Nelson’s syndrome (NS) is a long-term complication of bilateral adrenalectomy in patients with Cushing’s disease. The best therapeutic strategy in NS has not been well defined. Gamma knife radiosurgery (GKRS) is very effective to stop the growth of the pituitary adenoma, which is the main goal of the treatment of patients with NS. We report the largest series of patients with NS treated by GKRS at a single center.
The study was an observational, retrospective analysis of 28 consecutive patients with NS treated by GKRS in our department between 1995 and 2019. All patients had a growing ACTH-secreting pituitary adenoma. The main outcome of the study was to assess by the Kaplan–Meier method the risk of tumor progression after GKRS.
The median follow-up after GKRS treatment was 98 months (IQR 61–155 months, range 7–250 months). Two patients (7.1%) had a recurrence of disease during follow-up. The 10-year progression-free survival was 91.7% (95% CI 80.5–100%). No patient had deterioration of visual function or oculomotor function after GKRS. New onset of hypogonadism and hypothyroidism occurred in 18.8% and 14.3% of the patients at risk.
Our study confirms that GKRS may stop the tumor growth in the majority of patients with NS, even though very aggressive adenomas may ultimately escape this treatment. Safety of GKRS was good in our experience, but due attention must be paid to planning the distribution of radiation to critical structures, especially in patients previously treated by radiation.
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Tritos NA, Biller BMK (2019) Current management of Cushing’s disease. J Intern Med 286:526–541. https://doi.org/10.1111/joim.12975
Alexandraki KI, Kaltsas GA, Isidori AM, Storr HL, Afshar F, Sabin I, Akker SA, Chew SL, Drake WM, Monson JP, Besser GM, Grossman AB (2013) Long-term remission and recurrence rates in Cushing’s disease: predictive factors in a single-centre study. Eur J Endocrinol 168:639–648. https://doi.org/10.1530/EJE-12-0921
Petersenn S, Beckers A, Ferone D, van der Lely A, Bollerslev J, Boscaro M, Brue T, Bruzzi P, Casanueva FF, Chanson P, Colao A, Reincke M, Stalla G, Tsagarakis S (2015) 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 172:R227-239. https://doi.org/10.1530/EJE-14-0883
Mortini P, Barzaghi LR, Albano L, Panni P, Losa M (2018) Microsurgical therapy of pituitary adenomas. Endocrine 59:72–81. https://doi.org/10.1007/s12020-017-1458-3
Ram Z, Nieman LK, Cutler GB Jr, Chrousos GP, Doppman JL, Oldfield EH (1994) Early repeat surgery for persistent Cushing’s disease. J Neurosurg 80:37–45. https://doi.org/10.3171/jns.1994.80.1.0037
Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, Schoenherr U, Mills D, Salgado LR, Biller BM, Pasireotide B2305 Study Group (2012) A 12-month phase 3 study of pasireotide in Cushing’s disease. N Engl J Med 366:914–924. https://doi.org/10.1056/NEJMoa1105743 ((Erratum. In: N Engl J Med (2012) 367:780))
Lacroix A, Gu F, Gallardo W, Pivonello R, Yu Y, Witek P, Boscaro M, Salvatori R, Yamada M, Tauchmanova L, Roughton M, Ravichandran S, Petersenn S, Biller BMK, Newell-Price J, Pasireotide G2304 Study Group (2018) Efficacy and safety of once-monthly pasireotide in Cushing’s disease: a 12 months clinical trial. Lancet Diabetes Endocrinol 6:17–26. https://doi.org/10.1016/S2213-8587(17)30326-1
Fleseriu M, Castinetti F (2016) Updates on the role of adrenal steroidogenesis inhibitors in Cushing’s syndrome: a focus on novel therapies. Pituitary 19:643–653. https://doi.org/10.1007/s11102-016-0742-1
Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Buchfelder M, Colao A, Hermus AR, Hofland LJ, Klibanski A, Lacroix A, Lindsay JR, Newell-Price J, Nieman LK, Petersenn S, Sonino N, Stalla GK, Swearingen B, Vance ML, Wass JA, Boscaro M (2008) Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 93:2454–2462. https://doi.org/10.1210/jc.2007-2734
Reincke M, Ritzel K, Oßwald A, Berr C, Stalla G, Hallfeldt K, Reisch N, Schopohl J, Beuschlein F (2015) A critical reappraisal of bilateral adrenalectomy for ACTH-dependent Cushing’s syndrome. Eur J Endocrinol 173:M23-32. https://doi.org/10.1530/EJE-15-0265
Assié G, Bahurel H, Coste J, Silvera S, Kujas M, Dugué MA, Karray F, Dousset B, Bertherat J, Legmann P, Bertagna X (2007) Corticotroph tumor progression after adrenalectomy in Cushing’s Disease: a reappraisal of Nelson’s Syndrome. J Clin Endocrinol Metab 92:172–179. https://doi.org/10.1210/jc.2006-1328
Barber TM, Adams E, Ansorge O, Byrne JV, Karavitaki N, Wass JA (2010) Nelson’s syndrome. Eur J Endocrinol 163:495–507. https://doi.org/10.1530/EJE-10-0466
Patel J, Eloy JA, Liu JK (2015) Nelson’s syndrome: a review of the clinical manifestations, pathophysiology, and treatment strategies. Neurosurg Focus 38:E14. https://doi.org/10.3171/2014.10.FOCUS14681
Reincke M, Albani A, Assie G, Bancos I, Brue T, Buchfelder M, Chabre O, Ceccato F, Daniele A, Detomas M, Di-Dalmazi G, Elenkova A, Findling J, Grossman AB, Gomez-Sanchez CE, Heaney AP, Honegger J, Karavitaki N, Lacroix A, Laws ER, Losa M, Murakami M, Newell-Price J, Pecori-Giraldi F, Pérez-Rivas LG, Pivonello R, Rainey WE, Sbiera S, Schopohl J, Stratakis CA, Theodoropoulou M, van Rossum EFC, Valassi E, Zacharieva S, Rubinstein G, Ritzel K (2021) Corticotroph tumor progression after bilateral adrenalectomy (Nelson’s syndrome): systematic review and expert consensus recommendations. Eur J Endocrinol. https://doi.org/10.1530/EJE-20-1088 ((Online ahead of print))
Fountas A, Lim ES, Drake WM, Powlson AS, Gurnell M, Martin NM, Seejore K, Murray RD, MacFarlane J, Ahluwalia R, Swords F, Ashraf M, Pal A, Chong Z, Freel M, Balafshan T, Purewal TS, Speak RG, Newell-Price J, Higham CE, Hussein Z, Baldeweg SE, Dales J, Reddy N, Levy MJ, Karavitaki N (2020) Outcomes of patients with Nelson’s syndrome after primary treatment: a multicenter study from 13 UK pituitary centers. J Clin Endocrinol Metab 105(5):dgz200. https://doi.org/10.1210/clinem/dgz200
Azad TD, Veeravagu A, Kumar S, Katznelson L (2015) Nelson syndrome: update on therapeutic approaches. World Neurosurg 83:1135–1140. https://doi.org/10.1016/j.wneu.2015.01.038
Losa M, Spatola G, Albano L, Gandolfi A, Del Vecchio A, Bolognesi A, Mortini P (2017) Frequency, pattern, and outcome of recurrences after gamma knife radiosurgery for pituitary adenomas. Endocrine 56:595–602. https://doi.org/10.1007/s12020-016-1081-8
Sheehan JP, Kondziolka D, Flickinger J, Lunsford LD (2003) Radiosurgery for nonfunctioning pituitary adenoma. Neurosurg Focus 14:e9. https://doi.org/10.3171/foc.2003.14.5.10
Albano L, Losa M, Nadin F, Barzaghi LR, Parisi V, Del Vecchio A, Bolognesi A, Mortini P (2019) Safety and efficacy of multisession gamma knife radiosurgery for residual or recurrent pituitary adenomas. Endocrine 64:639–647. https://doi.org/10.1007/s12020-019-01876-2
Losa M, Mazza E, Terreni MR, McCormack A, Gill AJ, Motta M, Cangi MG, Talarico A, Mortini P, Reni M (2010) Salvage therapy with temozolomide in patients with aggressive or metastatic pituitary adenomas: experience in 6 cases. Eur J Endocrinol 163:843–851. https://doi.org/10.1530/EJE-10-0629
Graffeo CS, Perry A, Carlstrom LP, Meyer FB, Atkinson JLD, Erickson D, Nippoldt TB, Young WF, Pollock BE, Van Gompel JJ (2017) Characterizing and predicting the Nelson-Salassa syndrome. J Neurosurg 127:1277–1287. https://doi.org/10.3171/2016.9.JNS161163
Gil-Cárdenas A, Herrera MF, Díaz-Polanco A, Rios JM, Pantoja JP (2007) Nelson’s syndrome after bilateral adrenalectomy for Cushing’s disease. Surgery 141:147–151. https://doi.org/10.1016/j.surg.2006.12.003
Salehi F, Scheithauer BW, Moyes VJ, Drake WM, Syro LV, Manoranjan B, Sharma S, Horvath E, Kovacs K (2010) Low immunohistochemical expression of MGMT in ACTH secreting pituitary tumors of patients with Nelson syndrome. Endocr Pathol 21:227–229. https://doi.org/10.1007/s12022-010-9138-3
Pernicone PJ, Scheithauer BW, Sebo TJ, Kovacs KT, Horvath E, Young WF Jr, Lloyd RV, Davis DH, Guthrie BL, Schoene WC (1997) Pituitary carcinoma: a clinicopathologic study of 15 cases. Cancer 79:804–812. https://doi.org/10.1002/(sici)1097-0142(19970215)79:4%3c804::aid-cncr18%3e3.0.co;2-3
Landman RE, Horwith M, Peterson RE, Khandji AG, Wardlaw SL (2002) Long-term survival with ACTH-secreting carcinoma of the pituitary: a case report and review of the literature. J Clin Endocrinol Metab 87:3084–3089. https://doi.org/10.1210/jcem.87.7.8667
Pérez-Rivas LG, Theodoropoulou M, Puar TH, Fazel J, Stieg MR, Ferraù F, Assié G, Gadelha MR, Deutschbein T, Fragoso MC, Kusters B, Saeger W, Honegger J, Buchfelder M, Korbonits M, Bertherat J, Stalla GK, Hermus AR, Beuschlein F, Reincke M (2018) Somatic USP8 mutations are frequent events in corticotroph tumor progression causing Nelson’s tumor. Eur J Endocrinol 178:57–63. https://doi.org/10.1530/EJE-17-0634
Kemink SA, Grotenhuis JA, De Vries J, Pieters GF, Hermus AR, Smals AG (2001) Management of Nelson’s syndrome: observation in fifteen patients. Clin Endocrinol (Oxf) 54:45–52. https://doi.org/10.1046/j.1365-2265.2001.01187.x
Zieliński G, Witek P, Maksymowicz M (2015) Outcomes in pituitary surgery in Nelson’s syndrome—therapeutic pitfalls. Endokrynol Pol 66:504–513. https://doi.org/10.5603/EP.2015.0062
Pollock BE, Young WF Jr (2002) Stereotactic radiosurgery for patients with ACTH-producing pituitary adenomas after prior adrenalectomy. Int J Radiat Oncol Biol Phys 54:839–841. https://doi.org/10.1016/s0360-3016(02)02975-9
Mauermann WJ, Sheehan JP, Chernavvsky DR, Laws ER, Steiner L, Vance ML (2007) Gamma Knife surgery for adrenocorticotropic hormone-producing pituitary adenomas after bilateral adrenalectomy. J Neurosurg 106:988–993. https://doi.org/10.3171/jns.2007.106.6.988
Vik-Mo EO, Øksnes M, Pedersen PH, Wentzel-Larsen T, Rødahl E, Thorsen F, Schreiner T, Aanderud S, Lund-Johansen M (2009) Gamma knife stereotactic radiosurgery of Nelson syndrome. Eur J Endocrinol 160:143–148. https://doi.org/10.1530/EJE-08-0687
Marek J, Ježková J, Hána V, Kršek M, Liščák R, Vladyka V, Pecen L (2015) Gamma knife radiosurgery for Cushing’s disease and Nelson’s syndrome. Pituitary 18:376–384. https://doi.org/10.1007/s11102-014-0584-7
Caruso JP, Patibandla MR, Xu Z, Vance ML, Sheehan JP (2018) A long-term study of the treatment of Nelson’s syndrome with Gamma Knife Radiosurgery. Neurosurgery 83:430–436. https://doi.org/10.1093/neuros/nyx426
Cordeiro D, Xu Z, Li CE, Iorio-Morin C, Mathieu D, Sisterson ND, Kano H, Attuati L, Picozzi P, Sheehan KA, Lee CC, Liscak R, Jezkova J, Lunsford LD, Sheehan J (2019) Gamma Knife radiosurgery for the treatment of Nelson’s syndrome: a multicenter, international study. J Neurosurg 12:1–6. https://doi.org/10.3171/2019.4.JNS19273
Jenkins PJ, Trainer PJ, Plowman PN, Shand WS, Grossman AB, Wass JA, Besser GM (1995) The long-term outcome after adrenalectomy and prophylactic pituitary radiotherapy in adrenocorticotropin-dependent Cushing’s syndrome. J Clin Endocrinol Metab 80:165–171. https://doi.org/10.1210/jcem.80.1.7829606
Mehta GU, Sheehan JP, Vance ML (2013) Effect of stereotactic radiosurgery before bilateral adrenalectomy for Cushing’s disease on the incidence of Nelson’s syndrome. J Neurosurg 119:1493–1497. https://doi.org/10.3171/2013.7.JNS13389
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Conflict of interest
The authors declare that they have no conflict of interest.
Research involving human participants
All procedures performed during this observational, retrospective study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Each patient gave informed consent to the treatment with gamma knife radiosurgery.
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The dataset generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Losa, M., Detomas, M., Bailo, M. et al. Gamma knife radiosurgery in patients with Nelson’s syndrome. J Endocrinol Invest (2021). https://doi.org/10.1007/s40618-021-01531-6
- Pituitary neoplasm
- Bilateral adrenalectomy
- Cushing’s disease