Nelson syndrome: comprehensive review of pathophysiology, diagnosis, and management

Abstract

ELSON syndrome is a rare clinical manifestation of an enlarging pituitary adenoma that can occur following bilateral adrenalectomy performed in the treatment of CD. It is characterized by skin and mucus membrane hyperpigmentation and excess ACTH secretion. Diagnostic criteria for NS have been quite variable. Some authors 77 have defined NS as high levels of ACTH associated with skin hyperpigmentation after bilateral adrenalectomy regardless of pituitary enlargement, 80 whereas others consider the presence of an expanding pituitary adenoma causing visual field disturbance as a requirement for diagnosis. 114 With modern day imaging, and for the purposes of this review, corticotroph tumor progression and high ACTH have been proposed as a basis for the diagnosis of NS. 4 Historical Perspective The first suggestion that the adrenal gland was essential for life came from Brown-Séquard, who showed in the 1850s that bilateral adrenalectomy in animals caused death within a few days. 66 Harvey Cushing 13 was the first to link adrenal hypersecretion of cortisol to the presence of a pituitary tumor. The concept of the hypothalamic-pituitary-adrenal axis evolved further with the demonstration of the existence of ACTH-releasing factor in 1955 by Saffran and Schally. 98 The first case report of the characteristic triad of NS was published by Don Nelson in 1958. 78 He described a 33-year-old woman who developed marked skin hyperpigmentation, high plasma ACTH levels, and imaging evidence of a pituitary tumor (enlarged sella on skull radiographs) 3 years after bilateral adrenalectomy for CD. In 1960, Nelson and colleagues 79 formally described the syndrome of pituitary hypersecretion of ACTH and pituitary tumor enlargement, which has since become the eponymous syndrome. Corticotropin-releasing hormone was finally isolated and sequenced by Vale and coworkers in 1981, 113 and with the availability of radioimmunoassay, the elevation of plasma ACTH levels after bilateral adrenalectomy became diagnostic for NS. Historically, patients with CD were treated with bilateral

Characterizing and predicting the Nelson-Salassa syndrome

“…41 Other authors have found comparable progression rates between patients who underwent radiotherapy and those who did not-including Moore and colleagues, 30 who observed NSS in approximately 10% of both groups in a study of 120 postbilateral ADX CD patients-and numerous studies have either failed to find a significant protective effect associated with EBRT or noted frequent progression despite treatment. 2,19,27,28,37,42 In part, the present results support this conclusion; more specifically, when examining the 11-patient subgroup that received treatment for persistent CD, 6 developed NSS, while 5 did not ( Table 5).…”

“…22 Still others have recommend close clinical followup, reserving intervention for the onset of symptoms, particularly given the heightened risks of repeat surgery in patients who had potentially undergone radiosurgery-including CSF leak, hemorrhage, or worsening pituitary dysfunction. 1,2,36 Given our finding that the majority of patients with radiographic NSS never develop clinically meaningful symptoms-as well as the possibility that NSS patients may be divisible into 2 phenotypic subgroups stratified by tumor aggressiveness-we concur that expectant management is a reasonable option for the majority of asymptomatic patients. Preliminarily, in the absence of symptoms, we suggest as treatment thresholds either 5 mm of tumor growth on a single scan or continued tumor growth on 2 separate imaging studies; however, further study is clearly required to better interrogate this nuanced question and establish more definitive recommendations.…”

“…In our analysis, age, tumor size, and history of EBRT were the only outcomes significantly associated with development of NSS-including an extensive array of clinical, laboratory, pathological, and treatment outcomes, many of which were thought to predict NSS in previous analyses (Tables 1-5). [1][2][3]10,36 Although not universally observed, young age at CD diagnosis is perhaps the most frequently reproduced predictor of NSS; correspondingly, we recommend that patients presenting in their 4th decade of life or younger be considered for earlier and closer surveillance for NSS-particularly within the first 5 years after bilateral ADX (Fig. 3).…”

“…Post-bilateral ADX pituitary screening protocols vary by institution, although it is generally agreed that pituitary MRI should be completed within the 1st year and carried out on at least a biannual basis for life. [1][2][3]10,36 However, the possibility that NSS comprises 2 distinct tumor phenotypes and the correspondingly high likelihood of MRI identifying asymptomatic tumor progression in patients who are unlikely to develop clinical symptoms, calls the necessity of this practice into question-particularly in lower risk patients.…”

“…1,3,36 Furthermore, although the finding was not significant, our analysis and previous studies have suggested a trend toward increased all-cause mortality and a shorter interval from bilateral ADX to death in patients with NSS, although the mechanism driving this is not clinically apparent at present, and requires further evaluation in a larger, prospective study. [1][2][3]10,36 With this in mind, many authors have advocated immediate intervention, with Kemink and colleagues 12 demonstrating that, in a series of 15 patients with CD who underwent bilateral ADX, of the 8 who were initially watched following NSS diagnosis, 6 went on to require repeat TSS. 22 Still others have recommend close clinical followup, reserving intervention for the onset of symptoms, particularly given the heightened risks of repeat surgery in patients who had potentially undergone radiosurgery-including CSF leak, hemorrhage, or worsening pituitary dysfunction.…”