Intracranial desmoplastic small round cell tumor presenting as a suprasellar mass.

Desmoplastic small round cell tumors (DSRCTs) are rare, aggressive neoplasms that typically arise from abdominal and pelvic peritoneum in young adults. Other primary sites are uncommon, and an intracranial origin is exceptionally rare. Here the authors report the first case of a DSRCT presenting as a primary suprasellar tumor causing panhypopituitarism and severe bitemporal hemianopia in a young man. Macroscopic debulking of the tumor was undertaken, and histology revealed features of DSRCT. Reverse transcription polymerase chain reaction confirmed the presence of Ewing's sarcoma-Wilms tumor 1 (EWS-WT1) gene rearrangement specific to DSRCT. Postoperative whole-body imaging showed no primary malignancy elsewhere. The tumor recurred 4 months after surgery, and this was followed by cervical and mediastinal lymph node metastases. The patient died 20 months after initial presentation of rapidly progressive disease. DSRCTs should be included in the differential diagnosis of an unusual suprasellar mass in young adults. Early diagnosis is essential, and once the tumor is identified histologically, gross-total resection and radical postoperative treatment involving radiotherapy, chemotherapy, and close surveillance are required because of the lesion's potential for rapidly progressive malignancy.

Hypothalamic obesity: prevalence, associations and longitudinal trends in weight in a specialist adult neuroendocrine clinic.

OBJECTIVE: Obesity is highly prevalent among adults with acquired, structural hypothalamic damage. We aimed to determine hormonal and neuroanatomical variables associated with weight gain and obesity in patients following hypothalamic damage and to evaluate the impact of early instigation of weight loss measures to prevent or limit the severity of obesity in these patients. DESIGN: Retrospective study of 110 adults with hypothalamic tumours attending a specialist neuroendocrine clinic. BMI was calculated at diagnosis and at last follow-up clinic visit. Endocrine data, procedures, treatments and weight loss measures were recorded and all available brain imaging reviewed. RESULTS: At last follow-up, 82.7% of patients were overweight or heavier (BMI≥25 kg/m(2)), 57.2% were obese (BMI≥30 kg/m(2)) and 14.5% were morbidly obese (BMI≥40 kg/m(2)). Multivariate analysis revealed that use of desmopressin (odds ratio (OR)=3.5; P=0.026), GH (OR=2.7; P=0.031) and thyroxine (OR=3.0; P=0.03) was associated with development of new or worsened obesity. Neuroimaging features were not associated with weight gain. Despite proactive treatments offered in clinic in recent years (counselling, dietetic and physical activity advice, and anti-obesity medications), patients have continued to gain weight. CONCLUSIONS: Despite increased awareness, hypothalamic obesity is difficult to prevent and to treat. Improved understanding of the underlying pathophysiologies and multicentre collaboration to examine efficacy of novel obesity interventions are warranted.

Low prevalence of hypopituitarism after subarachnoid haemorrhage using confirmatory testing and with BMI-specific GH cut-off levels.

OBJECTIVE: Hypopituitarism following subarachnoid haemorrhage (SAH) has been reported to be a frequent occurrence. However, there is considerable heterogeneity between studies with differing patient populations and treatment modalities and most importantly employing differing endocrine protocols and (normal) reference ranges of GH. We aimed to examine prospectively a cohort of SAH survivors for development of hypopituitarism post-SAH using rigorous endocrine testing and compare GH response to glucagon stimulation with a cohort of healthy controls of a similar BMI. DESIGN AND METHODS: Sixty-four patients were investigated for evidence of hypopituitarism 3 months post-SAH with 50 patients tested again at 12 months. Glucagon stimulation testing (GST), with confirmation of deficiencies by GHRH/arginine testing for GH deficiency (GHD) and short synacthen testing for ACTH deficiency, was used. Basal testing of other hormonal axes was undertaken. RESULTS: Mean age of patients was 53±11.7 years and mean BMI was 27.5±5.7 kg/m(2). After confirmatory testing, the prevalence of hypopituitarism was 12% (GHD 10%, asymptomatic hypocortisolaemia 2%). There was no association between hypopituitarism and post-SAH vasospasm, presence of cerebral infarction, Fisher grade, or clinical grading at presentation. There was a significant correlation between BMI and peak GH to glucagon stimulation in both patients and controls. CONCLUSIONS: Identification of 'true' GHD after SAH requires confirmatory testing with an alternative stimulation test and application of BMI-specific cut-offs. Using such stringent criteria, we found a prevalence of hypopituitarism of 12% in our population.

Pituitary adenomas in childhood, adolescence and young adulthood: presentation, management, endocrine and metabolic outcomes.

OBJECTIVE: To elucidate the long-term outcomes of pituitary adenomas diagnosed in childhood and adolescence, knowledge of which remains sparse. DESIGN AND METHODS: A retrospective review of patients aged ≤21 years at diagnosis of pituitary adenoma, attending a neuroendocrine service in Liverpool, UK, between 1984-2009. RESULTS: There were 41 patients (33 female), mean age at diagnosis 17.3 years (range 11-21) and mean follow-up 9.6 years; 29 patients had prolactinomas (15 macroprolactinomas), 6 non-functioning pituitary adenomas (NFPAs), 5 Cushing's disease (CD) and 1 acromegaly. All prolactinoma patients received dopamine agonists (DAs) and three also underwent pituitary surgery. Furthermore, ten patients underwent surgery: five with CD, one with acromegaly and four with NFPA. Four received radiotherapy after surgery. Another ten patients received hormone replacement: nine hydrocortisone, five thyroxine, seven sex steroids and five GH; another seven had severe asymptomatic GH deficiency. Three female patients were treated for infertility (two successfully). Thirteen patients gained significant weight (body mass index (BMI) increase >2 kg/m(2)) since diagnosis and 16 in total are now obese (BMI>30 kg/m(2)). Five were treated with orlistat and one attended a weight management service. Two received antihypertensive medications, two had type 2 diabetes and four were treated for dyslipidaemia. CONCLUSIONS: This is one of the largest reviews of patients aged 21 or younger at diagnosis of pituitary adenoma followed up by a single service. Two-thirds had prolactinomas, all were treated with DAs and three underwent surgery. Increased cardiovascular risk factors (obesity and dyslipidaemia) and infertility are important sequelae and active identification and treatment are necessary.

Inferior petrosal sinus ACTH and prolactin responses to CRH in ACTH-dependent Cushing's syndrome: a single centre experience from the United Kingdom.

Inferior petrosal sinus sampling (IPSS) of ACTH with CRH stimulation helps distinguish pituitary ACTH-dependent Cushing's syndrome from the ectopic ACTH syndrome (EAS). The usefulness of the paradoxical response of other pituitary hormones including prolactin to CRH remains controversial. Data from 33 IPSS procedures carried out at the Walton Centre for Neurology and Neurosurgery in Liverpool were analyzed. Patients were selected for this procedure if they had been diagnosed with ACTH dependent Cushing's syndrome and the majority had no obvious pituitary adenoma on Magnetic Resonance Imaging. Satisfactory simultaneous bilateral catheterization was accomplished in 23/33 (success rate 70%). The diagnostic sensitivity of a basal central/peripheral ACTH ratio >2.0 and >3 post-CRH was 94%. In two patients with subsequently confirmed EAS the maximal central/peripheral ACTH ratio was <2.0 on basal samples and did not change following CRH. The maximal central/peripheral prolactin ratio was noted at 5 min post-CRH, coinciding with the maximal central/peripheral ACTH ratio. The intersinus gradient (ISG) of ACTH was paralleled by a consistent ISG of prolactin and in 7 out of 9 patients (with successful bilateral IPSS and unilateral adenomas) the ISG of prolactin correctly lateralized the microadenoma whereas the ISG of ACTH correctly lateralized in 8 out of 9 patients. Neither of the patients with EAS achieved a central/peripheral prolactin ratio >2 in the basal state and >3 post-CRH. Bilateral catheterization of inferior petrosal sinuses can be successful in up to 70% of cases. Prolactin measurements do not have superior lateralizing capability compared with ACTH but may be useful in the differential diagnosis of pituitary-driven from EAS.

Ablative thyroid treatment for thyrotoxicosis due to thyrotropin-producing pituitary tumours.

Thyrotropin (TSH)-secreting pituitary adenomas (TSHomas) are rare tumours. It has been suggested that thyroid surgery or radioiodine treatment should not be considered in patients with such tumours as these treatments may facilitate rapid tumour expansion. We studied the effects of thyroid ablative treatment on tumour size and thyroid status in two patients with TSHomas. Patients studied were: (1) a female with a TSHoma who declined to undergo pituitary surgery and underwent a total thyroidectomy instead and (2) a male patient who opted for radioiodine treatment for his recurrent TSHoma. Changes in tumour size on serial magnetic resonance imaging scans, and restoration of euthyroidism were studied. No marked changes in tumour size or features of aggressiveness occurred in these patients over periods of 8 and 12 years. Euthyroidism was restored and maintained in both patients. Ablative thyroid treatment can be a safe and successful option to treat TSHomas.

Macroprolactinomas and epilepsy.

OBJECTIVE: To assess the prevalence and characteristics of epilepsy in patients with macroprolactinomas. Secondly, to report the response to dopamine agonist (DA) therapy. PATIENTS: A case note analysis of all patients with a diagnosis of macroprolactinoma attending a neuroendocrine clinic between 1996 and 2006. Those with epilepsy at diagnosis of macroprolactinoma were examined in detail. RESULTS: There were 64 patients with macroprolactinoma and 29 of these had tumours with suprasellar extension compressing/invading the optic apparatus and/or surrounding brain structures. Six of these 29 patients (four men), had a history of seizures at the time of diagnosis, five of whom had features suggestive of temporal lobe epilepsy. None of the other 35 patients had epilepsy. All six patients with epilepsy had invasive prolactinomas on cranial imaging and marked hyperprolactinaemia (median prolactin 369 000 mU/l, range 28 000 to > 750 000). Seizures had been present for a median of 2 years (range 1-23 years) before the diagnosis of macroprolactinoma. A rapid reduction in seizure frequency occurred in all patients with initiation of DA therapy. Four have been seizure-free between 18 months to 15 years despite only small reductions in tumour size. CONCLUSIONS: Invasive macroprolactinomas can commonly be associated with epilepsy, particularly of temporal lobe origin. It is essential to enquire about epileptic symptoms, as the seizure disorder may have been undiagnosed/untreated for years. DA therapy can reduce ictal frequency and the doses of anti-epileptic drugs. Complete freedom from epilepsy can also occur.

Is there a role for ghrelin and peptide-YY in the pathogenesis of obesity in adults with acquired structural hypothalamic damage?

CONTEXT: Obesity is a common sequel to hypothalamic tumors and their treatment, but the underlying mechanisms are not fully established. OBJECTIVE: Our objective was to evaluate the role of ghrelin and peptide-YY (PYY) in human hypothalamic obesity. SETTING: The study took place at a University Medical Center. PARTICIPANTS: Subjects included 14 adult patients (six male, eight female) with tumors of the hypothalamic region and 15 healthy controls (six male and nine female) matched for age, body mass index, and percentage of body fat. INTERVENTIONS: Plasma ghrelin and total PYY were measured using RIAs after an overnight fast and 15, 30, 60, 120, and 180 min after a mixed meal. MAIN OUTCOME MEASURES: We assessed ghrelin, PYY, and appetite ratings. RESULTS: The fall in ghrelin levels after the test meal was similar in the two groups. There was no statistically significant change postprandially in circulating PYY in the patients with hypothalamic damage. Fasting leptin levels and postprandial insulin responses were also similar in the two groups. Patients with hypothalamic damage reported higher hunger ratings at 3 h after the meal (P = 0.01) and a stronger desire to eat at 2 h (P = 0.01) and 3 h (P = 0.02) compared with the control group. CONCLUSIONS: Adult patients with structural hypothalamic damage show impaired satiety, but the changes observed in circulating ghrelin and PYY concentrations in response to a test meal do not indicate a central role for these gut hormones in the control of appetite and the pathogenesis of obesity in these patients.

Endocrine and neuroanatomic features associated with weight gain and obesity in adult patients with hypothalamic damage.

PURPOSE: Obesity is a common consequence in patients with tumors of the hypothalamic region and of related treatment in children. Much less information is available on adult patients and long-term survivors. The aims of this study were to estimate the prevalence of obesity in adult patients with acquired structural hypothalamic damage and to define the characteristics of patients at greatest risk of obesity. METHODS: A retrospective study was conducted of 52 patients (25 women; median age at diagnosis, 44 years; range, 17 to 78 years) with tumors involving the hypothalamic region. These included 22 craniopharyngiomas, 24 pituitary adenomas, and six other hypothalamic tumors. Changes in body mass index were determined, magnetic resonance imaging scans were scored by a radiologist for tumor size and the extent of involvement of the hypothalamus, and current hormone replacement therapy was recorded, to identify possible features associated with new or worsened obesity (defined as a body mass index > or =30 kg/m(2) at the latest follow-up, which had increased by at least 2 kg/m(2) since diagnosis of the tumor). RESULTS: Serial body mass index data from diagnosis to the latest follow-up were available for 42 patients. After a median of 5 years (range, 1 to 19 years) of follow-up, most patients with hypothalamic damage were obese (52% [n = 22] vs. 24% [n = 10] at the time of diagnosis, P < 0.0001). In a multivariate model, use of desmopressin (odds ratio [OR] = 13; 95% confidence interval [CI]: 2.0 to 86; P = 0.007) and growth hormone replacement (OR = 7.6; 95% CI: 1.1 to 51; P = 0.04) were associated with new or worsened obesity during follow-up. No correlation was found between the initial size or location of the tumor and subsequent weight gain. CONCLUSION: Obesity is highly prevalent in adult survivors of hypothalamic tumors. Use of desmopressin and growth hormone therapy, but not size or location of the tumor, were associated with weight gain and obesity following diagnosis. These findings may be helpful in identifying patients at increased risk of obesity, to whom earlier intervention could be offered.

The relationship of ghrelin to biochemical and anthropometric markers of adult growth hormone deficiency.

INTRODUCTION: Ghrelin is the natural ligand of the growth hormone secretagogue receptor (GHS-R) and potently stimulates GH release in humans. Ghrelin is found in the hypothalamus, but most circulating ghrelin is derived from the stomach. Ghrelin stimulates food intake but circulating levels are low in obesity. We hypothesized that GH deficiency (GHD) might be associated with increased circulating ghrelin concentrations as a result of low GH levels. We therefore measured circulating ghrelin concentrations, leptin and body composition in subjects with GHD and healthy controls. METHODS: Subjects with GHD (n = 18) were compared to healthy control subjects (n = 18), matched for body mass index (BMI). They underwent assessment of body composition [waist circumference, BMI and percentage body fat (using bioimpedance)]. Plasma ghrelin, leptin, insulin, GH and IGF-1 were measured in the fasting state. Plasma ghrelin was measured using a specific radioimmunassay, and the other hormones using commercially available assays. RESULTS: The groups were well-matched for BMI (GHD vs. control; 32.9 +/- 10.8 vs. 31.3 +/- 11.7, P = ns) and waist circumference (GHD vs. control; 102.9 +/- 20.0 vs. 99.8 +/- 25.2, P = ns), but percentage body fat (GHD vs. control; 37.0 +/- 9.1 vs. 29.4 +/- 13.0, P = 0.06) tended to be higher in the GHD group. As expected, IGF-1 was lower in GHD (GHD vs. control; 12.5 +/- 6.8 vs. 19.2 +/- 5.8 nmol/l, P = 0.003). Ghrelin [GHD vs. controls; geometric mean (95% CI); 828.8 (95% CI 639.9-1074.2) vs. 487.9 (95% CI 297.2-800.2) pmol/l] and leptin [GHD vs. controls; 13.2 (95% CI 6.6-26.5) vs. 7.9 (95% CI 3.7-16.9) ng/ml] were similar in the two groups. Plasma ghrelin correlated inversely with waist circumference and waist hip ratio in GHD subjects (r = -0.6, P = 0.02) but not with IGF-1 or GH concentrations. There was no significant correlation in the control subjects. CONCLUSION: Circulating ghrelin concentrations are influenced by body fat distribution, but not by levels of either GH or IGF-1. However, given that obesity is associated with reduced ghrelin concentrations and that GHD is commonly associated with increased body fat, it is possible that these two opposing influences on circulating ghrelin levels result in normal concentrations in subjects with GHD.