Nelson syndrome

Nelson syndrome

Handbook of Clinical Neurology, Vol. 124 (3rd series) Clinical Neuroendocrinology E. Fliers, M. Korbonits, and J.A. Romijn, Editors © 2014 Elsevier B...

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Handbook of Clinical Neurology, Vol. 124 (3rd series) Clinical Neuroendocrinology E. Fliers, M. Korbonits, and J.A. Romijn, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 22

Nelson syndrome: definition and management T.M. BARBER1, E. ADAMS2, AND J.A.H. WASS2* Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, UK

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Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK

INTRODUCTION Overall, Nelson syndrome is encountered infrequently in clinical practice. However, it is a relatively common complication of treatment for refractory Cushing’s disease, occurrence rates in such patients being 8–43% for adults (Nagesser et al., 2000) and 25–66% for children (Hopwood and Kenny, 1977; Thomas et al., 1984; Wright-Pascoe et al., 2001), although its presentation has been reported to be delayed up to 24 years post-total bilateral adrenalectomy (TBA) and mean presentation 15 years post-TBA (Nagesser et al., 2000). The first case of Nelson syndrome was described in 1958; the patient was a 33-year-old woman who, 3 years previously, had undergone TBA for refractory Cushing’s disease. The presenting features in this case included skin hyperpigmentation, visual field defects, raised plasma adrenocorticotropic hormone (ACTH) levels, and a large sellar mass (a pituitary corticotropinoma) demonstrated on an X-ray of the skull (Nelson et al., 1958). Surgical removal of the tumor resulted in resolution of her symptoms (Nelson et al., 1958). Effective modern management of corticotropinomas that are refractory to transsphenoidal surgery (TSS) remain a clinical challenge. Options include repeating the TSS procedure, the use of drugs that block cortisol production, the administration of pituitary irradiation, and finally, TBA (Kelly, 2007). The scenarios in which TBA tends to be implemented include the presence of an undetectable or surgically unresectable corticotropinoma, or the recurrence of a corticotropinoma following TSS (Porterfield et al., 2008). In such cases, TBA can be associated with an 85–100% success rate at controlling hypercortisolemia depending on the successful removal of all adrenal tissue (Kelly, 2007; Nagesser et al., 2000),

particularly when life-threatening manifestations of hypercortisolism occur (with immediate control of hypercortisolemia) (Kelly et al., 1983). However, TBA can result in the development of Nelson syndrome (Newell-Price et al., 2006). Nelson syndrome is a potentially life-threatening condition (mortality rate 12% in the first reported case series (Sprague, 1953)) and can be associated with significant morbidity. However, the mortality rate associated with this condition has diminished significantly in recent times, and mortality was absent in two more recently reported case series (McCance et al., 1993; Jenkins et al., 1995). The improved mortality of Nelson syndrome is attributable at least in part to its earlier diagnosis and effective management. This in turn has resulted from improved awareness and screening for the condition with advancements in radiologic techniques and biochemical assays (Barber et al., 2010). A central feature of Nelson syndrome is the enlargement of an underlying pituitary corticotropinoma (with positive immunostaining for ACTH and ACTH secretion being associated with more aggressive and invasive tumors) (Fig. 22.1) (Bradley et al., 2003; De Tommasi et al., 2005). Before computed tomography (CT) and magnetic resonance imaging (MRI) scans were available, detection of Nelson tumors usually resulted from the late clinical manifestations of such tumor invasion and compression of surrounding structures. The introduction of MRI, with its highly resolved images, facilitated the early detection of enlarging corticotropinomas post-TBA and therefore enabled earlier diagnosis and management of Nelson syndrome. Aspects of Nelson syndrome remain poorly understood, including its pathophysiology and the factors that are predictive for its onset and progression. In this

*Correspondence to: Professor J.A.H. Wass, Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LJ, UK. Tel: þ44-7973841508, E-mail: [email protected] nhs.uk

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Fig. 22.1. Sagittal (A) and coronal (B) gadolinium-enhanced T1-weighted magnetic resonance images (MRI) showing an invasive corticotropinoma in a patient with Nelson syndrome. (Reproduced from Barber et al., 2010, copyright BioScientifica).

chapter, we discuss key aspects of Nelson syndrome relating to its diagnosis and effective management (summarized in Table 22.1): 1. 2. 3. 4. 5.

Effective diagnosis of Nelson syndrome Predictive factors for the onset and progression of Nelson syndrome Pathophysiology of Nelson syndrome Pathologic features of corticotropinomas in Nelson syndrome Effective management of Nelson syndrome.

EFFECTIVE DIAGNOSIS OF NELSON SYNDROME Clinical, biochemical, and radiologic features Prior to the introduction of modern imaging techniques and sensitive assays, Nelson syndrome often presented with late clinical features resulting from compressive effects and invasion of an enlarging pituitary corticotropinoma into surrounding structures, metastases being unusual (Moore et al., 1976; Pernicone et al., 1997; Garcia et al., 2007). Late manifestations also include visual field defects (Ernest and Ekman, 1972; Moore et al., 1976; Assie et al., 2007) and cranial nerve palsies (McCance et al., 1993). The highly resolved imaging techniques of CT and MRI and the availability of sensitive ACTH assays has resulted in earlier diagnosis of Nelson syndrome and substantially reduced the frequency with which it presents with these late features. In modern practice, Nelson syndrome more typically presents clinically with hyperpigmentation of skin and mucous membranes (extensor surfaces, flexures, scars, areolae), with a frequency of up to 42% (Kelly et al., 2002), although visual field defects have been reported in some series in 10–57% (Banasiak and Malek, 2007). Other less frequent manifestations of Nelson syndrome include headaches, diabetes insipidus (Rees and Zilva, 1959), pituitary

apoplexy (Ernest and Ekman, 1972; Kasperlik-Zaluska et al., 1983), panhypopituitarism, paratesticular tumors (Kasperlik-Zaluska et al., 1983), presenting with testicular pain and oligospermia (Johnson and Scheithauer, 1982), and paraovarian tumors (Baranetsky et al., 1979). In men, adrenal tissue may be present anywhere along the route of descent of the testis, and particularly in the paratesticular area. In women, adrenal rest cells can occur within the ovaries, their likely origin being from mesonephric remnants. The gonadal features of Nelson syndrome result from hyperstimulation and hyperplasia of gonadal adrenal rest cells (Shekarriz et al., 1996), and can be mistaken for a relapse of Cushing’s disease (Johnson and Scheithauer, 1982). Biochemically, Nelson syndrome is characterized by marked elevation of plasma ACTH levels following adrenalectomy, with basal and pulsatile volumes of ACTH secretions being up to six- and ninefold larger respectively in patients with Nelson syndrome compared to those with Cushing’s disease (van Aken et al., 2004). Given that ACTH levels are affected by exogenously administered steroids, it is important that attention be given to the timing of the blood sample which should be taken at 08:00 hours, prior to the morning dose of glucocorticoid replacement and ideally 20 hours following the last dose of glucocorticoid tablet (Munir and Newell-Price, 2007). A further sample for ACTH should be taken at 2 hours following the morning dose of glucocorticoid tablet. Radiologically, Nelson syndrome is characterized by an enlarging pituitary mass when compared with images taken post-TSS (often regrowth of pituitary remnant tissue) (Banasiak and Malek, 2007). Use of high-resolution MRI that is capable of identifying tumors as small as 3 mm in diameter enables identification of early tumor progression so that prompt therapeutic intervention can be instigated (Banasiak and Malek, 2007). Whilst many patients develop Nelson syndrome early following TBA for refractory Cushing’s disease (20% in the first

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Table 22.1 Summary of the clinicopathologic features of Nelson syndrome and its effective management Clinical features

Hypothesized predictive factors

Hypothesized pathophysiology

Management

Hyperpigmentation of skin/ mucous membranes Visual field defects

Residual pituitary tumor

Released negative feedback hypothesis Aggressive corticotropinoma hypothesis

Pituitary surgery

Raised ACTH level

Neoadjuvant radiotherapy post-TBA Duration of Cushing’s disease pre-TBA Residual adrenal remnant post-TBA Age Raised urinary cortisol Insufficient exogenous steroid post-TBA Lack of cortisol suppressibility on high-dose dexamethasone pre-TBA

Enlarging sellar mass Cranial nerve palsies Headaches Diabetes insipidus Pituitary apoplexy Panhypopituitarism

ACTH levels in the first postoperative year

Adjuvant pituitary radiotherapy Stereotactic radiosurgery Selective somatostatin analogs PPAR g agonists Sodium valproate Dopamine agonists Temozolomide

Paratesticular tumors (testicular pain and oligospermia) Paraovarian tumors ACTH, adrenocorticotropic hormone; TBA, total bilateral adrenalectomy; PPAR g, peroxisome proliferator-activated receptor gamma.

year and 35% in the first 2 years post-TBA (Assie et al., 2007)), the development of Nelson syndrome has also been reported up to 24 years post-TBA (Assie et al., 2007). It is therefore imperative that all such patients undergo lifelong pituitary imaging, with the first MRI scan at 3 months post-TBA (Banasiak and Malek, 2007), followed by repeat scans at 6-monthly intervals for 2 years and then yearly scans thereafter (lifelong). In this scenario, any increase in tumor size is significant (Barber et al., 2010).

Diagnostic criteria Unfortunately, there is no clear consensus in the literature for a set of diagnostic criteria for Nelson syndrome. This has adverse implications for both clinical management of the condition and direct comparisons between studies that employ different diagnostic criteria. The utility of hyperpigmentation as a diagnostic criterion for Nelson syndrome poses problems in that this may lack sensitivity as a marker of ACTH levels (Kimura et al., 1996). There is clearly a need for a single set of diagnostic criteria. Based on the existing literature, we published a proposal for a new set of diagnostic criteria for Nelson syndrome, to improve how we approach this condition in

both clinical and research settings (Barber et al., 2010). In our proposal, a prerequisite for diagnosis of Nelson syndrome is previous TBA surgery and pre-existing Cushing’s disease. Other criteria include: an expanding pituitary mass lesion; elevated ACTH levels (08:00 hours presteroid level > 500 ng/L based on ACTH levels in those patients who develop Nelson syndrome in previous case series) (Kasperlik-Zaluska et al., 1983; Pereira et al., 1998; Nagesser et al., 2000; Assie et al., 2007; Banasiak and Malek, 2007; Gil-Cardenas et al., 2007); and progressive elevations of ACTH levels on at least three consecutive and separate time-points (a rise of ACTH by > 30% of the initial post-TBA sample) (Barber et al., 2010). Our proposal, based on observations from current literature, is an attempt to unify the diagnostic criteria for Nelson syndrome, to facilitate diagnosis and screening in the clinical setting, and to enable direct comparisons between future studies on patients with this condition.

PREDICTIVE FACTORS FOR THE ONSET AND PROGRESSION OF NELSON SYNDROME It is difficult to predict which patients with a history of Cushing’s disease will subsequently develop Nelson

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syndrome following TBA. This underlies the importance of effective screening for Nelson syndrome in all such patients. However, there are some indicators that may predict future development of this condition:

Residual pituitary tumor shown on imaging prior to total bilateral adrenalectomy It is clear from a number of studies that the presence of residual pituitary tumor following TSS treatment for Cushing’s disease is a risk factor for future development of Nelson syndrome post-TBA (Jenkins et al., 1995; Sonino et al., 1996; Pereira et al., 1998; Hawn et al., 2002). In one study on 30 such patients, it was reported that in those who developed Nelson syndrome, 30% had radiologic evidence of residual tumor at the time of TBA, the majority (55%) being macroscopically visible (Jenkins et al., 1995). In contrast, only 17% of those patients who did not develop Nelson syndrome had radiologic evidence of residual tumor at the time of TBA, and only 33% of these were macroscopically visible (Jenkins et al., 1995). In a further series, it was reported that the development of Nelson syndrome occurred in 30% with versus 26% without residual pituitary tumor post-TSS (Gil-Cardenas et al., 2007). The utility of residual pituitary tumor as a predictive factor for the future development of Nelson syndrome is dependent upon the resolution of the imaging technique employed (usually MRI), and direct comparison of post-TBA pituitary images with those taken post-TSS.

Adrenocorticotropic hormone levels in the first postoperative year Elevated levels of ACTH following TBA may be associated with future development of Nelson syndrome (Barnett et al., 1983; McCance et al., 1993; Pereira et al., 1998) through association with corticotropinoma progression (Assie et al., 2007). However, it has been observed in long-term follow-up studies that persistent elevations of ACTH levels may occur in up to 42% of post-TBA patients (McCance et al., 1993), with only some of these patients developing Nelson syndrome. Although a rise in plasma ACTH of > 100 ng/L in the first year post-TBA may help to predict the future development of Nelson syndrome (Assie et al., 2007), this assertion requires further validation through long-term studies before it can be usefully adopted as a clinical tool. Other possible predictors including plasma ACTH levels pre-TBA and following metyrapone suppression should also be fully assessed in future studies.

Administration of neoadjuvant radiotherapy post-total bilateral adrenalectomy surgery In patients who undergo TBA for refractory Cushing’s disease, neoadjuvant pituitary radiotherapy (administered at the time of TBA or soon after this procedure) is often considered. There is some controversy in the literature regarding the efficacy of pituitary neoadjuvant radiotherapy administered to patients with Cushing’s disease at the time of TBA in the prevention of the subsequent development of Nelson syndrome. In a longterm study over 15 years following TBA in 39 patients with Cushing’s disease, none of those who received neoadjuvant radiotherapy (versus 50% of those who did not) had subsequent development of Nelson syndrome (Gil-Cardenas et al., 2007). Another study has also demonstrated a potential benefit of neoadjuvant radiotherapy, with development of Nelson syndrome in 25% of those receiving radiotherapy versus 50% of those who did not (Jenkins et al., 1995). However, other studies do not show that lack of pituitary radiotherapy at the time of TBA is associated with future development of Nelson syndrome (Moore et al., 1976; Manolas et al., 1984; McCance et al., 1993; Sonino et al., 1996). Clearly, pituitary radiotherapy is associated with future development of adverse sequelae and these potential risks need to be balanced with potential benefits of this prophylactic treatment. Given the risks associated with residual pituitary tumor outlined above, a pragmatic approach is to administer prophylactic neoadjuvant pituitary radiotherapy to those patients with the presence of pituitary remnant tissue prior to TBA surgery, but not in those without residual tissue. The role of radiosurgery in this scenario should be explored in future studies.

Duration of Cushing’s disease prior to total bilateral adrenalectomy In one study involving 43 patients who were followed up for a median of 10 years post-TBA, those who developed pituitary enlargement had had symptoms of Cushing’s disease prior to TBA for twice as long as those who developed no pituitary enlargement (Kelly et al., 1983). In a smaller study with seven patients with Cushing’s disease who had undergone TBA, there was no association between the duration of Cushing’s disease and the development of Nelson syndrome (Moreira et al., 1993). There is some controversy in the literature therefore, and further studies are required to clarify the potential role of Cushing’s disease duration pre-TBA as a potential predictor of subsequent Nelson syndrome development.

NELSON SYNDROME: DEFINITION AND MANAGEMENT

Residual adrenal remnant after total bilateral adrenalectomy The presence of a small adrenal remnant post-TBA does not appear to protect against the subsequent development of Nelson syndrome (Manolas et al., 1984). Furthermore, there is a risk of recurrence of hypercortisolemia (resulting from raised ACTH levels) if adrenal remnant tissue is left in situ (Barber et al., 2010). This was demonstrated in a large study in which of those patients with Cushing’s disease who had been treated with TBA and in whom adrenal remnants had been left in situ (n ¼ 12 representing 27% of the sample), two patients developed early recurrence of Cushing’s disease from hyperfunctioning adrenal remnant tissue (Nagesser et al., 2000).

Age Age may be a predictive factor for subsequent development of Nelson syndrome, with younger patients – particularly children (Hopwood and Kenny, 1977; Thomas et al., 1984) – at the time of TBA being at higher risk (Moore et al., 1976; Kemink et al., 1994; Imai et al., 1996). However, once again controversy exists, with not all studies showing age at TBA to be a risk factor for Nelson syndrome development (Assie et al., 2007). It is possible that children may develop more aggressive subtypes of corticotropinomas, although other age-related factors may exist (Leinung and Zimmerman, 1994).

High urinary cortisol For some macrocorticotropinomas, urinary cortisol levels pre-TBA may reflect tumor size and functionality, and thereby predict subsequent development of Nelson syndrome post-TBA (Boscaro et al., 2009; Nagesser et al., 2000; Sonino et al., 1996). However, such an association between pre-TBA urinary cortisol levels and risk of Nelson syndrome development post-TBA has not been demonstrated in some studies (Barnett et al., 1983; Kelly et al., 1983; Pereira et al., 1998), precluding adoption of urinary cortisol levels as a reliable predictive factor in clinical practice.

Insufficient exogenous steroid replacement therapy post-total bilateral adrenalectomy surgery Although it is possible that suboptimal or absent steroid replacement therapy may increase the risk of Nelson syndrome development post-TBA (Pollock and Young, 2002; Kasperlik-Zaluska et al., 2006), or promote the development of an aggressive tumor subtype

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(Banasiak and Malek, 2007; Nagesser et al., 2000), most studies have not shown this to be the case (Barnett et al., 1983; Kelly et al., 1983; Nagesser et al., 2000).

Lack of cortisol suppression on high-dose dexamethasone pre-total bilateral adrenalectomy It is possible that the minority (20%) of patients who lack suppression of cortisol on high-dose dexamethasone preTSS may be at higher risk of developing Nelson syndrome (Barber et al., 2010). However, existing evidence is lacking: in a study of 48 patients with Cushing’s disease who underwent TBA (eight of whom subsequently developed Nelson syndrome), the suppressibility of cortisol following administration of dexamethasone (8 mg and 16 mg) prior to TBA did not appear to predict the subsequent development of Nelson syndrome (Kemink et al., 1994). Given the unpredictability of which patients go on to develop Nelson syndrome following TBA, further larger studies are required to explore pre-TSS and pre-TBA cortisol suppressibility as a possible clinical predictor of this outcome. It is clear that there is much controversy in the current literature regarding the clinical utility of a number of potential predictors for the development of Nelson syndrome post-TBA. It is therefore imperative that all patients with a history of Cushing’s disease who undergo TBA surgery also undergo close long-term follow-up to enable early identification and management of incipient Nelson syndrome.

PATHOPHYSIOLOGY OF NELSON SYNDROME Although the pathophysiology of Nelson syndrome is incompletely understood, various hypotheses exist. One such hypothesis is that following TBA, a drop in the previously elevated cortisol levels results in reduced negative feedback on corticotroph cells and restoration of hypothalamic corticotropin-releasing hormone (CRH) production (Barber et al., 2010), which, in turn, may drive corticotroph neoplasia. A similar mechanism may occur rarely with the development of neoplasia in occasional patients with Addison’s disease (Sugiyama et al., 1996). Data from rodent studies appear to support this hypothesis, with elevations in CRH levels (Carey et al., 1984), POMC gene products, and corticotroph cell hyperplasia (Wynn et al., 1985) observed following adrenalectomy in rats, and increased hypothalamic arginine vasopressin (AVP) production (McNicol and CarbajoPerez, 1999), which may induce corticotroph proliferation (van Wijk et al., 1995) following adrenalectomy in

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mice. Furthermore, it has been demonstrated in rodents that chronic CRH infusion can result in corticotroph cell hyperplasia (Gertz et al., 1987). Finally, cortisol lowers the proliferation rate of human pituitary adenoma cells in vitro (Resetic et al., 1990). Although the “released negative-feedback” hypothesis is attractive, there are some important inconsistencies from both clinical and laboratory observations. Not all patients with a history of Cushing’s disease develop Nelson syndrome during long-term follow-up following TBA. Furthermore, Nelson syndrome develops mostly in those post-TBA patients who receive adequate steroid replacement therapy exogenously (Barber et al., 2010). A further inconsistent observation is that corticotrophs from patients with Nelson syndrome demonstrate attenuated negative-feedback responses to glucocorticoids in vivo (Wolfsen and Odell, 1980). Furthermore, secretion of POMC-derived peptides from Cushing’s disease patients does not appear to be attenuated by glucocorticoids (Cook et al., 1976). An alternative explanation to the released negativefeedback hypothesis for the pathophysiology of Nelson syndome is that this condition tends to develop in the subgroup of patients with Cushing’s disease with aggressive forms of corticotropinomas (Assie et al., 2007). Such patients also have a higher chance of relapse following TSS (7–12% of patients with Cushing’s disease treated with TSS have a relapse within one year following the procedure (Lanzi et al., 1998)) and subsequent need for TBA. Consistent with this hypothesis is the observation that compared with patients with less aggressive forms of pituitary tumor, patients with invasive corticotropinomas at the time of TSS are also at greater risk of subsequently developing Nelson syndrome at an earlier stage following TBA (Nagesser et al., 2000; Gil-Cardenas et al., 2007). The de novo development of a new corticotropinoma that is clonally distinct from the original tumor is also possible in some patients, although there is little evidence to support this alternative theory. A more complete understanding of the pathophysiology of Nelson syndrome (including molecular and histopathologic features of Nelson tumors) would facilitate future therapeutic developments and would also assist in the development of novel predictive factors. In one small study on 12 patients with Cushing’s disease, it was shown that mitotic figures or Ki-67-expressing nuclei in corticotroph adenomas at baseline was not predictive of adenoma progression following TBA (Assie et al., 2007). Further cell-based studies in larger numbers of subjects are required to define the molecular characteristics of those corticotropinomas that subsequently develop into Nelson tumors. These data could then be used for predictive purposes in

clinical practice, based on histopathologic and immunocytochemical features (including percentage of mitoses and Ki-67-immunopositive nuclei) of tumor derived at TSS.

PATHOLOGIC FEATURES OF CORTICOTROPINOMAS IN NELSON SYNDROME There are many similarities (both histologic and molecular) between the corticotropinomas that develop in Cushing’s disease and those that develop in Nelson syndrome (Bertagna, 1992; Assie et al., 2004). The tumors in both conditions manifest monoclonality, originating from the same corticotroph cells (Herman et al., 1990). Furthermore, cells from these tumors maintain some normal functional activity including POMC processing (RaffinSanson et al., 2003), expression of functional CRH and vasopressin V3 receptors (de Keyzer et al., 1997), and usually expression of the two isoforms of glucocorticoid receptor (Dahia et al., 1997). Morphologically, Nelson tumor cells can appear distinct from corticotropinomas in Cushing’s disease, including unique ultrastructural features (inconspicuous type 1 cytokeratin filaments (Herman et al., 1990)) and larger cells with significant pleomorphism (Machado et al., 2005; Nagesser et al., 2000). Despite the similarities outlined above, and as alluded to earlier, compared to those that develop in Cushing’s disease, corticotropinomas that develop in Nelson syndrome tend to be macroadenomas, manifest higher proliferation (1.1% versus 0.5%) and lower p27 labeling indices (13% versus 28%) and are more invasive (Scheithauer et al., 2006). The aggressiveness of Nelson tumors is further supported by clinical observations. In one study, four out of seven corticotroph carcinomas developed in the context of Nelson syndrome (average interval 15.3 years (Pernicone et al., 1997)). In a further study involving 33 ACTH-producing pituitary carcinomas, 15 (45%) developed in the context of Nelson syndrome (Landman et al., 2002). Although the actual prevalence of pituitary carcinoma developing in the context of Nelson syndrome is not clear (with case series often not reporting on such an outcome), even in the context of Nelson syndrome the development of pituitary carcinoma is rare (Landman et al., 2002).

EFFECTIVE MANAGEMENT OF NELSON SYNDROME Pituitary surgery Wherever possible, pituitary surgery should be the firstline treatment option for Nelson syndrome, with success rates that range between 10% and 70% (Wolfsen and

NELSON SYNDROME: DEFINITION AND MANAGEMENT Odell, 1980; Kemink et al., 2001; Kelly et al., 2002; De Tommasi et al., 2005). Most Nelson tumors are amenable to a transsphenoidal procedure, although in 33% of cases (particularly those with extrasellar extension) a transcranial approach is required (De Tommasi et al., 2005). Perhaps not surprisingly, long-term remission and complication rates are related to tumor size, with those confined to the sellar region having the most successful outcome (Kemink et al., 2001). Although mortality following the surgical management of Nelson syndrome is low at 5% (Kelly et al., 2002; Xing et al., 2002), morbidity rates are high, with up to 69% of patients developing postoperative panhypopituitarism (Banasiak and Malek, 2007), 15% developing a CSF leak, 8% developing meningitis, and 5% acquiring a cranial nerve palsy (Kelly et al., 2002; Xing et al., 2002).

Adjuvant radiotherapy Despite surgical intervention, Nelson tumors may still subsequently progress in some patients (Kelly et al., 2002), with adjuvant radiotherapy being required in between 20% and 30% of such patients (Ludecke et al., 1982; Wislawski et al., 1985; Kemink et al., 2001; Kelly et al., 2002). As alluded to earlier in this chapter, a pragmatic approach would be to administer adjuvant radiotherapy as a preventive strategy at the time of TBA to those patients with Nelson syndrome who also have remnant corticotroph tumor tissue. Administration of this form of therapy should be balanced with its potential complications.

Stereotactic radiosurgery The role of Gamma Knife surgery (GKS) in Nelson syndrome is unclear (Levy et al., 1991; Ganz et al., 1993; Wolffenbuttel et al., 1998; Mauermann et al., 2007), although this therapy appears to be most effective when administered soon after TBA (Vik-Mo et al., 2009). It is also known that GKS is most effective when the anatomic target is clear and discrete. Therefore, GKS may be less effective following surgical management when the tumor border may become indistinct (Ganz et al., 1993; Mauermann et al., 2007). Consideration should also be given to the adverse effects of GKS that include panhypopituitarism (Degerblad et al., 1986) and cranial nerve palsies, which precludes this form of therapy for tumors that are adjacent to the optic apparatus and those that invade the cavernous sinus. The current literature on the effectiveness of GKS in Nelson syndrome is limited and conflicting, with one study showing no tumor regrowth at 7 years post-GKS therapy (Vik-Mo et al., 2009) and another showing remission rates to be only 14% ( Jane et al., 2003). Clearly additional studies are

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required to explore further the role of GKS in the management of Nelson syndrome.

Selective somatostatin analogs It is hypothesized that somatostatin analogs (SSAs) act through reducing plasma ACTH levels (KasperlikZaluska et al., 2005) and tumor volume (Petrini et al., 1994), although human evidence to support the use of SSAs in patients with Nelson syndrome is lacking. There is some evidence to suggest that pasireotide (SOM 230, having affinity to somatostatin receptors 1, 2, 3 and 5) inhibits ACTH secretion in vitro from human corticotroph cells from patients with Cushing’s disease (Hofland et al., 2005), inhibits ACTH release in vivo (Schmid, 2008) and reduces the proliferative rate of human corticotroph cells (Batista et al., 2006). Pasireotide has also been shown to provide long-term efficacy in patients with Cushing’s disease (Colao et al., 2012). Again, however, further studies are required to explore the possible future role of SSAs in the effective management of patients with Nelson syndrome.

Peroxisome proliferator-activated receptor g agonists The withdrawal of rosiglitazone has limited somewhat the prospects of peroxisome proliferator-activated receptor (PPAR) g agonist drugs as future therapies for Nelson syndrome, particularly given that much of the (limited) current evidence to support the use of PPAR g agonists in this context relates to rosiglitazone. Furthermore, PPAR g agonists remain unlicensed for use in Nelson syndrome. However, there is some evidence to suggest that this class of drug may be useful in Nelson syndrome. It is known that expression of PPAR g receptors occurs in normal corticotrophs, and especially in corticotroph adenoma cells (Heaney et al., 2002). Furthermore, transcription of POMC mRNA from murine corticotrophs cultured in vitro is reduced fourfold when exposed to rosiglitazone (Heaney et al., 2002). This drug has also been demonstrated to cause cell cycle arrest, apoptosis, and reduced ACTH secretion from corticotroph cells in a mouse model of Cushing’s disease (Heaney et al., 2002). However, human data have been disappointing, with one reported study on the use of rosiglitazone in patients with Nelson syndrome (n ¼ 7) demonstrating no lowering of ACTH levels (Mullan et al., 2006). In support of this, two more recent studies on the use of rosiglitazone in Nelson syndrome also reported on its ineffectiveness as a treatment in this condition (Kreutzer et al., 2009; Munir et al., 2007).

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Sodium valproate It is possible that use of sodium valproate, which inhibits the hypothalamic reuptake of GABA, thereby reducing CRH release, may be effective in patients with Nelson syndrome (Batista et al., 2006). This hypothesis has not been supported by data from patients with Nelson syndrome (Kasperlik-Zaluska et al., 2005), with no beneficial effects on ACTH levels (Kasperlik-Zaluska et al., 2005; Batista et al., 2006), or corticotropinoma growth (Batista et al., 2006).

Dopamine agonists It is known that dopamine receptors are expressed ubiquitously within pituitary adenomas. Support for the efficacy of dopamine agonists in Nelson syndrome include the observation that ACTH levels are reduced by administration of bromocriptine (Batista et al., 2006) and even that remission of Nelson syndrome (Pivonello et al., 1999; Shraga-Slutzky et al., 2006) and tumor resolution (Casulari et al., 2004) can occur in response to the use of cabergoline therapy. Future directions include the identification of dopamine receptor subclass in Nelson tumors to enable novel therapeutic developments (Barber et al., 2010).

Temozolomide Although more data are required, the existing literature reveals that the alkylating agent temozolomide represents a promising therapy for patients with Nelson syndrome, especially those with aggressive tumors. One case report demonstrated an excellent response to temozolomide therapy with a significant reduction in ACTH level and regression of the underlying tumor following just four cycles of treatment in a patient with an aggressive Nelson tumor that had previously failed to respond to surgery, radiotherapy, and Gamma Knife treatment modalities (Moyes et al., 2009). It has been suggested that in patients with aggressive pituitary tumors, immunoexpression of the DNA repair protein 0(6)methylguanine DNA methyl transferase (MGMT) is predictive of the response to temozolomide therapy (McCormack et al., 2009), low expression of MGMT being correlated with tumor responsiveness to temozolomide in patients with regrowth of nonfunctioning pituitary adenomas (Widhalm et al., 2009). The efficacy and placement of temozolomide therapy in Nelson syndrome should be a focus for future research.

CONCLUSIONS To the nonspecialist, Nelson syndrome is encountered infrequently in the clinical arena. However, its associated morbidity and mortality, and the importance of early

diagnosis and instigation of effective therapy, promotes Nelson syndrome as a condition of high importance and worthy of cognizance amongst all clinicians. The diagnosis and management of Nelson syndrome, due at least in part to the frequent aggressiveness of the underlying corticotropinoma, can be a challenge. It is imperative that all patients at risk of developing this condition (patients with a history of Cushing’s disease who have been treated with TBA) are followed up long-term and undergo close screening with ACTH levels and MRI scans of the pituitary at regular intervals. Unfortunately, the current literature in the field of Nelson syndrome is littered with controversy due partly to the rarity of the condition, but also to factors such as lack of consensus regarding diagnostic criteria, for example. It is our hope that widespread acceptance and adoption of the diagnostic criteria for Nelson syndrome set out in this chapter will enable the generation of a robust and reliable evidence base on which to generate appropriate guidance regarding management of this condition. Other future directions include further exploration of the molecular aspects of Nelson tumors, including quantification of CRH-receptor and glucocorticoid-receptor densities, and associations of these molecular features with clinicopathologic outcomes. Further research on the predictive factors for and pathophysiology of Nelson syndrome will enable a more focused approach towards screening and development of future novel therapeutic agents, ultimately benefiting the patients who develop this important condition.

ACKNOWLEDGMENTS We acknowledge all the patients, relatives, nurses, and physicians who contributed to the ascertainment of the various clinical samples reported on in this chapter.

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