Clinical Features and Remission Rates in Cushing’s Disease: A Comparison of MRI-Detectable and MRI-Undetectable Pituitary Adenomas

Abstract

We aimed to characterize the clinical features and remission rates of patients with Cushing’s Disease (CD) without magnetic resonance imaging (MRI) detectable pituitary adenoma compared to CD patients with MRI-detectable pituitary adenoma.All patients with adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome (CS) without MRI-detectable pituitary adenoma underwent high-dose dexamethasone suppression test, corticotropin-releasing hormone stimulation test, and/or bilateral inferior petrosal sinus sampling (BIPSS). The diagnosis of CD in patients without MRI-detectable adenoma was confirmed when the results of dynamic testing and sampling concordantly indicated ACTH-producing adenoma.These patients were included in MRI-undetectable group. Patients with ACTH-dependent CS had pituitary adenoma≥6 mm and those with pituitary adenoma<6 mm but BIPSS findings indicative of CD were included in MRI-detectable adenoma group. The study included 60 patients without MRI-detectable adenoma and 74 patients with MRI-detectable adenoma. At presentation, patients without MRI-detectable adenoma were older [47 years (30.25–58) vs. 40.5 years (29–49), p=0.036]. Hypertension (65% vs. 47.3%), diabetes mellitus (58.3% vs. 39.2%), and cardiovascular disease (13.3% vs. 2.7%) were more common in patients without MRI-detectable adenoma (p=0.040, p=0.027, p=0.020; respectively). The transsphenoidal surgery as initial treatment was higher in the patients with MRI-detectable adenoma group (97.3% vs. 80%, p=0.001). Third-month remission (60.4% vs. 63.8%, p=0.700) after surgery, and remission rates in the last visit (65.3% vs. 79.7%, p=0.077) were similar between the two groups. Inconclusion, the absence of an MRI-detectable adenoma underscores the necessity for comprehensive management.

Keywords

Cushing’s disease - management - pituitary adenoma - sella imaging - transsphenoidal surgery

Publication History

Received: 12 October 2024

Accepted after revision: 22 January 2025

Article published online:
06 March 2025

• References

• 1 Mehta GU, Lonser RR, Oldfield EH. The history of pituitary surgery for Cushing disease: historical vignette. J Neurosurg 2012; 116: 261-268
• 2 Nieman LK. Cushing’s syndrome: update on signs, symptoms and biochemical screening. Eur J Endocrinol 2015; 173: M33-M38
• 3 Nieman LK, Biller BM, Findling JW. et al. The diagnosis of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008; 93: 1526-1540
• 4 Ferriere A, Tabarin A. Cushing’s disease. Presse Méd 2021; 50: 104091
• 5 Gadelha MR, Vieira Neto L. Efficacy of medical treatment in C ushing’s disease: a systematic review. Clin Endocrinol 2014; 80: 1-12
• 6 Swearingen B, Biller BM, Barker FG. et al. Long-term mortality after transsphenoidal surgery for Cushing disease. Ann Inter Med 1999; 130: 821-824
• 7 Batista D, Courkoutsakis NA, Oldfield EH. et al. Detection of adrenocorticotropin-secreting pituitary adenomas by magnetic resonance imaging in children and adolescents with cushing disease. J Clin Endocrinol Metab 2005; 90: 5134-5140
• 8 Grober Y, Grober H, Wintermark M. et al. Comparison of MRI techniques for detecting microadenomas in Cushing’s disease. J Neurosurg 2018; 128: 1051-1057
• 9 Lonser RR, Nieman L, Oldfield EH. Cushing’s disease: pathobiology, diagnosis, and management. Journal of neurosurgery 2017; 126: 404-417
• 10 Sabahi M, Shahbazi T, Maroufi SF. et al. MRI–Negative Cushing’s disease: a review on therapeutic management. World Neurosurg 2022; 162: 126-137. e121
• 11 Jagannathan J, Sheehan JP, Jane JA. Evaluation and management of Cushing syndrome in cases of negative sellar magnetic resonance imaging. Neurosurg Focus 2007; 23: 1-7
• 12 Chow JT, Thompson GB, Grant CS. et al. Bilateral laparoscopic adrenalectomy for corticotrophin–dependent Cushing’s syndrome: a review of the Mayo Clinic experience. Clin Endocrinol 2008; 68: 513-519
• 13 Bertagna X, Guignat L. Approach to the Cushing’s disease patient with persistent/recurrent hypercortisolism after pituitary surgery. J Clin Endocrinol Metab 2013; 98: 1307-1318
• 14 Fleseriu M, Auchus R, Bancos I. et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol 2021; 9: 847-875
• 15 Lacroix A, Feelders RA, Stratakis CA. et al. Cushing’s syndrome. Lancet 2015; 386: 913-927
• 16 Bertagna X, Guignat L, Groussin L. et al. Cushing’s disease. Best Pract Res Clin Endocrinol Metab 2009; 23: 607-623
• 17 Hayes AR, Grossman AB. The ectopic adrenocorticotropic hormone syndrome: rarely easy, always challenging. Endocrinol Metab Clin 2018; 47: 409-425
• 18 Oldfield EH, Doppman JL, Nieman LK. et al. Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome. N Eng J Med 1991; 325: 897-905
• 19 Wu ZQ, Xu HG. Preanalytical stability of adrenocorticotropic hormone depends on both time to centrifugation and temperature. J Clin Lab Anal 2017; 31: e22081
• 20 Asa SL, Mete O, Perry A. et al. Overview of the 2022 WHO classification of pituitary tumors. Endocr Pathol 2022; 33: 6-26
• 21 Ragnarsson O, Olsson DS, Chantzichristos D. et al. The incidence of Cushing’s disease: a nationwide Swedish study. Pituitary 2019; 22: 179-186
• 22 Valassi E. Clinical presentation and etiology of Cushing’s syndrome: Data from ERCUSYN. J Neuroendocrinol 2022; 34: e13114
• 23 Tatsi C, Bompou ME, Flippo C. et al. Paediatric patients with Cushing disease and negative pituitary MRI have a higher risk of nonremission after transsphenoidal surgery. Clin Endocrinol 2021; 95: 856-862
• 24 Sun Y, Sun Q, Fan C. et al. Diagnosis and therapy for Cushing’s disease with negative dynamic MRI finding: a single-centre experience. Clin Endocrinol 2012; 76: 868-876
• 25 Sharifi G, Amin AA, Sabahi M. et al. MRI-negative Cushing’s disease: management strategy and outcomes in 15 cases utilizing a pure endoscopic endonasal approach. BMC Endocr Disord 2022; 22: 154
• 26 Akirov A, Shimon I, Fleseriu M. et al. Clinical study and systematic review of pituitary microadenomas vs. macroadenomas in Cushing’s disease: does size matter?. J Clin Med 2022; 11: 1558
• 27 Machado M, Alcantara A, Pereira A. et al. Negative correlation between tumour size and cortisol/ACTH ratios in patients with Cushing’s disease harbouring microadenomas or macroadenomas. J Endocrinol Investig 2016; 39: 1401-1409
• 28 Woo YS, Isidori AM, Wat WZ. et al. Clinical and biochemical characteristics of adrenocorticotropin-secreting macroadenomas. J Clin Endocrinol Metab 2005; 90: 4963-4969
• 29 Newell-Price J, Bertagna X, Grossman AB. et al. Cushing’s syndrome. Lancet 2006; 367: 1605-1617
• 30 Sharma S, Nieman L, Feelders R. Comorbidities in Cushing’s disease. Pituitary 2015; 18: 188-194
• 31 Hwang Y-C, Chung JH, Min Y-K. et al. Comparisons between macroadenomas and microadenomas in Cushing’s disease: characteristics of hormone secretion and clinical outcomes. J Korean Med Sci 2009; 24: 46
• 32 Mathioudakis N, Pendleton C, Quinones-Hinojosa A. et al. ACTH-secreting pituitary adenomas: size does not correlate with hormonal activity. Pituitary 2012; 15: 526-532
• 33 Bansal P, Lila A, Goroshi M. et al. Duration of post-operative hypocortisolism predicts sustained remission after pituitary surgery for Cushing’s disease. Endocr Connect 2017; 6: 625-636
• 34 Pouratian N, Prevedello DM, Jagannathan J. et al. Outcomes and management of patients with Cushing’s disease without pathological confirmation of tumor resection after transsphenoidal surgery. J Clin Endocrinol Metab 2007; 92: 3383-3388
• 35 Cebula H, Baussart B, Villa C. et al. Efficacy of endoscopic endonasal transsphenoidal surgery for Cushing’s disease in 230 patients with positive and negative MRI. Acta Neurochirurg 2017; 159: 1227-1236
• 36 Cristante J, Lefournier V, Sturm N. et al. Why we should still treat by neurosurgery patients with Cushing disease and a normal or inconclusive pituitary MRI. J Clin Endocrinol Metab 2019; 104: 4101-4113
• 37 Hofmann BM, Hlavac M, Martinez R. et al. Long-term results after microsurgery for Cushing disease: experience with 426 primary operations over 35 years. J Neurosurg 2008; 108: 9-18
• 38 Starke RM, Reames DL, Chen C-J. et al. Endoscopic transsphenoidal surgery for cushing disease: techniques, outcomes, and predictors of remission. Neurosurgery 2013; 72: 240-247
• 39 Jagannathan J, Smith R, DeVroom HL. et al. Outcome of using the histological pseudocapsule as a surgical capsule in Cushing disease. J Neurosurg 2009; 111: 531-539
• 40 Prevedello DM, Pouratian N, Sherman J. et al. Management of Cushing’s disease: outcome in patients with microadenoma detected on pituitary magnetic resonance imaging. J Neurosurg 2008; 109: 751-759