- Email: [email protected]
Nelson Syndrome: Update on Therapeutic Approaches
PEER-REVIEW REPORTS
Nelson Syndrome: Update on Therapeutic Approaches Tej D. Azad1, Anand Veeravagu1, Sunny Kumar1, Laurence Katznelson1,2
Key words ACTH - Bilateral adrenalectomy - Cushing’s disease - Nelson syndrome - Pituitary -
Abbreviations and Acronyms ACTH: Adrenocorticotropic hormone BLA: Bilateral adrenalectomy CD: Cushing’s disease CRH: Corticotropin-releasing hormone CS: Cushing’s syndrome GKS: Gamma knife radiosurgery LINAC: Linear accelerator NS: Nelson syndrome SRS: Stereotactic radiosurgery SSA: Somatostatin analog TMZ: Temozolomide TSS: Transsphenoidal surgery From the Departments of 1Neurosurgery and 2Medicine, Stanford University School of Medicine, Stanford, California, USA To whom correspondence should be addressed: Laurence Katznelson, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2015) 83, 6:1135-1140. http://dx.doi.org/10.1016/j.wneu.2015.01.038 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved.
INTRODUCTION Cushing’s disease (CD) refers to an adrenocorticotropic hormone (ACTH)-dependent form of hypercortisolism (Cushing’s syndrome, CS) due to a pituitary adenoma (50, 58). This is the most common etiology (70%e80%) of endogenous CS. CD often manifests as a pituitary gland tumor originating from corticotroph cells, leading to elevated production and secretion of ACTH. Ectopic ACTH or corticotropinreleasing hormone (CRH) production can also cause ACTH-dependent CS, albeit more rarely (10, 49). Transsphenoidal surgery (TSS) to remove the ACTH-producing adenoma is widely considered the first-line approach for patients with CD (10). Remission rates of 65%e90% are observed in microadenomas (<1 cm) (47, 67) and lower than 65% for
- OBJECTIVE:
To review the pathophysiology and therapeutic modalities availble for Nelson syndrome.
- METHODS:
We reviewed the current literature including managment for Nelson syndrome.
- RESULTS:
For patients with NS, surgical intervention is often the first-line therapy. With refractory NS or tumors with extrasellar involvement, radiosurgery offers an important alternative or adjuvant option. Pharmacologic interventions have demonstrated limited usefulness, although recent evidence supports the feasibility of a novel somatostatin analog for patients with NS. Modern neuroimaging, improved surgical techniques, and the advent of stereotactic radiotherapy have transformed the management of NS.
- CONCLUSIONS:
An up-to-date understanding of the pathophysiology underlying Nelson Syndrome and evidence-based management is imperative. Early detection may allow for more successful therapy in patients with Nelson Syndrome. Improved radiotherapeutic interventions and rapidly evolving pharmacologic therapies offer an opportunity to create targeted, multifocal treatment regiments for patients with Nelson Syndrome.
macroadenomas (>1 cm) (1). CD recurrence is reported in 20%e25% of patients after 10- to 15-year follow-up (52). Mortality for TSS in the hands of an experienced neurosurgeon is reported between 0 and 1.5% (7). In a recent analysis of 2 U.S. medical claims databases, 78.9% of 228 newly treated patients with CD underwent surgery as initial therapy (11). Given that 20%e30% of patients require further treatment, therapeutic alternatives or adjuncts must be considered. Second-line strategies include a second pituitary adenoma resection, radiation, or medical therapy (9, 10, 16, 53, 66). Bilateral adrenalectomy (BLA) is generally considered a third-line option for patients with CD (66). BLA is particularly valuable when the pituitary tumor is undetectable, inoperable, or persistent after surgery. BLA allows successful control of hypercortisolemia (85%e100% of patients) and thus deserves consideration in patients with particularly severe cortisol-related symptoms (33, 36, 47). A recent systematic review demonstrated that the procedure is associated with a morbidity of 18% and mortality of 3%
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(59). The consequences of BLA include primary adrenal insufficiency, possible hypercortisolism due to excess ACTH stimulation of residual adrenal tissue, and the development of an aggressive corticotroph tumor, Nelson syndrome (NS) (13, 48, 68). Long-term outcome after BLA is often favorable, although it can vary between patients (31, 51). The incidence of NS after BLA varies between 0 and 43% in adult patients who did not receive cranial radiation (47) and 25%e55% in the pediatric population (26, 65), with an occurrence of 21% identified in a recent systematic review (59). NS is usually noted within 3 years of BLA (4, 6, 28, 69). Risk factors for NS include young age and a high post-BLA plasma ACTH value, although clear ACTH cutoffs have not been defined (4). Diagnosis of NS requires one of the following: 1) expanding pituitary mass lesion compared with pre-BLA imaging or 2) plasma level of ACTH more than 200 ng/mL in addition to progressive elevations of ACTH (an increase of >30%) on at least 3 consecutive occasions (6, 62). Effective management of this condition
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involves surgery and/or radiotherapy, although pharmacologic treatments have been described. In the present report we critically review the pathophysiology and available treatment modalities for the development of corticotroph tumor after BLA. PATHOPHYSIOLOGY In 1958, Don Nelson described a 33-year-old female patient who underwent BLA for refractory CD. After BLA, she developed visual field defects, skin hyperpigmentation, elevated plasma ACTH, and a pronounced sellar mass (48). This constellation of signs and symptoms in the setting of a pituitary corticotroph adenoma after BLA is referred to as NS. The pathophysiology of NS likely involves the removal of the negative feedback of cortisol on hypothalamic and pituitary function as well as the growth potential of the corticotroph adenoma. This results in postoperative hypothalamic CRH production elevation (5). Rodent studies support this hypothesis. In a rat model, adrenalectomy resulted in up-regulation of CRH transcription and increased corticotroph cell numbers (42) In addition, long-term CRH infusion can produce hyperplastic growth of rat corticotroph cells (17). This CRH elevation increases propiomelanocortin production and stimulates growth of corticotrophic tumor cells, which retain their trophic response to CRH. These data support the model of CRH hyperstimulation in the pathogenesis of aggressive corticotroph adenoma development. It is important to note that effects of CRH in this setting have not been confirmed in humans and there has been debate about this hypothesized mechanism of adenomatous growth in NS (4). An alternative mechanism involving altered responsiveness to glucocorticoids has been hypothesized. For example, patients with NS may have an attenuated in vivo response to glucocorticoids (72). Karl et al. (29) noted a somatic frameshift mutation in the glucocorticoid receptor that was associated with NS, providing a mechanistic hypothesis for the pathogenesis of NS. Thus, an alternative hypothesis proposes that development of NS is related to aggressiveness of the original corticotropinoma, possibly
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promoted by the relative reduction in serum cortisol levels (4). This is supported by the observation that patients with invasive tumors at the time of TSS are at greater risk of subsequently developing NS at an earlier stage after BLA, relative to patients with less aggressive corticotropinomas (19, 47). The corticotroph adenoma in NS likely rises from the initial tumor cell population responsible for CD (3), although NS tumors tend to be larger macroadenomas and invasive (61). The resultant tumor is usually observed 1e4 years after BLA; it has been reported as acutely as 2 months and as far out as 24 years after surgery (19, 47). The pathophysiology underlying the aggressive clinical course of NS adenomas remains unclear. Aberrant signaling pathways, such as the b-catenin cascade, and key molecules, including cadherins and integrins, have been explored as components of the molecular mechanisms of corticotroph adenomas. Recent evidence suggests that atypical signaling and tumor suppressor inactivation are key aspects (15). As the mechanistic understanding of NS continues to develop, the ability to apply targeted therapy for this condition may improve. THERAPEUTIC OPTIONS Advanced imaging techniques and improved laboratory assays offer the opportunity for improved surveillance of NS in patients after BLA. Early detection of the growing tumor will improve the therapeutic index of all existing treatment modalities. At present, patients can be availed to surgical resection, radiotherapy, and in some instances, pharmacologic therapy. The natural history of NS is not promising—the corticotroph adenoma demonstrates aggressive behavior and can cause significant morbidity and even mortality (5). SURGICAL MANAGEMENT To gain a rapid reduction in tumor size and secretion, pituitary surgery with maximal resection of the adenoma is the first-line treatment for NS. A transsphenoidal approach is most common, although a transcranial procedure can be performed if extrasellar extension is observed (33% of cases) (5, 14, 34). De Tommasi et al. (14)
reported pituitary surgery in 3 patients with NS who had previously undergone pituitary surgery, radiotherapy, and eventually adrenalectomy. Remission was achieved in only 1 patient. A study by Xing et al. (73) reported removal of the NS tumor in 23 patients (21 transsphenoidal and 2 craniotomy) with remission in 26% of patients. Kelly et al. (34) reported surgical treatment for 13 patients with NS (9 transsphenoidal and 4 craniotomy) and observed tumor control in 70% and recovery of pigmentation and symptomatic improvement in 85% of patients. Overall, success rates of surgical management for NS vary from 10%e70%, with positive outcomes more likely for early neurosurgical treatment of small tumors before extrasellar involvement is observed (14, 30, 34, 37). With the advent of improved neuroimaging, these tumors can be detected earlier, allowing for improved outcomes after resection. Success in surgical treatment of NS is largely defined by long-term remission and minimal complication. Adverse events include panhypopituitarism (69%) (5), permanent diabetes insipidus (38%) (5), cerebrospinal fluid leak (15%) (34, 73), meningitis (8%) (34, 73), cranial nerve palsy (5%) (34, 73), and mortality (5%) (34, 73). Although surgical management is the first-line treatment for NS, it is less effective for tumors with extrasellar involvement. These patients are candidates for radiation therapy. RADIATION THERAPY Given the historically low cure rates of surgical intervention alone, radiation therapy is often used in the management of NS to prevent tumor enlargement, reduce plasma ACTH, and control hyperpigmentation. Radiotherapy after surgical management of pituitary tumors and BLA results in effective management rates of 70% as measured by reduction in ACTH levels and up to 90% as measured by tumor growth control (18, 38). Gamma knife radiosurgery (GKS) after diagnosis of NS remains the most common radiosurgical intervention in recent reports with effective decreases in ACTH seen in 67%e100 % of patients and control of tumor growth seen consistently in approximately 90% of patients (27, 40, 41) (Table 1). However, GKS may normalize serum ACTH in up to 17% of patients (40, 41). Common
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Table 1. Outcomes Using Radiation Therapy Mechanism (Reference Number)
Time of Treatment
Dosage
4-15-MeV linear accelerators (25)
Post-BLA 4500 cGy
6-MeV linear accelerator stereotactic radiosurgery (65)
Post-BLA Median 2000 cGy
6-MeV linear accelerator fractionated stereotactic radiotherapy (65)
Post-BLA Median 4930 cGy
Passive scattered proton therapy (64)
Post-BLA Median 2000 cGy
Cycles
Outcome
25 93.3% of patients experienced tumor shrinkage and call in plasma ACTH fractions n/a
60% of patients experienced control in tumor growth
27.5 50% of patients experienced control in tumor growth fractions n/a
75% of patients experienced complete response (normalization of ACTH)
Gamma knife (17)
Before BLA
n/a
n/a
No patients in XRT group developed NS
Gamma knife (39)
Before BLA
Median 2390 cGy (margin)
n/a
5% of patients in XRT group developed NS (historic 8%e29%)
n/a
91% of patients experienced control in tumor growth; 66% of patients showed reductions in ACTH; 20% of patients showed normalization of ACTH
Gamma knife (37)
Post-BLA Median 2500 cGy (margin), median 5000 cGy (maximal)
BLA, bilateral adrenalectomy; ACTH, adrenocorticotropic hormone; n/a, not available; NS, Nelson syndrome; XRT, radiation therapy.
complications of GKS included new-onset pituitary hormone deficiency in 7%e40% of patients, transitory partial III and VI cranial nerve deficits were seen in up to 20% of patients, specifically those who had previously received irradiation, and permanent nerve or visual deficits are seen in 5%e7% of patients (40, 41). Wilson et al. (71) analyzed the efficacy of linear accelerator (LINAC) stereotactic radiosurgery (SRS) in the management of NS. With a small sample of 5 subjects who underwent LINAC SRS, tumor control rates were seen in 60% of subjects, despite using radiation dosages consistent with reported literature. A group of investigators (59) also explored the efficacy of LINAC fractionated stereotactic radiotherapy involving the delivery of a radiation dose during several weeks in contrast to the one session of SRS, but found a low tumor control rate of 50% with a limited sample of only 2 patients. These studies show relatively limited efficacy of SRS in controlling ACTH hypersecretion in such patients. Particle radiation therapy has also been used to treat NS. Recently, Wattson et al. (70) described their use of proton therapy in patients with pituitary adenomas, including 74 patients with CD and 8 with NS. Among the NS patients, they found that 5 patients (63%) achieved complete remission within 3 years, defined as
more than 3 months of normal laboratory without medical treatment, and observed a median time to complete remission of 27 months. This suggests a role of proton beam therapy in the management of such patients. There are limited data to demonstrate a difference in efficacy of SRS versus fractionated radiation therapy when using LINAC for control of NS (71). Radiation therapy may also be used to prevent NS in subjects who have undergone BLA. Mehta et al. (43) reported significantly reduced NS incidence as low as 5% after BLA with prophylactic GKS. In that study, complications were limited to new pituitary hormone deficiency (10%) with no patients developing cranial neuropathy or visual deficits. Similarly, Gil-Cárdenas et al. (19) examined the clinical records of 39 patients undergoing BLA of whom 17 received prophylactic radiation therapy to the pituitary gland. In that study, 11 (50%) of the patients who had not received radiation therapy developed NS compared with none of the 17 subjects who had received prophylactic radiation. This suggests a protective role of prophylactic radiation to prevent NS. MEDICAL MANAGEMENT Medical therapies have traditionally been relatively ineffective in controlling either the corticotroph adenoma in CD or in NS.
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Medical management, with the goals of normalizing ACTH levels and tumor regression, has broadly been characterized by selective or inconsistent results. Valproic acid (2, 30, 35), rosiglitazone (21-23), and serotonin antagonists (57, 63) have been used in NS with limited success (45, 46). One class of agents, somatostatin analogs (SSAs), has emerged a promising collection of candidates. Expression of all 5 somatostatin receptor subtypes has been observed on human corticotroph tumors, with SSTR-5 suggested to be the dominant subtype. The commercially available SSAs, octreotide and lanreotide, are relatively ineffective (32, 39, 54). Because these SSAs bind primarily to SSTR-2, it is possible that an analog that targets SSTR-5 would be more effective. In vitro treatment with novel SSA pasireotide (that binds SSTR-5 to a greater extent) has been shown to variably suppress cell proliferation (range, 10%e70%) and attenuate ACTH secretion in 5 of 6 tumors (8). Given beneficial effects on serum ACTH and cortisol levels in patients, pasireotide was recently approved in the United States for use in CD (56). SSAs have the ability to inhibit ACTH secretion in humans, particularly in the presence of low cortisol levels, as would occur after BLA (24). We recently described a patient with NS who responded to pasireotide with a dramatic 10-fold decrease in ACTH levels, improved
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hyperpigmentation, and a reduction of suprasellar tumor growth as measured by neuroimaging. These clinical data are supported by in vitro studies demonstrating the effect of pasireotide on cell proliferation (8, 25). Another pharmacologic alternative for NS is temozolomide (TMZ). TMZ treatment, with and without capacitabine, for aggressive corticotroph adenomas has yielded improved symptoms and grossly reduced ACTH levels. One report (44) noted that the NS tumor demonstrated regression on MRI, whereas another study (64) reported tumor recurrence after 5 months. Use of TMZ may warrant further exploration, as NS adenomas have been shown, immunohistochemically, to have absent or low methylguanine-DNA methyltransferase expression (60). The identification of D2 dopamine receptors in corticotroph tumors (55) suggested a possible therapeutic effect, a dopamine receptor agonist to manage NS (20). Individual case studies have shown that the D2 receptor agonist cabergoline is effective in reducing ACTH levels and even led to complete disappearance of pituitary microadenomas after 1 year of treatment in a patient with NS (12).
CONCLUSION The risk of NS is a serious concern after BLA. However, circumstances favoring use of BLA for patients with CS will inevitably arise. Thus, a current understanding of the pathophysiology underlying NS and evidence-based management is imperative. With improved diagnostic techniques, surveillance of NS will continue to improve. Early detection may allow for more successful therapy. In addition, superior radiotherapeutic interventions and improving pharmacologic therapies offer an opportunity to create targeted, multifocal treatment regiments for patients with NS. REFERENCES 1. Aghi MK: Management of recurrent and refractory Cushing disease. Nat Clin Pract Endocrinol Metab 4:560-568, 2008.
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56. Pivonello R, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, Trovato A, Hughes G, Salgado LR, Lacroix A, Schopohl J, Biller BM: Pasireotide treatment significantly improves clinical signs and symptoms in patients with Cushing’s disease: results from a Phase III study. Clin Endocrinol (Oxf) 81:408-417, 2014.
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57. Prescott RW, Ratcliffe WA, Taylor PK: Effect of an oral serotonin antagonist, ketanserin, on plasma ACTH concentrations in Nelson’s syndrome. Br Med J (Clin Res Ed) 289:787-788, 1984. 58. Raff H, Findling JW: A physiologic approach to diagnosis of the Cushing syndrome. Ann Intern Med 138:980-991, 2003. 59. Ritzel K, Beuschlein F, Mickisch A, Osswald A, Schneider HJ, Schopohl J, Reincke M: Clinical review: outcome of bilateral adrenalectomy in Cushing’s syndrome: a systematic review. J Clin Endocrinol Metab 98:3939-3948, 2013. 60. Salehi F, Scheithauer BW, Moyes VJ, Drake WM, Syro LV, Manoranjan B, Sharma S, Horvath E, Kovacs K: Low immunohistochemical expression of MGMT in ACTH secreting pituitary tumors of patients with Nelson syndrome. Endocrinol Pathol 21:227-229, 2010. 61. Scheithauer BW, Gaffey TA, Lloyd RV, Sebo TJ, Kovacs KT, Horvath E, Yapicier O, Young WF Jr, Meyer FB, Kuroki T, Riehle DL, Laws ER Jr: Pathobiology of pituitary adenomas and carcinomas. Neurosurgery 59:341-353; discussion 341353, 2006. 62. Smith PW, Turza KC, Carter CO, Vance ML, Laws ER, Hanks JB: Bilateral adrenalectomy for refractory Cushing disease: a safe and definitive therapy. J Am Coll Surg 208:1059-1064, 2009. 63. Sonino N, Fava GA, Fallo F, Franceschetto A, Belluardo P, Boscaro M: Effect of the serotonin antagonists ritanserin and ketanserin in Cushing’s disease. Pituitary 3:55-59, 2000. 64. Thearle MS, Freda PU, Bruce JN, Isaacson SR, Lee Y, Fine RL: Temozolomide (Temodar(R)) and capecitabine (Xeloda(R)) treatment of an aggressive corticotroph pituitary tumor. Pituitary 14: 418-424, 2011. 65. Thomas CG Jr, Smith AT, Benson M, Griffith J: Nelson’s syndrome after Cushing’s disease in childhood: a continuing problem. Surgery 96: 1067-1077, 1984. 66. Tritos NA, Biller BM: Medical management of Cushing’s disease. J Neurooncol 117:407-414, 2014. 67. Tritos NA, Biller BM, Swearingen B: Management of Cushing disease. Nat Rev Endocrinol 7:279-289, 2011. 68. Vella A, Thompson GB, Grant CS, van Heerden JA, Farley DR, Young WF Jr: Laparoscopic adrenalectomy for adrenocorticotropindependent Cushing’s syndrome. J Clin Endocrinol Metab 86:1596-1599, 2001. 69. Vik-Mo EO, Oksnes M, Pedersen PH, WentzelLarsen T, Rodahl E, Thorsen F, Schreiner T, Aanderud S, Lund-Johansen M: Gamma knife stereotactic radiosurgery of Nelson syndrome. Eur J Endocrinol 160:143-148, 2009. 70. Wattson DA, Tanguturi SK, Spiegel DY, Niemierko A, Biller BM, Nachtigall LB, Bussiere MR, Swearingen B, Chapman PH, Loeffler JS, Shih HA: Outcomes of proton therapy for patients with functional pituitary adenomas. Int J Radiat Oncol Biol Phys 90:532-539, 2014.
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71. Wilson PJ, Williams JR, Smee RI: Nelson’s syndrome: single centre experience using the linear accelerator (LINAC) for stereotactic radiosurgery and fractionated stereotactic radiotherapy. J Clin Neurosci 21:1520-1524, 2014.
73. Xing B, Ren Z, Su C, Wang R, Yang Y, Hu Y: Microsurgical treatment of Nelson’s syndrome. Chin Med J (Engl) 115:1150-1152, 2002.
72. Wolfsen AR, Odell WD: The dose-response relationship of ACTH and cortisol in Cushing’s disease. Clin Endocrinol (Oxf) 12:557-568, 1980.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Received 11 November 2014; accepted 19 January 2015; published online 12 February 2015 Citation: World Neurosurg. (2015) 83, 6:1135-1140. http://dx.doi.org/10.1016/j.wneu.2015.01.038 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved.
Contact the Editorial Office Edward C. Benzel, M.D. Chairman, Department of Neurosurgery, Cleveland Clinic WORLD NEUROSURGERY Editor-in-Chief 9500 Euclid Avenue / S-40 Cleveland, OH 44195 Tel: 216-444-7381 Fax: 216-636-5101 E-mail: [email protected] Website: www.WORLDNEUROSURGERY.org
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Nelson Syndrome: Update on Therapeutic Approaches Tej D. Azad1, Anand Veeravagu1, Sunny Kumar1, Laurence Katznelson1,2
Key words ACTH - Bilateral adrenalectomy - Cushing’s disease - Nelson syndrome - Pituitary -
Abbreviations and Acronyms ACTH: Adrenocorticotropic hormone BLA: Bilateral adrenalectomy CD: Cushing’s disease CRH: Corticotropin-releasing hormone CS: Cushing’s syndrome GKS: Gamma knife radiosurgery LINAC: Linear accelerator NS: Nelson syndrome SRS: Stereotactic radiosurgery SSA: Somatostatin analog TMZ: Temozolomide TSS: Transsphenoidal surgery From the Departments of 1Neurosurgery and 2Medicine, Stanford University School of Medicine, Stanford, California, USA To whom correspondence should be addressed: Laurence Katznelson, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2015) 83, 6:1135-1140. http://dx.doi.org/10.1016/j.wneu.2015.01.038 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved.
INTRODUCTION Cushing’s disease (CD) refers to an adrenocorticotropic hormone (ACTH)-dependent form of hypercortisolism (Cushing’s syndrome, CS) due to a pituitary adenoma (50, 58). This is the most common etiology (70%e80%) of endogenous CS. CD often manifests as a pituitary gland tumor originating from corticotroph cells, leading to elevated production and secretion of ACTH. Ectopic ACTH or corticotropinreleasing hormone (CRH) production can also cause ACTH-dependent CS, albeit more rarely (10, 49). Transsphenoidal surgery (TSS) to remove the ACTH-producing adenoma is widely considered the first-line approach for patients with CD (10). Remission rates of 65%e90% are observed in microadenomas (<1 cm) (47, 67) and lower than 65% for
- OBJECTIVE:
To review the pathophysiology and therapeutic modalities availble for Nelson syndrome.
- METHODS:
We reviewed the current literature including managment for Nelson syndrome.
- RESULTS:
For patients with NS, surgical intervention is often the first-line therapy. With refractory NS or tumors with extrasellar involvement, radiosurgery offers an important alternative or adjuvant option. Pharmacologic interventions have demonstrated limited usefulness, although recent evidence supports the feasibility of a novel somatostatin analog for patients with NS. Modern neuroimaging, improved surgical techniques, and the advent of stereotactic radiotherapy have transformed the management of NS.
- CONCLUSIONS:
An up-to-date understanding of the pathophysiology underlying Nelson Syndrome and evidence-based management is imperative. Early detection may allow for more successful therapy in patients with Nelson Syndrome. Improved radiotherapeutic interventions and rapidly evolving pharmacologic therapies offer an opportunity to create targeted, multifocal treatment regiments for patients with Nelson Syndrome.
macroadenomas (>1 cm) (1). CD recurrence is reported in 20%e25% of patients after 10- to 15-year follow-up (52). Mortality for TSS in the hands of an experienced neurosurgeon is reported between 0 and 1.5% (7). In a recent analysis of 2 U.S. medical claims databases, 78.9% of 228 newly treated patients with CD underwent surgery as initial therapy (11). Given that 20%e30% of patients require further treatment, therapeutic alternatives or adjuncts must be considered. Second-line strategies include a second pituitary adenoma resection, radiation, or medical therapy (9, 10, 16, 53, 66). Bilateral adrenalectomy (BLA) is generally considered a third-line option for patients with CD (66). BLA is particularly valuable when the pituitary tumor is undetectable, inoperable, or persistent after surgery. BLA allows successful control of hypercortisolemia (85%e100% of patients) and thus deserves consideration in patients with particularly severe cortisol-related symptoms (33, 36, 47). A recent systematic review demonstrated that the procedure is associated with a morbidity of 18% and mortality of 3%
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(59). The consequences of BLA include primary adrenal insufficiency, possible hypercortisolism due to excess ACTH stimulation of residual adrenal tissue, and the development of an aggressive corticotroph tumor, Nelson syndrome (NS) (13, 48, 68). Long-term outcome after BLA is often favorable, although it can vary between patients (31, 51). The incidence of NS after BLA varies between 0 and 43% in adult patients who did not receive cranial radiation (47) and 25%e55% in the pediatric population (26, 65), with an occurrence of 21% identified in a recent systematic review (59). NS is usually noted within 3 years of BLA (4, 6, 28, 69). Risk factors for NS include young age and a high post-BLA plasma ACTH value, although clear ACTH cutoffs have not been defined (4). Diagnosis of NS requires one of the following: 1) expanding pituitary mass lesion compared with pre-BLA imaging or 2) plasma level of ACTH more than 200 ng/mL in addition to progressive elevations of ACTH (an increase of >30%) on at least 3 consecutive occasions (6, 62). Effective management of this condition
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involves surgery and/or radiotherapy, although pharmacologic treatments have been described. In the present report we critically review the pathophysiology and available treatment modalities for the development of corticotroph tumor after BLA. PATHOPHYSIOLOGY In 1958, Don Nelson described a 33-year-old female patient who underwent BLA for refractory CD. After BLA, she developed visual field defects, skin hyperpigmentation, elevated plasma ACTH, and a pronounced sellar mass (48). This constellation of signs and symptoms in the setting of a pituitary corticotroph adenoma after BLA is referred to as NS. The pathophysiology of NS likely involves the removal of the negative feedback of cortisol on hypothalamic and pituitary function as well as the growth potential of the corticotroph adenoma. This results in postoperative hypothalamic CRH production elevation (5). Rodent studies support this hypothesis. In a rat model, adrenalectomy resulted in up-regulation of CRH transcription and increased corticotroph cell numbers (42) In addition, long-term CRH infusion can produce hyperplastic growth of rat corticotroph cells (17). This CRH elevation increases propiomelanocortin production and stimulates growth of corticotrophic tumor cells, which retain their trophic response to CRH. These data support the model of CRH hyperstimulation in the pathogenesis of aggressive corticotroph adenoma development. It is important to note that effects of CRH in this setting have not been confirmed in humans and there has been debate about this hypothesized mechanism of adenomatous growth in NS (4). An alternative mechanism involving altered responsiveness to glucocorticoids has been hypothesized. For example, patients with NS may have an attenuated in vivo response to glucocorticoids (72). Karl et al. (29) noted a somatic frameshift mutation in the glucocorticoid receptor that was associated with NS, providing a mechanistic hypothesis for the pathogenesis of NS. Thus, an alternative hypothesis proposes that development of NS is related to aggressiveness of the original corticotropinoma, possibly
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promoted by the relative reduction in serum cortisol levels (4). This is supported by the observation that patients with invasive tumors at the time of TSS are at greater risk of subsequently developing NS at an earlier stage after BLA, relative to patients with less aggressive corticotropinomas (19, 47). The corticotroph adenoma in NS likely rises from the initial tumor cell population responsible for CD (3), although NS tumors tend to be larger macroadenomas and invasive (61). The resultant tumor is usually observed 1e4 years after BLA; it has been reported as acutely as 2 months and as far out as 24 years after surgery (19, 47). The pathophysiology underlying the aggressive clinical course of NS adenomas remains unclear. Aberrant signaling pathways, such as the b-catenin cascade, and key molecules, including cadherins and integrins, have been explored as components of the molecular mechanisms of corticotroph adenomas. Recent evidence suggests that atypical signaling and tumor suppressor inactivation are key aspects (15). As the mechanistic understanding of NS continues to develop, the ability to apply targeted therapy for this condition may improve. THERAPEUTIC OPTIONS Advanced imaging techniques and improved laboratory assays offer the opportunity for improved surveillance of NS in patients after BLA. Early detection of the growing tumor will improve the therapeutic index of all existing treatment modalities. At present, patients can be availed to surgical resection, radiotherapy, and in some instances, pharmacologic therapy. The natural history of NS is not promising—the corticotroph adenoma demonstrates aggressive behavior and can cause significant morbidity and even mortality (5). SURGICAL MANAGEMENT To gain a rapid reduction in tumor size and secretion, pituitary surgery with maximal resection of the adenoma is the first-line treatment for NS. A transsphenoidal approach is most common, although a transcranial procedure can be performed if extrasellar extension is observed (33% of cases) (5, 14, 34). De Tommasi et al. (14)
reported pituitary surgery in 3 patients with NS who had previously undergone pituitary surgery, radiotherapy, and eventually adrenalectomy. Remission was achieved in only 1 patient. A study by Xing et al. (73) reported removal of the NS tumor in 23 patients (21 transsphenoidal and 2 craniotomy) with remission in 26% of patients. Kelly et al. (34) reported surgical treatment for 13 patients with NS (9 transsphenoidal and 4 craniotomy) and observed tumor control in 70% and recovery of pigmentation and symptomatic improvement in 85% of patients. Overall, success rates of surgical management for NS vary from 10%e70%, with positive outcomes more likely for early neurosurgical treatment of small tumors before extrasellar involvement is observed (14, 30, 34, 37). With the advent of improved neuroimaging, these tumors can be detected earlier, allowing for improved outcomes after resection. Success in surgical treatment of NS is largely defined by long-term remission and minimal complication. Adverse events include panhypopituitarism (69%) (5), permanent diabetes insipidus (38%) (5), cerebrospinal fluid leak (15%) (34, 73), meningitis (8%) (34, 73), cranial nerve palsy (5%) (34, 73), and mortality (5%) (34, 73). Although surgical management is the first-line treatment for NS, it is less effective for tumors with extrasellar involvement. These patients are candidates for radiation therapy. RADIATION THERAPY Given the historically low cure rates of surgical intervention alone, radiation therapy is often used in the management of NS to prevent tumor enlargement, reduce plasma ACTH, and control hyperpigmentation. Radiotherapy after surgical management of pituitary tumors and BLA results in effective management rates of 70% as measured by reduction in ACTH levels and up to 90% as measured by tumor growth control (18, 38). Gamma knife radiosurgery (GKS) after diagnosis of NS remains the most common radiosurgical intervention in recent reports with effective decreases in ACTH seen in 67%e100 % of patients and control of tumor growth seen consistently in approximately 90% of patients (27, 40, 41) (Table 1). However, GKS may normalize serum ACTH in up to 17% of patients (40, 41). Common
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Table 1. Outcomes Using Radiation Therapy Mechanism (Reference Number)
Time of Treatment
Dosage
4-15-MeV linear accelerators (25)
Post-BLA 4500 cGy
6-MeV linear accelerator stereotactic radiosurgery (65)
Post-BLA Median 2000 cGy
6-MeV linear accelerator fractionated stereotactic radiotherapy (65)
Post-BLA Median 4930 cGy
Passive scattered proton therapy (64)
Post-BLA Median 2000 cGy
Cycles
Outcome
25 93.3% of patients experienced tumor shrinkage and call in plasma ACTH fractions n/a
60% of patients experienced control in tumor growth
27.5 50% of patients experienced control in tumor growth fractions n/a
75% of patients experienced complete response (normalization of ACTH)
Gamma knife (17)
Before BLA
n/a
n/a
No patients in XRT group developed NS
Gamma knife (39)
Before BLA
Median 2390 cGy (margin)
n/a
5% of patients in XRT group developed NS (historic 8%e29%)
n/a
91% of patients experienced control in tumor growth; 66% of patients showed reductions in ACTH; 20% of patients showed normalization of ACTH
Gamma knife (37)
Post-BLA Median 2500 cGy (margin), median 5000 cGy (maximal)
BLA, bilateral adrenalectomy; ACTH, adrenocorticotropic hormone; n/a, not available; NS, Nelson syndrome; XRT, radiation therapy.
complications of GKS included new-onset pituitary hormone deficiency in 7%e40% of patients, transitory partial III and VI cranial nerve deficits were seen in up to 20% of patients, specifically those who had previously received irradiation, and permanent nerve or visual deficits are seen in 5%e7% of patients (40, 41). Wilson et al. (71) analyzed the efficacy of linear accelerator (LINAC) stereotactic radiosurgery (SRS) in the management of NS. With a small sample of 5 subjects who underwent LINAC SRS, tumor control rates were seen in 60% of subjects, despite using radiation dosages consistent with reported literature. A group of investigators (59) also explored the efficacy of LINAC fractionated stereotactic radiotherapy involving the delivery of a radiation dose during several weeks in contrast to the one session of SRS, but found a low tumor control rate of 50% with a limited sample of only 2 patients. These studies show relatively limited efficacy of SRS in controlling ACTH hypersecretion in such patients. Particle radiation therapy has also been used to treat NS. Recently, Wattson et al. (70) described their use of proton therapy in patients with pituitary adenomas, including 74 patients with CD and 8 with NS. Among the NS patients, they found that 5 patients (63%) achieved complete remission within 3 years, defined as
more than 3 months of normal laboratory without medical treatment, and observed a median time to complete remission of 27 months. This suggests a role of proton beam therapy in the management of such patients. There are limited data to demonstrate a difference in efficacy of SRS versus fractionated radiation therapy when using LINAC for control of NS (71). Radiation therapy may also be used to prevent NS in subjects who have undergone BLA. Mehta et al. (43) reported significantly reduced NS incidence as low as 5% after BLA with prophylactic GKS. In that study, complications were limited to new pituitary hormone deficiency (10%) with no patients developing cranial neuropathy or visual deficits. Similarly, Gil-Cárdenas et al. (19) examined the clinical records of 39 patients undergoing BLA of whom 17 received prophylactic radiation therapy to the pituitary gland. In that study, 11 (50%) of the patients who had not received radiation therapy developed NS compared with none of the 17 subjects who had received prophylactic radiation. This suggests a protective role of prophylactic radiation to prevent NS. MEDICAL MANAGEMENT Medical therapies have traditionally been relatively ineffective in controlling either the corticotroph adenoma in CD or in NS.
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Medical management, with the goals of normalizing ACTH levels and tumor regression, has broadly been characterized by selective or inconsistent results. Valproic acid (2, 30, 35), rosiglitazone (21-23), and serotonin antagonists (57, 63) have been used in NS with limited success (45, 46). One class of agents, somatostatin analogs (SSAs), has emerged a promising collection of candidates. Expression of all 5 somatostatin receptor subtypes has been observed on human corticotroph tumors, with SSTR-5 suggested to be the dominant subtype. The commercially available SSAs, octreotide and lanreotide, are relatively ineffective (32, 39, 54). Because these SSAs bind primarily to SSTR-2, it is possible that an analog that targets SSTR-5 would be more effective. In vitro treatment with novel SSA pasireotide (that binds SSTR-5 to a greater extent) has been shown to variably suppress cell proliferation (range, 10%e70%) and attenuate ACTH secretion in 5 of 6 tumors (8). Given beneficial effects on serum ACTH and cortisol levels in patients, pasireotide was recently approved in the United States for use in CD (56). SSAs have the ability to inhibit ACTH secretion in humans, particularly in the presence of low cortisol levels, as would occur after BLA (24). We recently described a patient with NS who responded to pasireotide with a dramatic 10-fold decrease in ACTH levels, improved
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hyperpigmentation, and a reduction of suprasellar tumor growth as measured by neuroimaging. These clinical data are supported by in vitro studies demonstrating the effect of pasireotide on cell proliferation (8, 25). Another pharmacologic alternative for NS is temozolomide (TMZ). TMZ treatment, with and without capacitabine, for aggressive corticotroph adenomas has yielded improved symptoms and grossly reduced ACTH levels. One report (44) noted that the NS tumor demonstrated regression on MRI, whereas another study (64) reported tumor recurrence after 5 months. Use of TMZ may warrant further exploration, as NS adenomas have been shown, immunohistochemically, to have absent or low methylguanine-DNA methyltransferase expression (60). The identification of D2 dopamine receptors in corticotroph tumors (55) suggested a possible therapeutic effect, a dopamine receptor agonist to manage NS (20). Individual case studies have shown that the D2 receptor agonist cabergoline is effective in reducing ACTH levels and even led to complete disappearance of pituitary microadenomas after 1 year of treatment in a patient with NS (12).
CONCLUSION The risk of NS is a serious concern after BLA. However, circumstances favoring use of BLA for patients with CS will inevitably arise. Thus, a current understanding of the pathophysiology underlying NS and evidence-based management is imperative. With improved diagnostic techniques, surveillance of NS will continue to improve. Early detection may allow for more successful therapy. In addition, superior radiotherapeutic interventions and improving pharmacologic therapies offer an opportunity to create targeted, multifocal treatment regiments for patients with NS. REFERENCES 1. Aghi MK: Management of recurrent and refractory Cushing disease. Nat Clin Pract Endocrinol Metab 4:560-568, 2008.
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Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Received 11 November 2014; accepted 19 January 2015; published online 12 February 2015 Citation: World Neurosurg. (2015) 83, 6:1135-1140. http://dx.doi.org/10.1016/j.wneu.2015.01.038 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved.
Contact the Editorial Office Edward C. Benzel, M.D. Chairman, Department of Neurosurgery, Cleveland Clinic WORLD NEUROSURGERY Editor-in-Chief 9500 Euclid Avenue / S-40 Cleveland, OH 44195 Tel: 216-444-7381 Fax: 216-636-5101 E-mail: [email protected] Website: www.WORLDNEUROSURGERY.org
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