Course of Cushing`s disease and treatment outcomes in correlation with pituitary MRI in children

BACKGROUND: Cushing’s disease (CD) is a rare disorder of a persistent cortisol excess caused by ACTH-secreting pituitary tumor (corticotropinoma). Transsphenoidal surgery (TSS) is a treatment of choice for СD, which effectiveness range is from 70 to 90%. Recurrence rate after successful treatment is about 25%. If surgical treatment is unsuccessful or recurrence appear, radiation treatment is the next therapeutic option, which effectiveness range is also 90%, but the hypopituitarism rate as side effect of treatment is higher. Preoperative predictors of remission and recurrence are still unexplored what leads to further investigations.

AIM: Analysis of remission and recurrence rates of pediatric CD after successful treatment according to preoperative MRI and therapeutic option.

MATERIALS AND METHODS: We conducted a retrospective analysis of 90 pediatric patients with CD who were observed between 1992 and 2020 at the Endocrinology Research Centre.

RESULTS: The most common clinical symptoms of CD were weight gain [94%] and growth retardation [72%]. Pituitary tumor was detected on radiological imaging in 53/90 patients [59%], there were no signs of visible adenoma in 37/90 of patients [41%]. 63 of 90 patients underwent TSS (70%), 27 patients underwent radiosurgery (30%). Remission rate after TSS was 71% [45/63], after radiosurgery — 85% [23/27]. There were no significant differences in remission rates after radical treatment according to preoperative MRI results (P=0.21 after TSS and P=0.87 after radiosurgery, х2 analysis). Recurrence after successful treatment was diagnosed in 10 patients. There were no significant differences in time to recurrence according to preoperative MRI results (P=0.055, х2 analysis). Time to recurrence was statistically different after TSS compared to radiosurgery (P=0.007, Kaplan–Meier analysis) and in the group with developed adrenal insufficiency in the early postoperative period (P=0.04, Kaplan–Meier analysis). Analysis of side effect of treatment showed that the frequency of growth hormone and gonadotrophin deficiency was statistically higher after radiosurgery (р<0.01, Kruskel–Wallis ANOVA test). Diabetes insipidus was diagnosed only after TSS. CONCLUSION: Results of our study didn`t allow to use MRI-results as predictor of effectiveness treatment in pediatric CD. Therapeutic option has an impact on time to recurrence, not on recurrence rates. The frequency of growth hormone and gonadotrophin deficiency was statistically higher after radiosurgery compared to TSS. Further studies are needed to identify predictors of remission and recurrence in CD.>< 0.01, Kruskel–Wallis ANOVA test). Diabetes insipidus was diagnosed only after TSS.

CONCLUSION: Results of our study didn`t allow to use MRI-results as predictor of effectiveness treatment in pediatric CD. Therapeutic option has an impact on time to recurrence, not on recurrence rates. The frequency of growth hormone and gonadotrophin deficiency was statistically higher after radiosurgery compared to TSS. Further studies are needed to identify predictors of remission and recurrence in CD.

1. Sharma ST, Nieman LK, Feelders RA. Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015;7:281-293. doi: https://doi.org/10.2147/CLEP.S44336

2. Stratakis CA. An update on Cushing syndrome in pediatrics. Ann Endocrinol (Paris). 2018;79(3):125-131. doi: https://doi.org/10.1016/j.ando.2018.03.010

3. Storr HL, Savage MO. Management of endocrine disease: Paediatric Cushing’s disease. Eur J Endocrinol. 2015;173(1):R35-R45. doi: https://doi.org/10.1530/EJE-15-0013

4. Bochicchio D, Losa M, Buchfelder M. Factors influencing the immediate and late outcome of Cushing’s disease treated by transsphenoidal surgery: a retrospective study by the European Cushing’s Disease Survey Group. J Clin Endocrinol Metab. 1995;80(11):3114-3120. doi: https://doi.org/10.1210/jcem.80.11.7593411

5. Katznelson L, Bogan JS, Trob JR, et al. Biochemical assessment of Cushing’s disease in patients with corticotroph macroadenomas. J Clin Endocrinol Metab. 1998;83(5):1619-1623. doi: https://doi.org/10.1210/jcem.83.5.4845

6. Dimopoulou C, Schopohl J, Rachinger W, et al. Long-term remission and recurrence rates after first and second transsphenoidal surgery for Cushing’s disease: care reality in the Munich Metropolitan Region. Eur J Endocrinol. 2013;170(2):283-292. doi: https://doi.org/10.1530/EJE-13-0634

7. Tritos NA, Biller BM, Swearingen B. Management of Cushing disease. Nat Rev Endocrinol. 2011;7(5):279-289. doi: https://doi.org/10.1038/nrendo.2011.12

8. 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(1):9-18. doi: https://doi.org/10.3171/JNS/2008/108/01/0009

9. Shimon I, Ram Z, Cohen ZR, Hadani M. Transsphenoidal surgery for Cushing’s disease: endocrinological follow-up monitoring of 82 patients. Neurosurgery. 2002;51(1):57-62. doi: https://doi.org/10.1097/00006123-200207000-00008

10. Fomekong E, Maiter D, Grandin C, Raftopoulos C. Outcome of transsphenoidal surgery for Cushing’s disease: a high remission rate in ACTH-secreting macroadenomas. Clin Neurol Neurosurg. 2009;111(5):442-449. doi: https://doi.org/10.1016/j.clineuro.2008.12.011

11. Hammer GD, Tyrrell JB, Lamborn KR, et al. Transsphenoidal microsurgery for Cushing’s disease: initial outcome and longterm results. J Clin Endocrinol Metab. 2004;89(12):6348-6357. doi: https://doi.org/10.1210/jc.2003-032180

12. Rees DA, Hanna FW, Davies JS, et al. Long-term follow-up results of transsphenoidal surgery for Cushing’s disease in a single centre using strict criteria for remission. Clin Endocrinol (Oxf ). 2002;56(4):541-551. doi: https://doi.org/10.1046/j.1365-2265.2002.01511.x

13. Blevins LS Jr, Christy JH, Khajavi M, Tindall GT. Outcomes of therapy for Cushing’s disease due to adrenocorticotropin-secreting pituitary macroadenomas. J Clin Endocrinol Metab. 1998;83(1):63-67. doi: https://doi.org/10.1210/jcem.83.1.4525

14. Cannavò S, Almoto B, Dall’Asta C, et al. Long-term results of treatment in patients with ACTH-secreting pituitary macroadenomas. Eur J Endocrinol. 2003;149(3):195-200. doi: https://doi.org/10.1530/eje.0.1490195

15. 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(5):825-830. doi: https://doi.org/10.3171/jns.2005.103.5.0825

16. Mampalam TJ, Tyrrell JB, Wilson CB. Transsphenoidal microsurgery for Cushing disease. A report of 216 cases. Ann Intern Med. 1988;109(6):487-493. doi: https://doi.org/10.7326/0003-4819-109-6-487

17. Patil CG, Prevedello DM, Lad SP, et al. Late recurrences of Cushing’s disease after initial successful transsphenoidal surgery. J Clin Endocrinol Metab. 2008;93(2):358-362. doi: https://doi.org/10.1210/jc.2007-2013

18. Sonino N, Zielezny M, Fava GA, et al. Risk factors and long-term outcome in pituitary-dependent Cushing’s disease. J Clin Endocrinol Metab. 1996;81(7):2647-2652. doi: https://doi.org/10.1210/jcem.81.7.8675592

19. Patil CG, Veeravagu A, Prevedello DM, et al. Outcomes after repeat transsphenoidal surgery for recurrent Cushing’s disease. Neurosurgery. 2008;63(2):266-271. doi: https://doi.org/10.1227/01.NEU.0000313117.35824.9F

20. Estrada J, Boronat M, Mielgo M, et al. The long-term outcome of pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing’s disease. N Engl J Med. 1997;336(3):172-177. doi: https://doi.org/10.1056/NEJM199701163360303

21. Sheehan JM, Vance ML, Sheehan JP, et al. Radiosurgery for Cushing’s disease after failed transsphenoidal surgery. J Neurosurg. 2000;93(5):738-742. doi: https://doi.org/10.3171/jns.2000.93.5.0738

22. Minniti G, Osti M, Jaffrain-Rea ML, et al. Long-term follow-up results of postoperative radiation therapy for Cushing’s disease. J Neurooncol. 2007;84(1):79-84. doi: https://doi.org/10.1007/s11060-007-9344-0

23. Bilaniuk LT, Zimmerman RA, Wehrli FW, et al. Magnetic resonance imaging of pituitary lesions using 1.0 to 1.5 T field strength. Radiology. 1984;153(2):415-418. doi: https://doi.org/10.1148/radiology.153.2.6484173

24. Bilaniuk LT, Zimmerman RA, Wehrli FW, et al. Cerebral magnetic resonance: comparison of high and low field strength imaging. Radiology. 1984;153(2):409-414. doi: https://doi.org/10.1148/radiology.153.2.6541355

25. Lonser RR, Wind JJ, Nieman LK, et al. Outcome of surgical treatment of 200 children with Cushing’s disease. J Clin Endocrinol Metab. 2013;98(3):892-901. doi: https://doi.org/10.1210/jc.2012-3604

26. Storr HL, Drake WM, Evanson J, et al. Endonasal endoscopic transsphenoidal pituitary surgery: early experience and outcome in paediatric Cushing’s disease. Clin Endocrinol (Oxf ). 2014;80(2):270-276. doi: https://doi.org/10.1111/cen.12275

27. Barzaghi LR, Losa M, Capitanio JF, et al. Pediatric Pituitary Adenomas: Early and Long-Term Surgical Outcome in a Series of 85 Consecutive Patients. Neurosurgery. 2019;85(1):65-74. doi: https://doi.org/10.1093/neuros/nyy204

28. Oliveira RS, Castro MD, Antonini SR, et al. Surgical management of pediatric Cushing’s disease: an analysis of 15 consecutive cases at a specialized neurosurgical center. Arq Bras Endocrinol Metabol. 2010;54(1):17-23. doi: https://doi.org/10.1590/s0004-27302010000100004

29. Mehta GU, Ding D, Patibandla MR, et al. Stereotactic Radiosurgery for Cushing Disease: Results of an International, Multicenter Study. J Clin Endocrinol Metab. 2017;102(11):4284-4291. doi: https://doi.org/10.1210/jc.2017-01385

30. Marova EI, Kolesnikova GS, Arapova SD, et al. Factors predicting the outcomes of removal of corticotropinoms in Cushing’s disease. Endocrine surgery. 2016;10(4):20-31. (In Russ.) doi: https://doi.org/10.14341/serg2016420-30

31. Chen JC, Amar AP, Choi S, et al. Transsphenoidal microsurgical treatment of Cushing disease: postoperative assessment of surgical efficacy by application of an overnight low-dose dexamethasone suppression test. Neurosurg. 2003;98:967-973. doi: https://doi.org/10.3171/jns.2003.98/5/0967

32. Hameed N, Yedinak CG, Brzana J, et al. Remission rate after transsphenoidal surgery in patients with pathologically confirmed Cushing’s disease, the role of cortisol, ACTH assessment and immediate reoperation: a large single center experience. Pituitary. 2013;16:452-458. doi: https://doi.org/10.1007/s11102-012-0455-z

33. Ammini A, Bhattacharya S, Praksh Sahoo J, et al. Cushing’s disease: Results of treatment and factors affecting outcome. Hormones. 2011;10(3):222-229. doi: https://doi.org/10.14310/horm.2002.1312

34. Khandaeva PM, Belaya ZE, Rozhinskaya LY, et al. Five years follow up of patients with Сushing’s disease with and without visualized pituitary adenoma on MRI, who underwent transsphenoidal adenomectomy. Problems of Endocrinology. 2017;63(5):276-281 (In Russ.). doi: https://doi.org/10.14341/probl2017635276-281

35. Nadezhdina EY, Rebrova OY, Ivashenko OV, et al. Factors affecting the probability of recurrence of the Cushing’s disease within 3 years after effective neurosurgical treatment. Endocrine Surgery. 2018;12(2):70-80. (In Russ.). doi: https://doi.org/10.14341/serg9761

36. Pivonello R, De Leo M, Cozzolino A, Colao A. The Treatment of Cushing’s Disease. Endocr Rev. 2015;36(4):385-486. doi: https://doi.org/10.1210/er.2013-1048