Long-term outcomes of children treated for Cushing's disease: a single center experience.

PURPOSE: Pediatric Cushing's disease (CD) is rare and there are limited data on the long-term outcomes. We assessed CD recurrence, body composition, pituitary function and psychiatric comorbidity in a cohort of pediatric CD patients. METHODS: Retrospective review of 21 CD patients, mean age at diagnosis 12.1 years (5.7-17.8), managed in our center between 1986 and 2010. Mean follow-up from definitive treatment was 10.6 years (2.9-27.2). RESULTS: Fifteen patients were in remission following transsphenoidal surgery (TSS) and 5 were in remission following TSS + external pituitary radiotherapy (RT). One patient underwent bilateral adrenalectomy (BA). CD recurrence occurred in 3 (14.3 %) patients: 2 at 2 and 6 years after TSS and 1 7.6 years post-RT. The BA patient developed Nelson's syndrome requiring pituitary RT 0.6 years post-surgery. Short-term growth hormone deficiency (GHD) was present in 14 patients (81 % patients tested) (11 following TSS and 3 after RT) and 4 (44 % of tested) had long-term GHD. Gonadotropin deficiency caused impaired pubertal development in 9 patients (43 %), 4 requiring sex steroid replacement post-puberty. Four patients (19 %) had more than one pituitary hormone deficiency, 3 after TSS and 1 post-RT. Five patients (24 %) had long-term psychiatric co-morbidities (cognitive dysfunction or mood disturbance). There were significant long-term improvements in growth, weight and bone density but not complete reversal to normal in all patients. CONCLUSIONS: The long-term consequences of the diagnosis and treatment of CD in children is broadly similar to that seen in adults, with recurrence of CD after successful treatment uncommon but still seen. Pituitary hormone deficiencies occurred in the majority of patients after remission, and assessment and appropriate treatment of GHD is essential. However, while many parameters improve, some children may still have mild but persistent defects.

Long-term remission and recurrence rates in Cushing's disease: predictive factors in a single-centre study.

OBJECTIVE: To investigate the early and late outcomes of patients with Cushing's disease (CD) submitted to a neurosurgical procedure as first-line treatment. DESIGN: In this single-centre retrospective case notes study, 131 patients with CD with a minimum follow-up period of 6 years (124 operated by transsphenoidal surgery (TSS) and seven by the transcranial approach) were studied. Apparent immediate cure: post-operative 0900 h serum cortisol level <50 nmol/l; remission: cortisol insufficiency or restoration of 'normal' cortisol levels with resolution of clinical features; and recurrence: dexamethasone resistance and relapse of hypercortisolaemic features. RESULTS: In patients operated by TSS, remission of hypercortisolaemia was found in 72.8% of 103 microadenomas and 42.9% of 21 macroadenomas, with recurrence rates 22.7 and 33.3% respectively with a 15-year mean follow-up (range, 6-29 years). Of 27 patients with microadenomas operated after 1991, with positive imaging and pathology, 93% obtained remission with 12% recurrence. In multivariate analysis, the time needed to achieve recovery of hypothalamo-pituitaryadrenal axis was the only significant predictor of recurrence; all patients who recurred showed recovery within 3 years from surgery: 31.3% of patients had total hypophysectomy with no recurrence; 42% of patients with selective adenomectomy and 26.5% with hemi-hypophysectomy showed recurrence rates of 31 and 13% respectively (χ(2)=6.275, P=0.03). Strict remission criteria were not superior in terms of the probability of recurrence compared with post-operative normocortisolaemia. CONCLUSIONS: Lifelong follow-up for patients with CD appears essential, particularly for patients who have shown rapid recovery of their axis. The strict criteria previously used for 'apparent cure' do not appear to necessarily predict a lower recurrence rate.

Diagnosis and treatment of Cushing's disease in children.

Cushing's disease (CD) is rare in the paediatric age range, but presents a diagnostic and therapeutic challenge. Most paediatric endocrinologists have limited experience managing children or adolescents with CD and thus benefit from close consultation with adult colleagues. A diagnostic protocol for investigation is required which broadly follows the model for adult patients. Treatment strategies for CD are described and critically appraised. The management of paediatric CD patients after cure also presents challenges for optimizing growth, bone health, reproduction and body composition from childhood into and during adult life.

Recurrent pituitary ependymoma: a complex clinical problem.

Ependymomas rarely arise from the region of the pituitary fossa, with only four cases previously reported in the literature. We present a complex case of a recurrent ependymoma of the parasellar region which has been difficult to clinically manage due to its tendency to recurrence. Our patient has had four operations over the last 28 years, with external beam radiotherapy, but still has residual tumor and is currently panhypopituitary and with significant visual loss. We believe there is considerable uncertainty as to the optimal management of any future progression, which seems likely, and are currently considering the use of radiosurgery with careful sparing of the optic chiasm, or possibly the chemotherapeutic agent temozolomide. Our case emphasises the recurrent nature of this rare but difficult tumor.

Factors influencing cure by transsphenoidal selective adenomectomy in paediatric Cushing's disease.

OBJECTIVE: Early diagnosis and effective treatment of paediatric Cushing's disease (CD) is necessary to minimise associated morbidity. Accepted first-line treatment is selective transsphenoidal microadenomectomy (TSS), which can be technically difficult, and cure rates vary considerably between centres. In our paediatric CD patient group we have assessed the possible factors which may influence cure by TSS. SUBJECTS AND METHODS: From 1983-2004, 27 paediatric patients (16 males, 11 females; mean age+/-s.d., 13.1+/-3.2 yr; range, 6.4-17.8 yr) with CD were managed in our centre and underwent TSS. Sixteen patients (59%), seven males and nine females (mean age+/-s.d., 14.2+/-2.5 yr; range, 8.2-17.8 yr), were cured (post-operative serum cortisol < 50 nM). Eleven patients, nine males and two females (mean age+/-s.d., 11.5+/-3.6 yr; range, 6.4-17.8 yr) had post-operative cortisol levels above 50 nM (2-20 days), with mean serum cortisol levels at 09:00 h of 537 nM (range 269-900 nM) indicating a lack of cure. These 11 patients received external beam pituitary radiotherapy (RT). One patient with a pituitary macroadenoma had a post-operative cortisol level of < 50 nM but 0.8 yr later showed an elevated cortisol and residual disease. RESULTS: The patients cured by TSS alone were significantly older than those not cured (P = 0.038; Student's t test). All patients had CT/MRI pituitary imaging: 14 were reported to have microadenomas and one macroadenoma, while 12 were reported as normal. Bilateral simultaneous inferior petrosal sinus sampling (BSIPSS) with i.v. corticotropin-releasing hormone (CRH) administration was introduced as a pre-operative investigation in 1986 and was performed in 21 patients (78%), on BSIPSS, 16 (76%) had evidence suggesting pituitary adrenocorticotropic hormone (ACTH) secretion (central to peripheral (IPS:P) ACTH ratio after CRH of > or = 3.0) and 16 (76%) showed lateralisation of ACTH secretion (IPSG of > or = 1.4). There was concordance between the BSIPSS finding and the position of the microadenoma at surgery in 17/21 (81%) patients. Of the 16 patients showing lateralisation of ACTH secretion, 12 (75%) were cured by TSS. Of the four without lateralisation of ACTH, suggesting a midline lesion, 3 (75%) were cured by TSS. Post-operative pituitary hormone deficiencies in the patients cured by TSS were: pan-hypopituitarism 1/16, isolated growth hormone deficiency (GHD) (peak GH on glucagon/ITT < 1-17.9 mU/l) 9/16 and diabetes insipidus 3/16. CONCLUSION: Over a 21-year period selective adenomectomy by TSS cured 59% of all paediatric CD patients, with higher age favouring cure. Introduction of BSIPSS resulted in the demonstration of a high rate of lateralisation of ACTH secretion consistent with the surgical identification of the adenoma, and therefore appears likely to have contributed to the higher surgical cure rate.

Clinical and endocrine responses to pituitary radiotherapy in pediatric Cushing's disease: an effective second-line treatment.

Transsphenoidal surgery (TSS) is considered first-line treatment for Cushing's disease (CD). Options for treatment of postoperative persisting hypercortisolemia are pituitary radiotherapy (RT), repeat TSS, or bilateral adrenalectomy. From 1983 to 2001, we treated 18 pediatric patients (age, 6.4-17.8 yr) with CD. All underwent TSS, and 11 were cured (postoperative serum cortisol, <50 nM). Seven (39%) had 0900-h serum cortisol of 269-900 nM during the immediate postoperative period (2-20 d), indicating lack of cure. These patients (6 males and 1 female; mean age, 12.8 yr; range, 6.4-17.8 yr; 4 prepubertal; 3 pubertal) received external beam RT to the pituitary gland, using a 6-MV linear accelerator, with a dose of 45 Gy in 25 fractions over 35 d. Until the RT became effective, hypercortisolemia was controlled with ketoconazole (dose, 200-600 mg/d) (n = 4) and metyrapone (750 mg-3 g/d) +/- aminoglutethimide (1 g/d) or o'p'DDD (mitotane, 3 mg/d) (n = 3). All patients were cured after pituitary RT. The mean interval from RT to cure (mean serum cortisol on 5-point day curve, <150 nM) was 0.94 yr (0.25-2.86 yr). Recovery of pituitary-adrenal function (mean cortisol, 150-300 nM) occurred at mean 1.16 yr (0.40-2.86 yr) post RT. At 2 yr post RT, puberty occurred early in one male patient (age, 9.8 yr) but was normal in the others. GH secretion was assessed at 0.6-2.5 yr post RT in all patients: six had GH deficiency (peak on glucagon/insulin provocation, <1.0-17.9 mU/liter) and received human GH replacement. Follow-up of pituitary function 7.6 and 9.5 yr post RT in two patients showed normal gonadotropin secretion and recovery of GH peak to 29.7 and 19.2 mU/liter. The seven patients were followed for mean 6.9 yr (1.4-12.0 yr), with no evidence of recurrence of CD. In conclusion, pituitary RT is an effective and relatively rapid-onset treatment for pediatric CD after failure of TSS. GH deficiency occurred in 86% patients. Long-term follow-up suggests some recovery of GH secretion and preservation of other anterior pituitary function.