Horm Metab Res 2023; 55(08): 520-527
DOI: 10.1055/a-2047-6017
Original Article: Endocrine Care

Recurrent Cushing’s Disease in Adults: Predictors and Long-Term Follow-Up

Mustafa Ünal
1   Department of Internal Medicine, Kocaeli University, Kocaeli, Turkey
,
Alev Selek
2   Department of Endocrinology and Metabolism, Pituitary Center, Kocaeli University, Kocaeli, Turkey
,
2   Department of Endocrinology and Metabolism, Pituitary Center, Kocaeli University, Kocaeli, Turkey
,
Emre Gezer
2   Department of Endocrinology and Metabolism, Pituitary Center, Kocaeli University, Kocaeli, Turkey
,
Damla Köksalan
2   Department of Endocrinology and Metabolism, Pituitary Center, Kocaeli University, Kocaeli, Turkey
,
Zeynep Canturk
2   Department of Endocrinology and Metabolism, Pituitary Center, Kocaeli University, Kocaeli, Turkey
,
Berrin Cetinarslan
2   Department of Endocrinology and Metabolism, Pituitary Center, Kocaeli University, Kocaeli, Turkey
,
Burak Çabuk
3   Department of Neurosurgery, Pituitary Center, Kocaeli University, Kocaeli, Turkey
,
Ihsan Anık
3   Department of Neurosurgery, Pituitary Center, Kocaeli University, Kocaeli, Turkey
,
Savaş Ceylan
3   Department of Neurosurgery, Pituitary Center, Kocaeli University, Kocaeli, Turkey
› Author Affiliations

Abstract

Cushing’s disease (CD) is characterized by endogenous hypercortisolism that is associated with increased mortality and morbidity. Due to high recurrence rates in CD, the determination of high-risk patients is of paramount importance. In this study, we aimed to determine recurrence rates and clinical, laboratory, and histological predictors of recurrence in a high volume single-center. This retrospective study included 273 CD patients operated in a single pituitary center between 1997 and 2020. The patients with early postoperative remission were further grouped according to recurrence status (recurrent and sustained remission groups). Demographic, radiologic, laboratory, pathologic, and follow-up clinical data of the patients were analyzed and compared between groups. The recurrence rate was 9.6% in the first 5 years; however, the overall recurrence rate was 14.2% in this study. Higher preoperative basal ACTH levels were significantly correlated with CD recurrence even with ACTH levels adjusted for tumor size, Ki-67 levels, and tumoral invasion. Recurrence rates were significantly higher in patients with ACTH levels higher than 55 pg/ml, tumor diameter>9.5 mm, and if adrenal axis recovery was before 6 months. The severity of hypercortisolism, morbidities, and demographic factors except age were not predictive factors of recurrence. Based on our study data, younger age at diagnosis, a diagnosis of osteoporosis, higher preoperative ACTH levels, larger tumor size, invasive behavior, higher Ki 67 index, and early recovery of the adrenal axis during the postoperative period attracted attention as potential predictors of recurrent disease.



Publication History

Received: 06 February 2023

Accepted after revision: 23 February 2023

Article published online:
04 April 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Newell-Price J, Bertagna X, Grossman AB. et al. Cushing's syndrome. Lancet 2006; 367: 1605-1617
  • 2 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
  • 3 Liu Y, Liu X, Hong X. et al. Prediction of recurrence after transsphenoidal surgery for Cushing's disease: the use of machine learning algorithms. Neuroendocrinology 2019; 108: 201-210
  • 4 Kuo CH, Shih SR, Li HY. et al. Adrenocorticotropic hormone levels before treatment predict recurrence of Cushing's disease. J Formos Med Assoc 2017; 116: 441-447
  • 5 Guignat L, Bertherat J. Long-term follow-up and predictors of recurrence of Cushing's disease. J Neuroendocrinol 2022; 34: e13186
  • 6 Ferriere A, Cordroc'h C, Tabarin A. Evaluation and follow-up of patients with Cushing's disease after pituitary surgery. Encyclopedia of endocrine diseases. In: Martini L, Lacroix A, Mantero F (eds). Ilpo Huhtaniemi, Vol 3, 2nd ed. Amsterdam: Elsevier; 2019: 223-231
  • 7 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; 172: R227-R239
  • 8 Serban AL, Sala E, Carosi G. et al. Recovery of adrenal function after pituitary surgery in patients with Cushing disease: persistent remission or recurrence?. Neuroendocrinology 2019; 108: 211-218
  • 9 Aranda G, Enseñat J, Mora M. et al. Long-term remission and recurrence rate in a cohort of Cushing's disease: the need for long-term follow-up. Pituitary 2015; 18: 142-149
  • 10 Alexandraki KI, Kaltsas GA, Isidori AM. et al. Long-term remission and recurrence rates in Cushing's disease: predictive factors in a single-centre study. Eur J Endocrinol 2013; 168: 639-648
  • 11 Balomenaki M, Vassiliadi DA, Tsagarakis S. Cushing's disease: risk of recurrence following trans-sphenoidal surgery, timing and methods for evaluation. Pituitary 2022; 25: 718-721
  • 12 Braun LT, Rubinstein G, Zopp S. et al. Recurrence after pituitary surgery in adult Cushing's disease: a systematic review on diagnosis and treatment. Endocrine 2020; 70: 218-231
  • 13 Burke WT, Penn DL, Repetti CS. et al. Outcomes after repeat transsphenoidal surgery for recurrent Cushing disease: updated. Neurosurgery 2019; 85: E1030-E1036
  • 14 Pasternak-Pietrzak K, Moszczyńska E, Roszkowski M. et al. Predictive factors for the recurrence of Cushing's disease after surgical treatment in childhood. Endokrynol Pol 2020; 71: 313-318
  • 15 Ciric I, Zhao JC, Du H. et al. Transsphenoidal surgery for Cushing disease: experience with 136 patients. Neurosurgery 2012; 70: 70-80
  • 16 Zhang W, Sun M, Fan Y. et al. Machine learning in preoperative prediction of postoperative immediate remission of histology-positive Cushing's disease. Front Endocrinol (Lausanne) 2021; 12: 635795
  • 17 Selek A, Cetinarslan B, Canturk Z. et al. The utility of preoperative ACTH/cortisol ratio for the diagnosis and prognosis of Cushing's disease. J Neurosci Rural Pract 2018; 9: 106-111
  • 18 Selek A. Predicting factors of recurrence in patients with Cushing's Disease. Kocaeli Med J 2017; 6: 7
  • 19 Ragnarsson O. Cushing's syndrome – Disease monitoring: recurrence, surveillance with biomarkers or imaging studies. Best Pract Res Clin Endocrinol Metab 2020; 34: 101382
  • 20 Guaraldi F, Zoli M, Asioli S. et al. Results and predictors of outcome of endoscopic endonasal surgery in Cushing's disease: 20-year experience of an Italian referral Pituitary Center. J Endocrinol Invest 2020; 43: 1463-1471
  • 21 Ambrogio AG, Andrioli M, De Martin M. et al. Usefulness of desmopressin testing to predict relapse during long-term follow-up in patients in remission from Cushing's disease. Endocr Connect 2017; 6: 791-799
  • 22 Barbot M, Albiger N, Koutroumpi S. et al. Predicting late recurrence in surgically treated patients with Cushing's disease. Clin Endocrinol (Oxf) 2013; 79: 394-401
  • 23 Selek A, Cetinarslan B, Canturk Z. et al. The effect of somatostatin analogues on Ki-67 levels in GH-secreting adenomas. Growth Horm IGF Res 2019; 45: 1-5
  • 24 Liu X, Feng M, Zhang Y. et al. Expression of matrix metalloproteinase-9, pituitary tumor transforming gene, high mobility group A 2, and Ki-67 in adrenocorticotropic hormone-secreting pituitary tumors and their association with tumor recurrence. World Neurosurg 2018; 113: e213-e221
  • 25 Albani A, Pérez-Rivas LG, Dimopoulou C. et al. The USP8 mutational status may predict long-term remission in patients with Cushing's disease. Clin Endocrinol (Oxf) 2018; 89: 454-458
  • 26 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