National UK guidelines for the management of paediatric craniopharyngioma.

Although rare, craniopharyngiomas constitute up to 80% of tumours in the hypothalamic-pituitary region in childhood. Despite being benign, the close proximity of these tumours to the visual pathways, hypothalamus, and pituitary gland means that both treatment of the tumour and the tumour itself can cause pronounced long-term neuroendocrine morbidity against a background of high overall survival. To date, the optimal management strategy for these tumours remains undefined, with practice varying between centres. In light of these discrepancies, as part of a national endeavour to create evidence-based and consensus-based guidance for the management of rare paediatric endocrine tumours in the UK, we aimed to develop guidelines, which are presented in this Review. These guidelines were developed under the auspices of the UK Children's Cancer and Leukaemia Group and the British Society for Paediatric Endocrinology and Diabetes, with the oversight and endorsement of the Royal College of Paediatrics and Child Health using Appraisal of Guidelines for Research & Evaluation II methodology to standardise care for children and young people with craniopharyngiomas.

Hypothalamic-Pituitary Outcome after Treatment for Childhood Craniopharyngioma.

Although childhood-onset craniopharyngioma is a low-grade intracranial tumor with excellent prognosis in terms of overall survival, survivors may suffer from devastating consequences caused by hypothalamic damage. Disease- or treatment-related hypothalamic damage leads to disturbed hunger-satiety and thirst feelings, decreased energy expenditure, behavioral problems, disturbances of circadian rhythm, temperature dysregulation, and pituitary dysfunction. These children are at great risk for developing the metabolic syndrome and comorbidities leading to premature mortality. In this chapter, we shall discuss hypothalamic-pituitary morbidity and outcome of childhood-onset craniopharyngioma patients and future perspectives for improvement.

Recovery of hypothalamus-pituitary-gonadal dysfunction after the treatment of suprasellar germ cell tumors.

OBJECTIVE: To investigate the incidence of hypothalamus-pituitary-gonadal (HPG) axis initiation/recovery after treatment and to identify predictive risk factors for noninitiation/recovery. METHODS: A total of 127 consecutive suprasellar germ cell tumor (GCT) patients managed at Peking Union Medical College Hospital (2006-2019) were retrospectively analyzed. Prepubertal patients (followed up until 13 years of age for girls and 14 years of age for boys) and patients with HPG dysfunction (followed up for 2 years) were divided into the initiation/recovery and noninitiation/recovery groups. RESULTS: Of the 127 suprasellar GCT patients, 75 met the follow-up criteria, 28 (37.3%) of whom experienced HPG axis initiation/recovery. Compared to the noninitiation/recovery group, the initiation/recovery group included more males and had shorter delayed diagnosis times, smaller tumor sizes, lower panhypopituitarism rates, thinner pituitary stalk widths, lower visual deficit rates, and higher serum testosterone and estradiol levels. The cutoff values of pituitary stalk width, tumor size, and delayed diagnosis time used to predict noninitiation/recovery were 6.9 mm, 6.9 mm and 1.7 years, respectively. Tumor size ≥6.9 mm (odds ratio (OR) = 7.5, 95% CI: 2.2-25.8, P = 0.001), panhypopituitarism (OR = 5.0, 95% CI: 1.4-17.6, P = 0.013), and delayed diagnosis time ≥1.7 years (OR = 5.7, 95% CI: 1.5-20.7, P = 0.009) were risk factors for noninitiation/recovery. CONCLUSIONS: Among suprasellar GCT patients, nearly one-third of prepubertal patients and patients with HPG dysfunction experience HPG axis initiation/recovery after treatment. Tumor size ≥6.9 mm, panhypopituitarism, and delayed diagnosis time ≥1.7 years were identified as predictive risk factors for noninitiation/recovery.

Ayurvedic Management of Hyperprolactinemia Secondary to Pituitary Microadenoma: A Case Report.

Hyperprolactinemia is a relatively common diagnosis to be expected in an adolescent age group with chronic menstrual disturbances. The present case report documents the efficacy of Ayurvedic management in a 21-year-old female with secretory pituitary microadenoma, which was found to be responsible for menstrual disturbances. The patient, with high prolactin levels with pituitary microadenoma, was subjected to an Ayurvedic management protocol, including Shamana nasya for 7 days followed by Shamana Cikitsa for 3 months. Patient follow-up was 6 months in duration. The clinical presentation of this case points towards the diagnosis of Asrgdara in Ayurveda. This is the first such case documented where Ayurveda was used as the intervention in a case of pituitary microadenoma with hyperprolactinemia, resulting in the complete absence of microadenoma and normalization of the prolactin level.

Antibodies Against Hypothalamus and Pituitary Gland in Childhood-Onset Brain Tumors and Pituitary Dysfunction.

Purpose: To detect the presence of antipituitary (APA) and antihypothalamus antibodies (AHA) in subjects treated for brain cancers, and to evaluate their potential association with pituitary dysfunction. Methods: We evaluated 63 patients with craniopharyngioma, glioma, and germinoma treated with surgery and/or radiotherapy and/or chemotherapy at a median age of 13 years. Forty-one had multiple pituitary hormone deficiencies (MPHD), six had a single pituitary defect. GH was the most common defect (65.1%), followed by AVP (61.9%), TSH (57.1%), ACTH (49.2%), and gonadotropin (38.1%). APA and AHA were evaluated by simple indirect immunofluorescence method indirect immunofluorescence in patients and in 50 healthy controls. Results: Circulating APA and/or AHA were found in 31 subjects (49.2%) and in none of the healthy controls. In particular, 25 subjects out of 31 were APA (80.6%), 26 were AHA (83.90%), and 20 were both APA and AHA (64.5%). Nine patients APA and/or AHA have craniopharyngioma (29%), seven (22.6%) have glioma, and 15 (48.4%) have germinoma. Patients with craniopharyngioma were positive for at least one antibody in 39.1% compared to 33.3% of patients with glioma and to 78.9% of those with germinoma with an analogous distribution for APA and AHA between the three tumors. The presence of APA or AHA and of both APA and AHA was significantly increased in patients with germinoma. The presence of APA (P = 0.001) and their titers (P = 0.001) was significantly associated with the type of tumor in the following order: germinomas, craniopharyngiomas, and gliomas; an analogous distribution was observed for the presence of AHA (P = 0.002) and their titers (P = 0.012). In addition, we found a significant association between radiotherapy and APA (P = 0.03). Conclusions: Brain tumors especially germinoma are associated with the development of hypothalamic-pituitary antibodies and pituitary defects. The correct interpretation of APA/AHA antibodies is essential to avoid a misdiagnosis of an autoimmune infundibulo-neurohypophysitis or pituitary hypophysitis in patients with germinoma.

Surgery as a Viable Alternative First-Line Treatment for Prolactinoma Patients. A Systematic Review and Meta-Analysis.

CONTEXT: The improved remission and complication rates of current transsphenoidal surgery warrant reappraisal of the position of surgery as a viable alternative to dopamine agonists in the treatment algorithm of prolactinomas. OBJECTIVE: To compare clinical outcomes after dopamine agonist withdrawal and transsphenoidal surgery in prolactinoma patients. METHODS: Eight databases were searched up to July 13, 2018. Primary outcome was disease remission after drug withdrawal or surgery. Secondary outcomes were biochemical control and side effects during dopamine agonist treatment and postoperative complications. Fixed- or random-effects meta-analysis was performed to estimate pooled proportions. Robustness of results was assessed by sensitivity analyses. RESULTS: A total of 1469 articles were screened: 55 (10 low risk of bias) on medical treatment (n = 3564 patients) and 25 (12 low risk of bias) on transsphenoidal surgery (n = 1836 patients). Long-term disease remission after dopamine agonist withdrawal was 34% (95% confidence interval [CI], 26-46) and 67% (95% CI, 60-74) after surgery. Subgroup analysis of microprolactinomas showed 36% (95% CI, 21-52) disease remission after dopamine agonist withdrawal, and 83% (95% CI, 76-90) after surgery. Biochemical control was achieved in 81% (95% CI, 75-87) of patients during dopamine agonists with side effects in 26% (95% CI, 13-41). Transsphenoidal surgery resulted in 0% mortality, 2% (95% CI, 0-5) permanent diabetes insipidus, and 3% (95% CI, 2-5) cerebrospinal fluid leakage. Multiple sensitivity analyses yielded similar results. CONCLUSIONS: In the majority of prolactinoma patients, disease remission can be achieved through surgery, with low risks of long-term surgical complications, and disease remission is less often achieved with dopamine agonists.

Pediatric pituitary adenomas.

BACKGROUND: Pediatric pituitary adenomas are a rare medical entity that makes up a small portion of intracranial tumors in children and adolescents. Although benign, the majority of these lesions are secreting functional tumors with the potential for physiological sequela that can profoundly affect a child's development. FOCUS OF REVIEW: In this review, we discuss the medical and surgical management of these tumors with a focus on clinical presentation, diagnostic identification, surgical approach, and associated adjuvant therapies. We will also discuss our current treatment paradigm using endoscopic, open, and combined approaches to treat these tumors. The management of pituitary tumors requires a multidisciplinary team of surgeons, endocrinologists, and neuroanesthesiologists as well as neurocritical care specialists to deliver comprehensive care.

Craniopharyngioma: a roadmap for scientific translation.

OBJECTIVE Craniopharyngiomas are among the most challenging of intracranial tumors to manage because of their pattern of growth, associated morbidities, and high recurrence rate. Complete resection on initial encounter can be curative, but it may be impeded by the risks posed by the involved neurovascular structures. Recurrent craniopharyngiomas, in turn, are frequently refractory to additional surgery and adjuvant radiation or chemotherapy. METHODS The authors conducted a review of primary literature. RESULTS Recent advances in the understanding of craniopharyngioma biology have illuminated potential oncogenic targets for pharmacotherapy. Specifically, distinct molecular profiles define two histological subtypes of craniopharyngioma: adamantinomatous and papillary. The discovery of overactive B-Raf signaling in the adult papillary subtype has led to reports of targeted inhibitors, with a growing acceptance for refractory cases. An expanding knowledge of the biological underpinnings of craniopharyngioma will continue to drive development of targeted therapies and immunotherapies that are personalized to the molecular signature of each individual tumor. CONCLUSIONS The rapid translation of genomic findings to medical therapies for recurrent craniopharyngiomas serves as a roadmap for other challenging neurooncological diseases.

Leptin Involvement in Primary Brain and Pituitary Tumors: Therapeutic Potential, Prognostic Value, and Proposed Diagnostic Application.

Brain tumors are associated with increased mortality and morbidity and are the most common cancer type in children and young adults. The present review focuses on the interplay between leptin, the most extensively studied adipokine, and the onset, development, and treatment of primary brain and intracranial tumors. The two main mechanisms for increased leptin levels in intracranial tumor survivors, leptin resistance caused by hypothalamic damage, or secondary to obesity, are discussed. The contradicting mechanistic observations on leptin being able to both promote tumorinogenesis (e.g., in gliomas) as well as inhibit it (e.g., in adenomas) are also reported. Additionally, the relevant current and future clinical applications, including most notably the proposed use of serum leptin measurements for non-invasive brain tumor diagnostics, are also reported.

Pituitary Metastasis from Renal Cell Carcinoma: Description of a Case Report.

BACKGROUND Pituitary metastasis is uncommon, breast and lung cancers being the most frequent primary tumors. Renal cell carcinoma (RCC) is a rare cause of pituitary metastases, with only a few cases described to date. CASE REPORT We report a case of a 61-year-old man who presented with a progressive deterioration of visual acuity and field associated with a bitemporal hemianopsia. Two years ago, he underwent radical right nephrectomy for a clear cell RCC (ccRCC). The biological tests showed pan-hypopituitarism and diabetes insipidus. Brain MRI revealed a large sellar tumor lesion bilaterally infiltrating the cavernous sinuses, which was surgically resected. Histology confirmed a ccRCC pituitary metastasis. The patient received post-surgical radiotherapy. Considering the presence of concomitant extra-pituitary metastases, treatment with sunitinib was started, followed by several lines of therapy with axitinib, everolimus, and sorafenib because of tumor progression. The patient also presented with a pituitary tumor recurrence, which was treated by stereotaxic radiotherapy. He died five years after the initial diagnosis of RCC and 30 months after the diagnosis of the pituitary metastasis.  CONCLUSIONS There are no standardized treatment guidelines for management of pituitary metastases. Pituitary surgery plays a role in symptom palliation, and it does not have any relevant impact on survival. Exclusive radiotherapy or stereotaxic radiotherapy could be an alternative to surgery in patients whose general condition is poor or who have concomitant extra-pituitary metastases.

Investigating the Role of Hypothalamic Tumor Involvement in Sleep and Cognitive Outcomes Among Children Treated for Craniopharyngioma.

OBJECTIVE: Despite excellent survival prognosis, children treated for craniopharyngioma experience significant morbidity. We examined the role of hypothalamic involvement (HI) in excessive daytime sleepiness (EDS) and attention regulation in children enrolled on a Phase II trial of limited surgery and proton therapy. METHODS: Participants completed a sleep evaluation (N = 62) and a continuous performance test (CPT) during functional magnetic resonance imaging (fMRI; n = 29) prior to proton therapy. RESULTS: EDS was identified in 76% of the patients and was significantly related to increased HI extent (p = .04). There was no relationship between CPT performance during fMRI and HI or EDS. Visual examination of group composite fMRI images revealed greater spatial extent of activation in frontal cortical regions in patients with EDS, consistent with a compensatory activation hypothesis. CONCLUSION: Routine screening for sleep problems during therapy is indicated for children with craniopharyngioma, to optimize the timing of interventions and reduce long-term morbidity.

Risk-adapted treatment and follow-up management in childhood-onset craniopharyngioma.

Craniopharyngiomas are rare embryonic malformations of the sellar/parasellar region with low histological grade. Here, we review findings on the diagnosis, treatment, clinical course, follow-up, and prognosis of craniopharyngioma patients. Clinical manifestations develop from increased intracranial pressure, anterior visual pathway damage, and hypothalamic/pituitary deficiencies. If the tumor is favorably localized (no anatomical involvement with the hypothalamic and optical structures) therapy of choice is complete resection, meticulously performed to preserve hypothalamic and optic functions. In patients with unfavorable tumor involvement, optimal therapy is limited hypothalamus-sparing surgical strategy, followed by judicious irradiation dosage to minimize recurrences and progression. Surgical lesions and/or anatomical involvement of posterior hypothalamic areas result in serious sequelae, mainly hypothalamic syndrome. Craniopharyngioma is a chronic disease and must be managed as such, providing ongoing care of pediatric and adult patients by experienced multidisciplinary teams in the context of multicenter trials.

Somatostatin Analogue Treatment of a TSH-Secreting Adenoma Presenting With Accelerated Bone Metabolism and a Pericardial Effusion: A Case Report.

Increased bone turnover and other less frequent comorbidities of hyperthyroidism, such as heart failure, have only rarely been reported in association with central hyperthyroidism due to a thyrotropin (TSH)-secreting pituitary adenoma (TSHoma). Treatment is highly empirical and relies on eliminating the tumor and the hyperthyroid state.We report here an unusual case of a 39-year-old man who was initially admitted for management of pleuritic chest pain and fever of unknown origin. Diagnostic work up confirmed pericarditis and pleural effusion both refractory to treatment. The patient had a previous history of persistently elevated levels of alkaline phosphatase (ALP), indicative of increased bone turnover. He had also initially been treated with thyroxine supplementation due to elevated TSH levels. During the diagnostic process a TSHoma was revealed. Thyroxine was discontinued, and resection of the pituitary tumor followed by treatment with a somatostatin analog led to complete recession of the effusions, normalization of ALP, and shrinkage of pituitary tumor.Accelerated bone metabolism and pericardial and pleural effusions attributed to a TSHoma may resolve after successful treatment of the tumor. The unexpected clinical course of this case highlights the need for careful long-term surveillance in patients with these rare pituitary adenomas.

History before diagnosis in childhood craniopharyngioma: associations with initial presentation and long-term prognosis.

OBJECTIVE: Childhood craniopharyngiomas (CP) are often diagnosed after a long duration of history (DOH). Tumor size, hypothalamic involvement (HI), and obesity are associated with reduced overall survival (OS) and functional capacity (FC). The effect of DOH and specific symptoms in history on presentation at initial diagnosis and long-term prognosis are unknown. DESIGN: Retrospective analysis of patients' records and prospective longitudinal follow-up. METHODS: Histories of 411 CP patients recruited in HIT Endo, KRANIOPHARYNGEOM 2000 were retrospectively evaluated for DOH, symptoms, and characteristics. The effect of specific manifestations and DOH on clinical presentation and tumor characteristics at time of initial CP diagnosis and long-term outcome were analyzed. Main outcome measures were 10-year OS and progression-free survival (PFS), FC, and BMI during longitudinal follow-up. RESULTS: Median DOH was 6 months (range: 0.1-108 months) and correlated with age at diagnosis. Tumor size, HI, degree of resection, and BMI at diagnosis were not related to DOH. In multivariate analysis adjusted for age at diagnosis, only hydrocephalus was found to have a relevant influence on DOH. Visual and neurological deficits were associated with larger initial tumor size and impaired 10-year OS. Weight gain and growth failure were observed with longest DOH. PFS and FC were not related to any specific symptom. Endocrine deficits at diagnosis were associated with long DOH. CONCLUSIONS: CP is frequently diagnosed after long DOH, especially in older children. However, DOH was not associated with tumor size, HI, survival, or FC. Visual and neurological deficits necessitate rapid diagnostic workup.

Evaluation of a comprehensive care clinic model for children with brain tumor and risk for hypothalamic obesity.

The objectives of this study were to evaluate outcomes of a comprehensive care clinic (CCC) for children with hypothalamic obesity due to treatment for brain tumors by assessing weight parameters; health-related quality of life (HRQoL); and perception of health status, disease burden, care satisfaction, and physical activity. Thirty-nine patients (16 males) were reviewed. While attending the CCC the median %weight gain and percent ideal body weight (%IBW) of patients was lower (8.5%/year (range -3 to -14) and -4%/year (141.7-34), respectively) than the median %weight gain and %IBW (21.4% (15.8-32.0) and 19.9% (-18.7 to 149.2)) while treated in standard care. Rate of increase in %BMI slowed (4.5 kg/m(2) %/year (-17.8 to 8.4) vs. 8.4 kg/m(2) %/year (-3.1 to 28.1)) in patients attending the clinic compared to their before treatment in standard care. There was no change in blood pressure, fasting glucose, triglycerides or low-density lipoprotein cholesterol, and a significant increase in high-density lipoprotein cholesterol (1.09 +/- 0.33 to 1.24 +/- 0.04). After attending the CCC for a year, significant increases for child reported total HRQoL (63.7 +/- 18.4-71.3 +/- 13.3; P < 0.017), physical functioning (65.3 +/- 15.9-69.5 +/- 15.9; P < 0.045) and school functioning (61.1 +/- 21.0-71.1 +/- 16.5; P < 0.051) were found. Parents reported no significant change in HRQoL over the same period. Parents had significantly improved responses in areas of coordination of health care and understanding of their child's disease. Patients attending the CCC gained less weight while attending the clinic and exhibited improved HRQoL. Parents noticed improvements in various areas of their child's medical care.

Childhood craniopharyngioma. Recent advances in diagnosis, treatment and follow-up.

BACKGROUND: Craniopharyngioma are embryogenic malformations of the sellar area. With an overall incidence of 0.5-2 new cases per million population per year, 30-50% of all cases occur in childhood. Overall survival rates are high. However, quality of life (QoL) is substantially reduced in many survivors due to sequelae such as extreme obesity caused by hypothalamic lesions. METHODS: Based on retrospective analysis of 306 patients with childhood craniopharyngioma (HIT ENDO), we found that QoL was negatively related to hypothalamic involvement, tumor size and the number of neurosurgical interventions. RESULTS: Irradiation had no significant impact on long-term QoL. The prospective surveillance of 98 patients in KRANIOPHARYNGEOM 2000 revealed frequent and early events in terms of tumor relapse after apparently complete resection (EFS: 0.60 +/- 0.09 at 3 years) and tumor progression after incomplete resection (EFS: 0.22 +/- 0.09). CONCLUSION: We conclude that radical surgery in patients with hypothalamic involvement has a major negative impact on long-term QoL. Innovative treatment strategies are warranted to improve QoL in these patients at risk. Accordingly, the appropriate time point of irradiation after incomplete resection will be analyzed in KRANIOPHARYNGEOM 2007.

Craniopharyngioma: modern concepts in pathogenesis and treatment.

PURPOSE OF REVIEW: Craniopharyngioma is a benign tumour. Its tendency to recur after excision and the high surgical risk due to involvement of the most vital structures of the brain mean that alternatives to radical surgery should be considered, namely limited surgical procedures followed by radiotherapy. Since both options present inherent risks, optimal craniopharyngioma treatment remains controversial. This paper aims to critically review the recent literature on craniopharyngioma. RECENT FINDINGS: The management of children with craniopharyngioma has benefited from concerted efforts by national and international groups to improve outcome and reduce morbidity. From the current literature it is evident that there is a trend to better integrate all treatment modalities available, tailoring therapies to specific risk factors. Modern imaging and new surgical and radiotherapy techniques are increasing the possibility of cure. Biological markers are under investigation and this will increase our knowledge on craniopharyngioma. SUMMARY: Studies on treatment, biology and pathogenesis of craniopharyngioma, available in the current literature, grew considerably in the last year. Although a consensus has not been reached on all aspects of this complex disease, there is a trend in the field to move quickly towards a better understanding of the disease to improve treatment strategies and to produce clinical cooperative trials.

Benign adult brain tumors: an evidence-based medicine review.

BACKGROUND: Benign adult brain tumors can be managed conservatively or using surgery, radiation, or medicines. While randomized comparisons assessing tumor recurrence, quality of life, or survival are the ideal means of comparing treatments, it can be difficult to recruit patients to such trials and lengthy follow-up periods are needed because of the slowly progressive natural history of these tumors. METHODS: Review of the literature on benign adult brain tumors using evidence-based standards and focusing on meningiomas, pituitary adenomas, and vestibular schwannomas, which together represent the majority of WHO grade 1 adult brain tumors. RESULTS: Nearly all studies of benign adult brain tumors were of relatively poor quality (level 3 or poorer). These studies enable grade C recommendations. The safety of meningioma surgery in the elderly varies with institution, radiosurgery is a reliable alternative to surgery in small to medium-sized meningiomas, and the efficacy of drugs in therapy of meningiomas recurring after surgery is difficult to interpret due to a lack of uniform criteria in the studies. Radiosurgery is effective in nonfunctional pituitary adenomas recurring after surgery, while phototherapy is a newer treatment modality with potential benefits in pituitary adenomas that fail surgery or radiation. Vestibular schwannomas can be conservatively managed, but there are no reliable predictors of growth, so serial imaging is important. Radiosurgery has proven to be a reliable alternative to surgery for small to medium-sized vestibular schwannomas, but followup has been relatively short in most studies to date. CONCLUSIONS: While randomized clinical trials comparing conservative management, surgery, radiation, and medical management of benign adult benign tumors are unlikely to occur, there is some level 3 evidence that can assist in their treatment.

Gene therapy in the neuroendocrine system.

The implementation of experimental gene therapy in animal models of neuroendocrine diseases is an area of growing interest. In the hypothalamus, restorative gene therapy has been successfully implemented in Brattleboro rats, an arginine vasopressin (AVP) mutant which suffers from diabetes insipidus, and in Koletsky (fa(k)/fa(k)) and in Zucker (fa/fa) rats which have leptin receptor mutations that render them obese, hyperphagic and hyperinsulinemic. In the above models, viral vectors expressing AVP, leptin receptor b and proopiomelanocortin, respectively, were stereotaxically injected in the relevant hypothalamic regions. In rats, aging brings about a progressive degeneration and loss of hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons, which are involved in the tonic inhibitory control of prolactin secretion and lactotropic cell proliferation. Stereotaxic injection of an adenoviral vector expressing insulin-like growth factor I corrected their chronic hyperprolactinemia and restored TIDA neuron numbers. Spontaneous intermediate lobe pituitary tumors in a retinoblastoma (Rb) gene mutant mouse were corrected by injection of an adenoviral vector expressing the human Rb cDNA and experimental prolactinomas in rats were partially reduced by intrapituitary injection of an adenoviral vector expressing the HSV1-thymidine kinase suicide gene. These results suggest that further implementation of gene therapy strategies in neuroendocrine models may be highly rewarding.