Epidemiology and mortality of Cushing's syndrome.

Endogenous Cushing's syndrome (CS) is a rare endocrine disorder characterised by excess cortisol secretion due to either ACTH-dependent conditions [commonly an ACTH-producing pituitary adenoma (Cushing's disease)] or ACTH-independent causes (with most common aetiology being a benign adrenal adenoma). Overall, the annual incidence of CS ranges between 1.8 and 3.2 cases per million population. Mortality in active CS is elevated compared to the general population, and a number of studies support the view that survival is also compromised even after apparent successful treatment. The main cause of death is cardiovascular disease highlighting the negative impact of cortisol excess on cardiovascular risk factors. Early diagnosis and prompt treatment of the cortisol excess, as well as vigilant monitoring and stringent control of cardiovascular risk factors are key elements for the long-term prognosis of these patients.

Comorbidities in Cushing's disease.

INTRODUCTION: Cushing's disease is a rare disorder characterized by overproduction of ACTH from a pituitary adenoma leading to hypercortisolemia that in turn leads to increased morbidity and mortality. METHODS: Here we review the comorbidities associated with Cushing's disease and their impact on quality of life and mortality. RESULTS: Recent evidence suggests that correction of hypercortisolemia may not lead to complete resolution of comorbidities associated with this condition. In particular, increased cardiovascular risk may persist despite long-term remission of hypercortisolemia. This may be related to persistence of visceral adiposity, adverse adipokine profile, glucose intolerance, hypertension, dyslipidemia, atherosclerosis and a procoagulant phenotype. Prior prolonged exposure to glucocorticoids also may have irreversible effects on the central nervous system, leading to persistent cognitive and mood alterations. Osteoporosis and fractures, especially vertebral fractures, can further add to morbidity and a poor quality of life. Normalization of cortisol levels leads to significant improvement in comorbidities but long-term data regarding complete resolution are lacking and need further study. CONCLUSION: Early diagnosis and treatment of hypercortisolemia, aggressive management of comorbidities along with long-term follow-up is crucial for the optimal recovery of these patients.

Clinical and biochemical manifestations of Cushing's.

INTRODUCTION: Cushing's syndrome is associated with a number of clinical manifestations and co-morbidities which may not resolve even after long-term remission leading to excessive mortality. MATERIALS AND METHODS: This review summarizes the main manifestations of Cushing's syndrome (active or in remission) with particular focus on data from recently published literature. CONCLUSION: Obesity and metabolic alterations, hypertension and cardio/cerebrovascular complications, hypercoagulability/thromboembolism, neuropsychiatric, muscle/skeletal and immune consequences remain the most challenging. Cardiovascular consequences and immunosuppression determine the main causes of death in Cushing's syndrome necessitating early intervention when possible.

Cushing's disease: a single centre's experience using the linear accelerator (LINAC) for stereotactic radiosurgery and fractionated stereotactic radiotherapy.

Cushing's disease is hypercortisolaemia secondary to an adrenocorticotrophic hormone secreting pituitary adenoma. Primary management is almost always surgical, with limited effective medical interventions available. Adjuvant therapy in the form of radiation is gaining popularity, with the bulk of the literature related to the Gamma Knife. We present the results from our own institution using the linear accelerator (LINAC) since 1990. Thirty-six patients who underwent stereotactic radiosurgery (SRS), one patient who underwent fractionated stereotactic radiotherapy (FSRT) and for the purposes of comparison, 13 patients who had undergone conventional radiotherapy prior to 1990, were included in the analysis. Serum cortisol levels improved in nine of 36 (25%) SRS patients and 24 hour urinary free cortisol levels improved in 13 of 36 patients (36.1%). Tumour volume control was excellent in the SRS group with deterioration in only one patient (3%). The patient who underwent FSRT had a highly aggressive tumour refractory to radiation.

Predictors of mortality and long-term outcomes in treated Cushing's disease: a study of 346 patients.

CONTEXT: Active Cushing's disease (CD) confers a 4-fold increase in mortality and is associated with significant morbidities. Although excess mortality risk may persist even after CD treatment, predictors of risk in treated CD are not well understood. OBJECTIVE: To identify predictors of mortality, cardiovascular (CV) disease, and recurrence after long-term follow-up among patients with treated CD. DESIGN, SETTING, AND PATIENTS: A retrospective chart review was conducted to evaluate patients with CD who underwent transsphenoidal adenectomy with a single surgeon. OUTCOME MEASURES: Patients were categorized based on disease response after initial treatment. Cox proportional hazard models identified predictors of mortality, recurrence, and CV outcomes in the overall cohort and each subgroup. RESULTS: Three hundred forty-six subjects were included. Mean age was 39.9 years, and mean duration of follow-up was 6.3 years (range, 1 mo to 30 y). Duration of exposure to excess glucocorticoids, estimated by duration of symptoms before diagnosis until remission was achieved by any means, was 40.0 months. Multivariate analyses demonstrated that duration of glucocorticoid exposure elevated the risk of death (P = .038), as did older age at diagnosis (P = 0.0001) and preoperative ACTH concentration (P = .007). Among patients who achieved remission, depression increased the hazard of death (P < .01). Male sex, age at diagnosis, diabetes, and depression elevated the risk of CV disease (P < .05). CONCLUSION: Long-term follow-up of a large cohort of treated patients with CD identified several novel predictors of mortality. These data illustrate the importance of early recognition and treatment of CD. Long-term follow-up, with management of persistent comorbidities, is needed even after successful treatment of CD.

Excess mortality for patients with residual disease following resection of pituitary adenomas.

The importance of achieving tumor control in pituitary adenoma surgery is not entirely established. This manuscript reviews the literature linking residual pituitary tumor and hormonal hypersecretion to increases in long term mortality. When possible, we utilized meta-analysis methods to estimate a pooled standardized mortality ratio (SMR), which relates the risk of mortality for a cohort of patients compared to a similar age and gender matched cohort in the general population, for patients with endocrinologic evidence of residual disease. When this was not possible, we review the existing literature in the results and discussion section of this review. We identified 10 articles regarding acromegaly and three articles regarding Cushing's disease which presented SMR data for adult patients undergoing transphenoidal surgery with data divided into subgroups based on post-operative growth hormone levels. Using growth hormone levels of 2.5 µg/l as a cutoff, the mortality rate ratio was 1.83 (95% CI = 1.03-3.24) for patients with persistent acromegaly. Similarly, patients with persistent Cushing's disease experienced a marked increase in mortality rate ratio compared to those experiencing initial cure (mortality rate ratio = 3.25 (95% CI = 1.54-6.84). For other tumor subtypes, (i.e. Endocrine inactive adenomas, Prolactinomas, and TSH secreting tumors) there were not enough studies identified to allow for rigorous statistical analysis. There is an increasing body of data suggesting that treatment refractory acromegaly and Cushing's disease puts patients at risk for early mortality, suggesting that aggressive efforts to normalize hormone levels in these patients are justified.

Mortality and morbidity in Cushing's disease over 50 years in Stoke-on-Trent, UK: audit and meta-analysis of literature.

CONTEXT: Pituitary ACTH-dependent Cushing's disease (CD) is uncommon, and there are very limited data on long-term mortality. OBJECTIVE: The aim was to summarize what is known about mortality in ACTH-dependent CD, to report on our own data, and to provide a meta-analysis of six other reports that addressed mortality of CD. DESIGN AND METHODS: Vital status of 60 CD patients was recorded as of December 31, 2009, and the standardized mortality ratio (SMR) was calculated and compared with the general population of England and Wales, United Kingdom. A meta-analysis of SMRs from seven studies (including ours) was performed for overall mortality in CD. Where reported (four studies), a similar meta-analysis was performed for those patients whose hypercortisolism was in remission after treatment compared to those patients from the same center with persistent disease. RESULTS: 1. From Stoke-on-Trent, 51 of 60 patients were female, median age at diagnosis was in the range of 36-46 yr, and median follow-up was 15 yr. There were 13 deaths, nine due to cardiovascular disease. Overall SMR for the whole cohort was 4.8 (95% confidence interval, 2.8-8.3) (P < 0001). SMR for vascular disease was 13.8 (7.2-36.5) (P < 0001). For persistent disease (n = 6), SMR was 16 (6.7-38.4) vs. remission (n = 54) SMR of 3.3 (1.7-6.7); after adjustment for age and sex, relative risk of death for persistent disease was 10.7 (2.3-48.6) (P = 0.002). Hypertension and diabetes mellitus were associated with significantly worse survival. 2. Using a random effects model meta-analysis revealed an overall (remission plus persistent disease) SMR of 2.2 (1.45-3.41) (P < 0.001). Pooled SMR was 1.2 (0.45-3.2) (P = not significant) for patients in remission and 5.5 (2.7-11.3) (P = 0.001) for patients with persistent disease. Persistence of disease, older age at diagnosis, and presence of hypertension and diabetes are the main determinants of mortality. CONCLUSIONS: Overall mortality in CD is double that of the general population. However, patients with CD in remission fare much better than those with persistence of hypercortisolism, and they appear not to have an increased mortality rate. Hypertension and diabetes mellitus are risk factors for worse outcome. Because diagnosis and treatment of patients are at a young age, much longer follow-up of patients in remission is required before one can be confident that their mortality outcome is no different from that of the general population, especially because cardiovascular risk factors may persist after successful biochemical control of the disease.

ACTH-producing carcinoma of the pituitary with refractory Cushing's Disease and hepatic metastases: a case report and review of the literature.

BACKGROUND: Pituitary carcinomas are rare neuroendocrine tumors affecting the adenohypophysis. The hallmark of these lesions is the demonstration of distant metastatic spread. To date, few well-documented cases have been reported in the literature. CASE PRESENTATION: Here, we report the case of a fatal pituitary carcinoma evolving within two years from an adrenocorticotrophic hormone (ACTH)-secreting macroadenoma and review the global literature regarding this rare neuroendocrine tumor. CONCLUSION: Pituitary carcinomas are extremely rare neoplasms, representing only 0.1% to 0.2% of all pituitary tumors. To date, little is understood about the molecular basis of malignant transformation. The latency period between initial presentation of a pituitary adenoma and the development of distal metastases marking carcinoma is extremely variable, and some patients may live well over 10 years with pituitary carcinoma.