Prevalence of Nelson's syndrome after bilateral adrenalectomy in patients with cushing's disease: a systematic review and meta-analysis.

PURPOSE: Bilateral adrenalectomy (BA) still plays an important role in the management of Cushing's disease (CD). Nelson's syndrome (NS) is a severe complication of BA, but conflicting data on its prevalence and predicting factors have been reported. The aim of this study was to determine the prevalence of NS, and identify factors associated with its development. DATA SOURCES: Systematic literature search in four databases. STUDY SELECTION: Observational studies reporting the prevalence of NS after BA in adult patients with CD. DATA EXTRACTION: Data extraction and risk of bias assessment were performed by three independent investigators. DATA SYNTHESIS: Thirty-six studies, with a total of 1316 CD patients treated with BA, were included for the primary outcome. Pooled prevalence of NS was 26% (95% CI 22-31%), with moderate to high heterogeneity (I2 67%, P < 0.01). The time from BA to NS varied from 2 months to 39 years. The prevalence of NS in the most recently published studies, where magnet resonance imaging was used, was 38% (95% CI 27-50%). The prevalence of treatment for NS was 21% (95% CI 18-26%). Relative risk for NS was not significantly affected by prior pituitary radiotherapy [0.9 (95% CI 0.5-1.6)] or pituitary surgery [0.6 (95% CI 0.4-1.0)]. CONCLUSIONS: Every fourth patient with CD treated with BA develops NS, and every fifth patient requires pituitary-specific treatment. The risk of NS may persist for up to four decades after BA. Life-long follow-up is essential for early detection and adequate treatment of NS.

Nelson's Syndrome: An Update.

Nelson's syndrome (NS) is a condition which may develop in patients with Cushing's disease after bilateral adrenalectomy. Although there is no formal consensus on what defines NS, corticotroph tumor growth and/or gradually increasing ACTH levels are important diagnostic elements. Pathogenesis is unclear and well-established predictive factors are lacking; high ACTH during the first year after bilateral adrenalectomy is the most consistently reported predictive parameter. Management is individualized and includes surgery, with or without radiotherapy, radiotherapy alone, and observation; medical treatments have shown inconsistent results. A subset of tumors demonstrates aggressive behavior with challenging management, malignant transformation and poor prognosis.

Cushing's syndrome - Disease monitoring: Recurrence, surveillance with biomarkers or imaging studies.

Pituitary surgery is the first-line treatment for patients with Cushing's disease. For patients who are not considered candidates for pituitary surgery, pituitary radiation and bilateral adrenalectomy are further treatment alternatives. Not all patients are cured with pituitary surgery, and a substantial number of patients develop recurrence, sometimes many years after an apparently successful treatment. The same applies to patients treated with radiotherapy. Far from all patients are cured, and in many cases the disease recurs. Bilateral adrenalectomy, although always curative, causes chronic adrenal insufficiency and the remaining pituitary tumour can continue to grow and cause symptoms due to pressure on adjacent tissues, a phenomenon called Nelson's syndrome. In this paper the rate of recurrence of hypercortisolism, as well as the rate of development of Nelson's syndrome, following treatment of patients with Cushing's syndrome, will be reviewed. The aim of the paper is also to summarize clinical and biochemical factors that are associated with recurrence of hypercortisolism and how the patients should be monitored following treatment.

Outcomes of Patients with Nelson's Syndrome after Primary Treatment: A Multicenter Study from 13 UK Pituitary Centers.

CONTEXT: Long-term outcomes of patients with Nelson's syndrome (NS) have been poorly explored, especially in the modern era. OBJECTIVE: To elucidate tumor control rates, effectiveness of various treatments, and markers of prognostic relevance in patients with NS. PATIENTS, DESIGN, AND SETTING: Retrospective cohort study of 68 patients from 13 UK pituitary centers with median imaging follow-up of 13 years (range 1-45) since NS diagnosis. RESULTS: Management of Cushing's disease (CD) prior to NS diagnosis included surgery+adrenalectomy (n = 30; eight patients had 2 and one had 3 pituitary operations), surgery+radiotherapy+adrenalectomy (n = 17; two received >1 courses of irradiation, two had ≥2 pituitary surgeries), radiotherapy+adrenalectomy (n = 2), and adrenalectomy (n = 19). Primary management of NS mainly included surgery, radiotherapy, surgery+radiotherapy, and observation; 10-year tumor progression-free survival was 62% (surgery 80%, radiotherapy 52%, surgery+radiotherapy 81%, observation 51%). Sex, age at CD or NS diagnosis, size of adenoma (micro-/macroadenoma) at CD diagnosis, presence of pituitary tumor on imaging prior adrenalectomy, and mode of NS primary management were not predictors of tumor progression. Mode of management of CD before NS diagnosis was a significant factor predicting progression, with the group treated by surgery+radiotherapy+adrenalectomy for their CD showing the highest risk (hazard ratio 4.6; 95% confidence interval, 1.6-13.5). During follow-up, 3% of patients had malignant transformation with spinal metastases and 4% died of aggressively enlarging tumor. CONCLUSIONS: At 10 years follow-up, 38% of the patients diagnosed with NS showed progression of their corticotroph tumor. Complexity of treatments for the CD prior to NS diagnosis, possibly reflecting corticotroph adenoma aggressiveness, predicts long-term tumor prognosis.

Pregnancy does not accelerate corticotroph tumor progression in Nelson's syndrome.

CONTEXT: Pituitary surgery is the first line of treatment for Cushing's disease; when surgery fails, bilateral adrenalectomy may be proposed, particularly for women with a desire for pregnancy. Little is known about the impact of pregnancy on corticotroph tumor progression after bilateral adrenalectomy. OBJECTIVE: The aim was to evaluate the impact of pregnancy on corticotroph tumor progression after bilateral adrenalectomy in Cushing's disease and to assess maternal and pregnancy outcomes. DESIGN: We conducted a retrospective cohort study. SETTING: Patients who became pregnant after bilateral adrenalectomy were followed in a single center. PATIENTS: Twenty pregnancies from 11 patients with Cushing's disease were treated by bilateral adrenalectomy and no pituitary irradiation. MEASUREMENTS: Corticotroph tumor progression was assessed by serial pituitary magnetic resonance imaging and plasma ACTH measurements before, during, and after pregnancy. Comparisons were performed using paired Wilcoxon rank tests. Data on maternal and neonatal outcomes were recorded by correspondence from patients and obstetricians. RESULTS: Corticotroph tumor progression occurred in eight of 17 pregnancies, and ACTH increased in eight of 10 pregnancies. However, rates of increase during or after pregnancy were not faster than those observed before pregnancy. Maternal complications occurred in four pregnancies from two patients, including gestational hypertension in three and gestational diabetes mellitus in three. Among these four pregnancies, three had a favorable outcome, and one led to an in utero death after eclampsia, due to loss to follow-up. No other maternal or fetal complications were reported. CONCLUSION: Pregnancy does not accelerate corticotroph tumor progression after bilateral adrenalectomy. Pregnancy is manageable, provided the patients can be followed closely.

Nelson's syndrome after bilateral adrenalectomy for Cushing's disease.

BACKGROUND: Presentation and outcome of Nelson's syndrome after bilateral adrenalectomy is variable. METHODS: Clinical records of 39 patients who underwent bilateral adrenalectomy for primary or recurrent Cushing's disease during a 15-year period were analyzed for frequency and evolution of Nelson's syndrome. RESULTS: The study included 32 females and 7 males with a mean age of 31 years; 20 patients had a hypophysectomy as the initial procedure, and 19 had an adrenalectomy. Of the group, 17 patients received prophylactic radiation therapy to the pituitary gland. A total of 11 patients, none of whom had received prophylactic radiation therapy, developed Nelson's syndrome (determined by skin hyperpigmentation, elevated serum ACTH levels, and enlargement of a previous pituitary tumor or development of a new tumor in patients with no previous pituitary abnormality) over a mean follow-up period of 53 months. Treatment for Nelson's syndrome included valproic acid, radiation therapy, and hypophysectomy as monotherapy or combined therapy. Of the remaining 28 patients, 10 (7 without prophylactic radio therapy) developed skin hyperpigmentation and increased ACTH levels without a tumor. CONCLUSIONS: Nelson's syndrome is a frequent complication after bilateral adrenalectomy in the absence of prophylactic radiotherapy (28%). The syndrome can be successfully controlled by medical treatment and or radiotherapy; patients rarely require hypophysectomy.

The Nelson's syndrome... revisited.

Adrenalectomy is a radical therapeutic approach to control hypercortisolism in some patients with Cushing's disease. However it may be complicated by the Nelson's syndrome, defined by the association of a pituitary macroadenoma and high ACTH secretion after adrenalectomy. This definition has not changed since the end of the fifties. Today the Nelson's syndrome must be revisited with new to criteria using more sensitive diagnostic tools, especially the pituitary magnetic resonance imaging. In this paper we will review the pathophysiological aspects of corticotroph tumor growth, with reference to the impact of adrenalectomy. The main epidemiological data on the Nelson's syndrome will be presented. More importantly, we will propose a new pathophysiological and practical approach to this question which attempts to evaluate the Corticotroph Tumor Progression after adrenalectomy, rather than to diagnose the Nelson's syndrome. We will discuss the consequences for the management of Cushing's disease patients after adrenalectomy, and will also draw some perspectives.

Microsurgical treatment of Nelson's syndrome.

OBJECTIVE: To discuss the etiology, diagnostic criteria and treatment of Nelson's syndrome. METHODS: Twenty-three patients with Nelson's syndrome who were treated in our department over the last 19 years were analyzed retrospectively. Removal of adenoma by the transsphenoidal approach was done in 21 patients and by transfrontal craniotomy in 2. The follow-up period ranged from six months to nine years. RESULTS: The incidence of Nelson's syndrome was 7.7% in a series of 300 patients with Cushing's disease treated by microsurgery in the same period. Hyperpigmentation was relieved and adrenocorticotropic hormone (ACTH) levels decreased in all patients after tumor excision. Eight patients with visual disturbance improved after surgery. The curative and remission rates were 56.5% and 26.1%, respectively. CONCLUSIONS: Transsphenoidal microsurgical removal of pituitary ACTH adenoma is the first choice in the prevention and treatment of Nelson's syndrome. Regular follow-up examinations should be performed over a long time.

The long-term outcome after adrenalectomy and prophylactic pituitary radiotherapy in adrenocorticotropin-dependent Cushing's syndrome.

We have reviewed our experience of adrenalectomy performed as part of the management of 56 patients with ACTH-dependent Cushing's syndrome between 1946 and 1993. Forty-three patients were operated on at our institution. Surgery-related mortality did not occur, but complications developed in 14 (33%); these were minor in 12. Eleven patients (29%) of the 38 for whom long-term follow-up data were available and who did not have a proven ectopic source of ACTH subsequently developed Nelson's syndrome, diagnosed on the basis of clinical pigmentation and markedly elevated ACTH levels that were not normally suppressible with glucocorticoids. The effects of prophylactic pituitary radiotherapy were assessed in 38 patients who underwent adrenalectomy at our institution and 18 who underwent surgery elsewhere. Patients who had received prophylactic radiotherapy were less likely to develop Nelson's syndrome (5 of 20, 25%) compared to those who did not (18 of 36, 50%; P > 0.07), and there was a low incidence of radiotherapy-induced hypopituitarism. We conclude that total adrenalectomy has proved to be a safe and effective operation and still may be indicated in selected patients with ACTH-dependent Cushing's syndrome; because prophylactic pituitary radiotherapy reduces the incidence of subsequent Nelson's syndrome by 50%, it should always be considered in the management of these patients.

[Cushing syndrome in children]. / Syndromes de Cushing de l'enfant.

In pediatric patients, endogenous Cushing syndrome is an infrequent condition almost always due to one of two conditions. 1) Adrenal gland tumors account for 70% of Cushing syndromes in young pediatric patients. They cause rapidly progressive hypercorticism not due to increased ACTH production (elevated plasma and urine cortisol levels, very low ACTH and LPH levels unchanged by dexamethasone, metyrapone or CRH). Imaging techniques determine the side and spread of the tumor and look for metastases. Following surgical removal, patients with indicators of malignant disease (tumor weight above 30 g, extracapsular spread or metastases, independently from pathological data) are given op'DDD. 2) Cushing disease occurs in peripubertal patients and causes overweight with delayed statural gain. ACTH production is increased (positive dexamethasone suppression test and provocative metopirone and CRH tests) as a result of a pituitary adenoma which should be looked for by magnetic resonance imaging and whose removal ensures recovery in 50% of cases. Other therapeutic tools include op'DDD, radiation to the pituitary, and bilateral adrenalectomy as the last resort given the high risk of post-adrenalectomy pituitary tumor (50% of pediatric patients). Other causes are exceedingly rare: primary nodular hyperplasia of the adrenal glands and production of ACTH by a nonpituitary tumor. Corticosteroid treatment is the most common cause of Cushing syndrome in children.

Nelson's syndrome: incidence and prognosis.

Fifty patients bilaterally adrenalectomized for Cushing's disease were followed for 1 to 22 (mean, 12) years. In 14 of them (28%) Nelson's syndrome appeared within 1.5 to 12 (mean, 4.8) years after adrenalectomy. All the patients were deeply pigmented, 12 had a radiologically demonstrable tumour and six had visual defects. Plasma ACTH levels ranged from 450 to 8000 ng/l. However in every case at least one estimation during circadian studies equalled 2000 ng/l. One patient with an anaplastic pituitary tumour died 3 years after the discovery of the tumour. Anaplasia was also diagnosed in another patient with recurrence of pituitary tumour after a transsphenoidal operation. Symptoms of tumour infarction occurred in two patients, followed by clinical remission of Nelson's syndrome. In the majority of cases the course was benign. We conclude that all cases, however, should be followed indefinitely because Nelson's tumours are not infrequently aggressive.

Incidence of Nelson's syndrome after adrenalectomy for Cushing's disease in children: results of a nationwide survey.

To establish the incidence of Nelson's syndrome in children treated with total bilateral adrenalectomy (TBA) for Cushing's disease, a survey was made of members of The Lawson Wilkins Pediatric Endocrine Society. Thirty-one patients aged 10 months to 16 years had been treated with TBA for Cushing's disease; one had been treated with ortho para prime isomer of dichlorodiphenyldichloroethane alone. Postadrenalectomy hyperpigmentation was reported in 18 patients. Sella enlargement was detected in eight patients (25%) after 1 to 5.5 years (mean, three years) post-TBA. Five of these patients have had documented pituitary adenomas to date. This incidence is higher than the adult figure of 10% to 16%.