool=bestpractice.com
Patients may require temporary or prolonged treatment for deficiencies of thyrotropin, gonadotrophin, growth hormone, or antidiuretic hormone and corticosteroids.
A 2018 study did not find significant differences between endoscopic and microscopic pituitary surgery in remission percentage. Although the short term recurrence was lower for endoscopic surgery, both groups had a recurrence rate of approximately 4% per person/year.[119]Qiao N. Outcome of endoscopic vs microsurgical transsphenoidal resection for Cushing's disease. Endocr Connect. 2018 Jan;7(1):R26-37.
https://ec.bioscientifica.com/view/journals/ec/7/1/EC-17-0312.xml
http://www.ncbi.nlm.nih.gov/pubmed/29311226?tool=bestpractice.com
A 2021 study in young people with pituitary tumours found favourable outcomes and lower re-treatment rates with endonasal endoscopic surgery compared with microscopic transsphenoidal surgery.[120]Dhandapani S, Narayanan R, Jayant SS, et al. Endonasal endoscopic versus microscopic transsphenoidal surgery in pituitary tumors among the young: a comparative study & meta-analysis. Clin Neurol Neurosurg. 2021 Jan;200:106411.
http://www.ncbi.nlm.nih.gov/pubmed/33338824?tool=bestpractice.com
Adrenocorticotrophic hormone (ACTH)-independent Cushing syndrome
Patients who undergo unilateral adrenalectomy for a causative adrenal adenoma are uniformly cured of their disease. Recurrence in the contralateral adrenal gland is exceedingly rare. Patients with bilateral adrenalectomy will need monitoring and corticosteroid and mineralocorticoid replacement. Outlook for patients with adrenal carcinoma depends upon the stage at which it is diagnosed. Beyond surgical resection, benefit of additional treatments is debated and should be patient-specific.
Ectopic ACTH production
Encompasses a diverse group. The nature of the tumour secreting ACTH largely determines the outcomes. Many ACTH-secreting tumours are aggressive and grow rapidly. In these cases, complete resection of the tumour is difficult, and patients generally succumb to tumour-related complications. Individuals with indolent ACTH-secreting tumours often have complete tumour resection with resolution of hypercortisolism as well as symptoms.