Long-term outcome after bilateral adrenalectomy in Cushing's disease with focus on Nelson's syndrome

ABSTRACT Objective We analyzed the clinical, biochemical, and imaging findings of adrenalectomized patients with Cushing's disease (CD) in order to compare the characteristics of those who developed Nelson's syndrome (NS) versus those who did not develop this complication (NNS), aiming to identify possible predictive factors for its occurrence. Subjects and methods We performed a retrospective review of the clinical records of a group of patients with CD who underwent TBA between 1974 and 2011. Results Out of 179 patients with CD, 13 (7.3%) underwent TBA. NS occurred in 6 of them (46%) after a mean of 24 months from the total bilateral adrenalectomy (TBA). Age at diagnosis, duration of Cushing's syndrome (CS) until TBA, and steroid replacement doses were similar in both groups. Initial urinary cortisol levels (24-hour urinary free cortisol [UFC]) were significantly higher in the NS group than in the NNS group (p = 0.009). Four patients in the NS group and three of those in the NNS group received radiotherapy before TBA (p = 0.26). Three patients in the NS group presented residual tumors before TBA, compared with none in the NNS group (p = 0.04). At 1 year after TBA, the median ACTH level was 476 ng/L (240-1500 ng/L) in the NS group and 81 ng/L (48-330 ng/L) in the NNS group (p = 0.0007). Conclusion In conclusion, a residual tumor before TBA, higher 24-hour UFC at diagnosis, and increasing ACTH levels within 1 year after TBA emerged as predictive factors of development of NS.

Long-term outcome after bilateral adrenalectomy in Cushing's disease with focus on Nelson's syndrome.

OBJECTIVE: We analyzed the clinical, biochemical, and imaging findings of adrenalectomized patients with Cushing's disease (CD) in order to compare the characteristics of those who developed Nelson's syndrome (NS) versus those who did not develop this complication (NNS), aiming to identify possible predictive factors for its occurrence. SUBJECTS AND METHODS: We performed a retrospective review of the clinical records of a group of patients with CD who underwent TBA between 1974 and 2011. RESULTS: Out of 179 patients with CD, 13 (7.3%) underwent TBA. NS occurred in 6 of them (46%) after a mean of 24 months from the total bilateral adrenalectomy (TBA). Age at diagnosis, duration of Cushing's syndrome (CS) until TBA, and steroid replacement doses were similar in both groups. Initial urinary cortisol levels (24-hour urinary free cortisol [UFC]) were significantly higher in the NS group than in the NNS group (p = 0.009). Four patients in the NS group and three of those in the NNS group received radiotherapy before TBA (p = 0.26). Three patients in the NS group presented residual tumors before TBA, compared with none in the NNS group (p = 0.04). At 1 year after TBA, the median ACTH level was 476 ng/L (240-1500 ng/L) in the NS group and 81 ng/L (48-330 ng/L) in the NNS group (p = 0.0007). CONCLUSION: In conclusion, a residual tumor before TBA, higher 24-hour UFC at diagnosis, and increasing ACTH levels within 1 year after TBA emerged as predictive factors of development of NS.

Nelson's 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. Despite numerous studies and reports, there is no formal consensus of what defines Nelson's syndrome. Thus, 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, and it is likely that overall the modern 'Nelson's syndrome' represents a different disease entity from that of the last century. In the present paper, clinical and epidemiological features of Nelson's syndrome, as well as its treatment modalities, are reviewed.

A síndrome de Nelson (SN) é uma complicação potencialmente grave da adrenalectomia bilateral realizada para o tratamento da doença de Cushing e seu manejo permanece difícil. De todas as manifestações da SN, aquela que causa maior preocupação é o desenvolvimento de um tumor hipofisário localmente agressivo, que pode (pouco usualmente para a doença hipofisária) ocasionalmente causar a morte pelo próprio tumor. Este achado é especialmente pertinente, dado o uso cada vez mais freqüente na doença de Cushing, da adrenalectomia bilateral por via laparoscópica, uma modalidade terapêutica altamente efetiva para o controle do excesso de cortisol. Apesar de numerosos estudos e publicações, não existe um consenso formal sobre a definição da SN. Assim, alguns irão definir a SN de acordo com a descrição clássica, como uma massa hipofisária que evolui após a adrenalectomia bilateral, enquanto outros irão se basear nos níveis crescentes dos níveis de ACTH plasmático, mesmo na ausência de uma lesão ou massa hipofisária nitidamente visível à RM. Esses fatores precisam ser relembrados quando se avaliam as publicações sobre SN, na medida em que existe grande heterogeneidade, e é provável que no geral a "SN moderna" represente uma entidade patológica diferente daquela do século passado. Neste artigo, revisaremos achados clínicos e epidemiológicos da SN e também suas modalidades terapêuticas.

[Nelson's Syndrome: a case report]. / Síndrome de Nelson: relato de caso.

The aim of this article is to present and discuss several aspects of the pathogenesis, the clinical, hormonal, and imaging diagnosis, and the treatment of Nelson's syndrome, based on a typical patient's report, in whom several therapeutic approaches were shown to be ineffective.

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.

Síndrome de Nelson: relato de caso / Nelson's Syndrome: a case report

O objetivo deste artigo é apresentar e discutir alguns aspectos da patogênese, do diagnóstico clínico, hormonal e radiológico e do tratamento da síndrome de Nelson, com base no relato de um paciente típico portador da doença, no qual várias abordagens terapêuticas mostraram-se ineficazes.

The aim of this article is to present and discuss several aspects of the pathogenesis, the clinical, hormonal, and imaging diagnosis, and the treatment of Nelson's syndrome, based on a typical patient's report, in whom several therapeutic approaches were shown to be ineffective.

Nelson's 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. Despite numerous studies and reports, there is no formal consensus of what defines Nelson's syndrome. Thus, 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, and it is likely that overall the modern 'Nelson's syndrome' represents a different disease entity from that of the last century. In the present paper, clinical and epidemiological features of Nelson's syndrome, as well as its treatment modalities, are reviewed.

A clinico-pathological study of Cushing's syndrome at the University Hospital of the West Indies and a review of the literature.

Cushing's syndrome is an uncommon but important disease. Twenty-one confirmed cases of spontaneous Cushing's syndrome were documented at the University Hospital of the West Indies over a 21-year period. They were predominantly young females (F:M ratio of 17:4; mean age 25 years and 3 months). The commonest presenting symptoms were amenorrhoea (41%) and obesity (19%). Common clinical features were cushingnoid features (95%), hypertension (76%) and hirsutism (82%). Twenty-nine per cent had frank hyperglycaemia. Cushing's syndrome was due to Cushing's disease in 10 cases, adrenal adenoma in 3 and adrenal carcinoma in 2 cases. In 4 cases with presumed adrenal hyperplasia, the histology was either unavailable or was not consistent with the diagnosis. Two cases appear now to have had the ectopic ACTH Syndrome. Adrenalectomy was the commonest treatment offered. There were no intra-operative or post-operative deaths but recurrence was common after subtotal adrenalectomy in Cushing's disease. Twenty-seven per cent of the patients developed Nelson's syndrome, which was fatal in 50%. Long-term hormone replacement therapy was unnecessary after surgery for adrenal adenomas. Treatment of Cushing's syndrome was well tolerated by the patients.

A clinico-pathological study of Cushing's syndrome at the University Hospital of the West Indies and a review of literature

Cushing's syndrome is an uncommon but important disease. Twenty-one confirmed cases of spontaneous Cuching's syndrome were documented at the University Hospital of the West Indies over a 21-year period. They were predominantly young females (F:M ratio of 17:4; mean age 25 years and three months). The commonest presenting symptoms were amenorrhoea (41 percent) and obesity (19 percent). Common clinical features were cushingnoid features (95 percent), hypertension (76 percent) and hirsutism (82 percent). Twenty-nine per cent had frank hyperglycaemia. Cushing's syndrome was due to Cushing's disease in 10 cases, adrenal adenoma in 3 and adrenal carcinoma in 2 cases. In 4 cases with presumed adrenal hyperplasia, the histology was either unavailable or was not consistent with the diagnosis. Two cases appear now to have had ectopic ACTH syndrome. Adrenalectomy was the commonest treatment offered. There were no intra-operative or post-operative deaths but recurrence was common after subtotal adrenalectomy in Cushing's disease. Twenty-seven per cent of the patients developed Nelson's syndrome, which was fatal in 50 per cent. Long-term hormone replacement therapy was unnecessary after surgery for adrenal adenomas. Treatment of Cushing's syndrome was well tolerated by the patients. (AU)

A clinico-pathological study of Cushing's syndrome at the University Hospital of the West Indies and a review of the literature

Cushing's syndrome is an uncommon but important disease. Twenty-one confirmed cases of spontaneous Cushing's syndrome were documented at the University Hospital of the West Indies over a 21-year period. They were predominantly young females (F:M ratio of 17:4; mean age 25 years and 3 months). The commonest presenting symptoms were amenorrhoea (41) and obesity (19). Common clinical features were cushingnoid features (95), hypertension (76) and hirsutism (82). Twenty-nine per cent had frank hyperglycaemia. Cushing's syndrome was due to Cushing's disease in 10 cases, adrenal adenoma in 3 and adrenal carcinoma in 2 cases. In 4 cases with presumed adrenal hyperplasia, the histology was either unavailable or was not consistent with the diagnosis. Two cases appear now to have had the ectopic ACTH Syndrome. Adrenalectomy was the commonest treatment offered. There were no intra-operative or post-operative deaths but recurrence was common after subtotal adrenalectomy in Cushing's disease. Twenty-seven per cent of the patients developed Nelson's syndrome, which was fatal in 50. Long-term hormone replacement therapy was unnecessary after surgery for adrenal adenomas. Treatment of Cushing's syndrome was well tolerated by the patients.

A study of patients with Nelson's syndrome.

OBJECTIVE: The prevalence of Nelson's syndrome has varied greatly, at least in part because of the variability of the diagnostic criteria employed by different authors. We define Nelson's syndrome as the presence of an enlarging pituitary tumour associated with elevated fasting plasma ACTH levels and hyperpigmentation in patients with Cushing's disease after bilateral adrenalectomy. We have compared patients with Cushing's disease who developed Nelson's syndrome after bilateral adrenalectomy with those who did not. Our objective was to find differences between the two groups which might predict the development of Nelson's syndrome. PATIENTS AND METHODS: We have reviewed the records of 30 patients with Cushing's disease after adrenalectomy, and divided them into two groups; I: 14 who developed Nelson's syndrome and II, 16 who did not. The two groups of patients were compared in their clinical, laboratory and imaging data as well as in the therapeutic procedures that preceded the adrenalectomy. RESULTS: The comparison between the two groups of patients demonstrated a highly significant difference in relation to the development of cutaneous hyperpigmentation (100% in group I and 19% in group II) and neuro-ophthalmological symptoms (21% in group I and 0% in group II) after adrenalectomy. There were no significant differences in laboratory data before adrenalectomy. After adrenalectomy, plasma ACTH levels increased significantly in the patients of both groups, but to much higher levels in those who developed Nelson's syndrome. Plasma ACTH concentrations above 154 pmol/l occurred only in the subjects with Nelson's syndrome. Before adrenalectomy, a pituitary tumour was more frequent in the patients who developed Nelson's syndrome (55% vs. 33% at transsphenoidal pituitary exploration). Pituitary surgery and irradiation were undertaken before adrenalectomy in approximately equal numbers of patients in each group. DISCUSSION: The prevalence of Nelson's syndrome was 47% in our series of 30 patients with Cushing's disease after bilateral adrenalectomy. No clinical or laboratory data before adrenalectomy predicted the development of the syndrome. The value of prophylactic pituitary irradiation could not be evaluated from our clinical material. However, after adrenalectomy, the presence of hyperpigmentation and ACTH levels above 154 pmol/l had positive predictive value for the development of Nelson's syndrome. In this situation magnetic resonance imaging (MRI) of the pituitary is mandatory and, if no tumour is detected, MRI should be repeated at intervals.