Nelson syndrome

Nelson’s syndrome is a potentially severe complication of bilateral adrenalectomy performed in the treatment of Cushing’s disease, and its management remains difficult. Of all of the features of Nelson’s syndrome, the one that causes most concern is the development of a locally aggressive pituitary tumour, which, unusually for pituitary disease, may occasionally cause death from the tumour itself. This feature is especially pertinent given the increasing use in Cushing’s disease of laparoscopic bilateral adrenal surgery as a highly effective treatment modality to control cortisol-excess. some will define Nelson’s syndrome according to the classical description with an evolving pituitary mass after bilateral adrenalectomy, whereas others will rely on increasing plasma ACTH levels, even in the absence of a clear pituitary mass lesion on MRI. These factors need to be borne in mind when considering the reports of Nelson’s syndrome, as there is great heterogeneity.

In 1958, Don Nelson et al. described the first case of the eponymous syndrome in a 33-year-old woman who had undergone total bilateral adrenalectomy (TBA) 3 years previously for the treatment of refractory Cushing’s disease. She presented with visual field defects, skin hyperpigmentation, raised plasma ACTH and a large sellar mass shown on skull X-ray. The sellar mass was a pituitary corticotrophinoma, and its surgical removal led to symptom resolution.

Diagnosis

Nelson’s syndrome usually presented with late clinical manifestations of an enlarging pituitary corticotrophinoma including frank visual field defects and cranial nerve palsies due to tumour compressive effects and invasion into surrounding structures. Such late features are less frequent at presentation of Nelson’s syndrome in modern times, but hyperpigmentation of skin and mucous membranes (particularly on extensor surfaces, flexures, over scars and on the areolae) remains an important clinical manifestation. Metastases from a corticotroph carcinoma are unusual. Other clinical features include headaches, pituitary apoplexy, diabetes insipidus , panhypopituitarism, testicular pain and oligospermia . Nelson’s syndrome occasionally presents with paraovarian tumours or paratesticular tumours  from hyperstimulation of adrenal rest cells within gonadal tissues . This atypical complication of adrenal rest cell hyperplasia/stimulation can sometimes masquerade as a relapse of Cushing’s disease and be mistaken for this.

The most consistent and reliable biochemical feature of Nelson’s syndrome is a marked elevation of plasma ACTH, which continues to rise after adrenalectomy.

The radiological features of Nelson’s syndrome are those of an enlarging pituitary mass. It is imperative that comparisons of pituitary appearances are made with those from a post-TSS scan. MRI provides the best imaging modality, with detection of tumours as small as 3 mm.

Early diagnostic criteria

Existing diagnostic criteria for Nelson’s syndrome focus on an enlarging pituitary tumour post TBA, rising plasma ACTH levels and presence of hyperpigmentation.

New criteria

For a diagnosis of Nelson’s syndrome to be made, a patient must have had prior treatment with total bilateral adrenalectomy (TBA) for Cushing’s disease (regardless of prior transsphenoidal surgery) in addition to at least one of the following two criteria (based on Refs (13) and (15)):
 An expanding pituitary mass lesion post TBA surgery (shown on MRI or CT scan) compared with MRI of the pituitary prior to TBA surgery
 An elevated level of ACTH to >500 ng/l from a single plasma sample taken at 0800 h prior to steroid administration and post TBA surgery, in addition to progressive elevations of ACTH levels from plasma samples taken on at least three consecutive occasions at different time-points post TBA surgery (a rise of ACTH by >30% of the initial post-TBA sample)

 

Treatment

Observation

If there is MRI evidence of limited tumour progression but with no anatomical compromise, observation and repeat imaging (3–6 months) is an acceptable strategy.

Surgical

Pituitary surgery may be performed for corticotroph tumour progression if the anatomy is favourable for such an approach. Given that the risk is of further tumour expansion an attempt at complete hypophysectomy has been recommended, and is associated with a good long-term control of local tumour growth and lowering of plasma ACTH levels, but at a cost of increased hypopituitarism, including diabetes insipidus . Despite pituitary surgery some patients will have further progression alternative or adjuvant therapy is indicated.

Radiotherapy

The use of fractionated external radiotherapy is well documented in the treatment of established Nelson’s syndrome . Over time radiotherapy lowers plasma ACTH levels, but is associated with increases in long-term hypopituitarism. Whilst radiotherapy may control tumour growth in many instances, some tumours may continue to expand. More recently, large series treated by stereotactic radiotherapy, delivered by the gamma knife have been reported . In cases of a clear anatomical target this too is an effective modality of therapy, and may also be used after fractionated radiotherapy, as long as the dose to the optic apparatus can be kept within safe limits.

Medical

There has been a long interest in medical therapy to attempt to control plasma ACTH and tumour growth. Unfortunately, apart from isolated case reports there is no medical therapy that has been shown to consistently achieve these goals. Disappointing or variable results have been seen with sodium valproate , and currently licensed somatostatin analogues  although the multi-ligand analogue SOM230 (pasireotide) may prove of benefit. There are only occasional responses found with dopamine agonists such as cabergoline. Recent interest has focused on the use of PPAR gamma agonists in Nelson’s syndrome. One report showed that two out of three patients responded to rosiglitazone with lowering of plasma ACTH levels, but one of these subsequently escaped. The orally active alkylating agent temozolomide has been shown to be highly effective in a few aggressive pituitary tumours and in lowering prolactin and controlling tumour growth in highly aggressive prolactinomas. One major drawback of this agent is high cost.