Outcomes of Pituitary Radiation for Cushing's Disease.

Achievement of biochemical remission with preservation of normal pituitary function is the goal of treatment for Cushing's disease. For patients with persistent or recurrent Cushing's disease after transsphenoidal resection, radiation therapy may be a safe and effective treatment. Stereotactic radiosurgery is favored over conventional fractionated external beam radiation. Hormonal recurrence rates range from 0% to 36% at 8 years after treatment. Tumor control rates are high. New pituitary hormone deficiency is the most common adverse effect after stereotactic radiosurgery and external beam radiation. The effects of radiation planning optimization and use of adjuvant medication on endocrine remission rates warrant investigation.

[Radiotherapy and radiosurgery in treatment of craniopharyngiomas]. / Luchevaia terapiia i radiokhirurgiia v lechenii kraniofaringiom.

Craniopharyngiomas are benign epithelial tumors having a dysembryogenetic origin, which are usually located in the sellar/parasellar and/or third ventricle regions. Gross total resection is the modern standard of treatment for these tumors because of a low recurrence rate. However, this surgery in some patients with craniopharyngioma often leads to the development or worsening of diencephalic disorders poorly responding to treatment. Perhaps, in these cases, subtotal or partial tumor resection or implantation of an Ommaya reservoir into the tumor cyst followed by stereotactic radiotherapy/radiosurgery may provide better functional outcomes and higher life quality in patients, with tumor growth control being reasonable (according to the published data, the mean 10-year disease-free survival is 66.9% after total tumor resection and 79.6% after combined treatment). The paper presents a review of the literature on radiological treatment of craniopharyngiomas. We discuss the issues of indications, optimal timing of radiotherapy/radiosurgery, its efficacy, and treatment outcomes in terms of complications and quality of life. Particular attention is paid to enlargement of craniopharyngioma cysts during and after radiological treatment.

BIOCHEMICAL CONTROL DURING LONG-TERM FOLLOW-UP OF 230 ADULT PATIENTS WITH CUSHING DISEASE: A MULTICENTER RETROSPECTIVE STUDY.

OBJECTIVE: Cushing disease (CD) results from excessive exposure to glucocorticoids caused by an adrenocorticotropic hormone-secreting pituitary tumor. Inadequately treated CD is associated with significant morbidity and elevated mortality. Multicenter data on CD patients treated in routine clinical practice are needed to assess treatment outcomes in this rare disorder. The study purpose was to describe the burden of illness and treatment outcomes for CD patients. METHODS: Eight pituitary centers in four U.S. regions participated in this multicenter retrospective chart review study. Subjects were CD patients diagnosed at ≥18 years of age within the past 20 years. Descriptive statistical analyses were conducted to examine presenting signs, symptoms, comorbidities, and treatment outcomes. RESULTS: Of 230 patients, 79% were female (median age at diagnosis, 39 years; range, 18 to 78 years). Length of follow-up was 0 to 27.5 years (median, 1.9 years). Pituitary adenomas were 0 to 51 mm. The most common presenting comorbidities included hypertension (67.3%), polycystic ovary syndrome (43.5%), and hyperlipidemia (41.5%). Biochemical control was achieved with initial pituitary surgery in 41.4% patients (91 of 220), not achieved in 50.0% of patients (110 of 220), and undetermined in 8.6% of patients (19 of 220). At the end of follow-up, control had been achieved with a variety of treatment methods in 49.1% of patients (110 of 224), not achieved in 29.9% of patients (67 of 224), and undetermined in 21.0% of patients (47 of 224). CONCLUSION: Despite multiple treatments, at the end of follow-up, biochemical control was still not achieved in up to 30% of patients. These multicenter data demonstrate that in routine clinical practice, initial and long-term control is not achieved in a substantial number of patients with CD. ABBREVIATIONS: BLA = bilateral adrenalectomy CD = Cushing disease CS = Cushing syndrome eCRF = electronic case report form MRI = magnetic resonance imaging PCOS = polycystic ovary syndrome.

Clinical Outcome After Extended Endoscopic Endonasal Resection of Craniopharyngiomas: Two-Institution Experience.

BACKGROUND: The extended endoscopic endonasal approach (EEA) to the anterior cranial base is used for the resection of craniopharyngiomas. OBJECTIVE: We present clinical experience and outcomes of using EEA for craniopharyngiomas. METHODS: A total of 116 patients in 2 remote institutions were enrolled in this retrospective study. Surgical, endocrinologic, and ophthalmologic outcomes were assessed. RESULTS: The mean follow-up was 35 months (range, 1-115). Gross total resection (GTR), near total resection (NTR, >95%), and subtotal resection (STR) were achieved in 46%, 39%, and 15% of the patients, respectively. Surgery performed after 2010 was the only variable significantly associated with greater extent of resection, which might be explained by the learning curve. Overall tumor recurrence rate was 15.5%, with a median interval until recurrence of 14.5 months (range, 3-58). Extent of resection was significantly associated with recurrence-free survival (P = 0.0116). Those who underwent NTR/STR followed by adjuvant radiotherapy had a similar median recurrence-free survival rate compared with those who underwent GTR (26.5 vs. 20 months, P = 0.167). Endocrinologic examination revealed that 47.4% of patients experienced worsening of anterior pituitary function following surgery while 25.5% developed new-onset diabetes insipidus. Of the 89 patients with preoperative visual deficits, 68 (76.4%) experienced improvement in visual field assessment. CONCLUSION: EEA is effective for the surgical resection of craniopharyngiomas, resulting in high rates of visual improvement and low complication rates. Adjuvant radiotherapy is a useful method for tumor control after incomplete resection.

Endoscopic Endonasal Surgery for Tumors of the Cavernous Sinus: A Series of 234 Patients.

BACKGROUND: Cavernous sinus (CS) tumors often are considered inoperable. We present our experience with endoscopic endonasal surgery (EES) and compare the outcomes for different tumor. METHODS: EES (medial or lateral approach) was used in 234 patients with CS tumors. The cohort included 175 (75%) pituitary adenomas and 59 (25%) nonadenomatous lesions. RESULTS: Presenting symptoms were significantly different between the 2 groups, with cranial neuropathies occurring mainly in nonadenomas (P < 0.0001). The overall gross total tumor resection rate from the CS was 37.3% (37.1% in adenomas, 38.1% in non-adenomas). In total, preexisting cranial nerve (CN) dysfunction improved in 56.4% of the patients. After treatment completion (including radiation of residual tumor), 83.3% of acromegalic patients, 50% of prolactinomas and 33.3% of Cushing's disease, were in remission. Visual loss improved in 86.8% of adenomas and in 70.8% of nonadenomas. Intracavernous CN palsies improved in 77.3% of adenomas and 42.4% of nonadenomas. New permanent CN palsies occurred in 7 nonadenomas, which is significantly greater than in adenomas (P = 0.007). The leak rate of cerebrospinal fluid was 6.3% for adenomas and 11.9% for nonadenomas. Four patients suffered an internal carotid artery injury with no neurologic sequelae in 3 cases and 1 death (0.4%). CONCLUSIONS: EES provides an easily accessible midline corridor to the CS with equivalent or superior results to transcranial approaches in the management of select tumors. Symptomatology due to CS invasion is more likely to improve in pituitary adenomas and the rate of surgical complications is greater in nonadenomas. Using a team approach, the overall mortality due to vascular injury is low.

Therapeutic trends and outcome of acromegaly: a single center experience over a 40-year period.

OBJECTIVE: To evaluate the therapeutic trends and long-term outcome of treatment modalities for acromegaly in our center over a 40-year period. DESIGN: We retrospectively studied 321 acromegalic patients (145 males/176 females) diagnosed and treated from the 1970s until September 2013. Patients were divided into two subgroups: group A consisted of 166 patients diagnosed before 1990 and group B of 155 patients diagnosed after 1990. Outcome was assessed with GH (random and/or post OGTT) and IGF1 measurements. RESULTS: More group A than group B patients were submitted to radiotherapy (57.8% vs 16.8% patients, respectively, p <0.001). In contrast, more patients of group B were offered surgery (70.3% vs 42.1% in group A, p <0.001) and/or medical treatment (70.3% vs 23.4% in group A, p <0.001). At latest follow-up, 68.4 % of patients in group B achieved GH <2.5 µg/l after treatment vs 39.8% in group A, p=0.001, 46.9% of patients in group B achieved GH <1 µg/l vs 20.3% in group A, p=0.001 and 47.1% of patients in group B achieved during OGTT GH nadir <0.4 µg/l vs 18.6% in group A, p=0.001. CONCLUSIONS: Transsphenoidal resection and medical treatment resulted in improved outcome in acromegalic patients treated over the last 20 years. However, the disease still remains uncontrolled in a considerable number of patients.

Hypopituitarism.

Hypopituitarism refers to deficiency of one or more hormones produced by the anterior pituitary or released from the posterior pituitary. Hypopituitarism is associated with excess mortality, a key risk factor being cortisol deficiency due to adrenocorticotropic hormone (ACTH) deficiency. Onset can be acute or insidious, and the most common cause in adulthood is a pituitary adenoma, or treatment with pituitary surgery or radiotherapy. Hypopituitarism is diagnosed based on baseline blood sampling for thyroid stimulating hormone, gonadotropin, and prolactin deficiencies, whereas for ACTH, growth hormone, and antidiuretic hormone deficiency dynamic stimulation tests are usually needed. Repeated pituitary function assessment at regular intervals is needed for diagnosis of the predictable but slowly evolving forms of hypopituitarism. Replacement treatment exists in the form of thyroxine, hydrocortisone, sex steroids, growth hormone, and desmopressin. If onset is acute, cortisol deficiency should be replaced first. Modifications in replacement treatment are needed during the transition from paediatric to adult endocrine care, and during pregnancy.

Central precocious puberty following the diagnosis and treatment of paediatric cancer and central nervous system tumours: presentation and long-term outcomes.

OBJECTIVES: To estimate the prevalence of central precocious puberty (CPP) after treatment for tumours and malignancies involving the central nervous system (CNS) and examine repercussions on growth and pubertal outcomes. DESIGN: Retrospective study of patients with tumours near and/or exposed to radiotherapy to the hypothalamus/pituitary axis (HPA). PATIENTS AND MEASUREMENTS: Patients with CPP were evaluated at puberty onset, completion of GnRH agonist treatment (GnRHa) and last follow-up. Multivariable analysis was used to test associations between tumour location, sex, age at CPP, GnRHa duration and a diagnosis of CPP with final height <-2SD score (SDS), gonadotropin deficiency (LH/FSHD) and obesity, respectively. RESULTS: Eighty patients (47 females) had CPP and were followed for 11·4 ± 5·0 years (mean ± SD). The prevalence of CPP was 15·2% overall, 29·2% following HPA tumours and 6·6% after radiotherapy for non-HPA tumours. Height <-2SDS was more common at the last follow-up than at the puberty onset (21·4% vs 2·4%, P = 0·005). Obesity was more prevalent at the last follow-up than at the completion of GnRHa or the puberty onset (37·7%, 22·6% and 20·8%, respectively, P = 0·03). Longer duration of GnRHa was associated with increased odds of final height <-2SDS (OR = 2·1, 95% CI 1·0-4·3) and longer follow-up with obesity (OR = 1·3, 95% CI 1·1-1·6). LH/FSHD was diagnosed in 32·6%. There was no independent association between CPP and final height <-2SDS, and LH/FSHD and obesity in the subset of patients with HPA low-grade gliomas. CONCLUSIONS: Patients with organic CPP experience an incomplete recovery of growth and a high prevalence of LH/FSHD and obesity. Early diagnosis and treatment of CPP may limit further deterioration of final height prospects.

Efficacy and complications of pituitary irradiation.

Radiation therapy is widely used in the management of intracranial (including sellar and parasellar) and systemic disorders. Although in many cases the irradiation aims to prevent the growth or regrowth and to control the hormonal hypersecretion of a pituitary tumor, in many others it adversely affects the hypothalamo-pituitary function simply because this area receives significant doses of radiation delivered for non-hypothalamo-pituitary disorders. The main long-term complications include hypopituitarism, optic neuropathy, cerebrovascular morbidity, and second brain tumors. Radiation technique and schedule are important determinants of these adverse effects.

Clinical outcome and evidence of high rate post-surgical anterior hypopituitarism in a cohort of TSH-secreting adenoma patients: Might somatostatin analogs have a role as first-line therapy?

PURPOSE: Thyrotropin-secreting pituitary adenomas (TSHomas) represent a rare subtype of pituitary tumors. Neurosurgery (NCH) is still considered the first-line therapy. In this study we aimed to investigate the outcome of different treatment modalities, including first line somatostatin analogs (SSA) treatment, with a specific focus on neurosurgery-related complications. METHODS: We retrospectively evaluated thirteen patients diagnosed for TSHomas (9 M; age range 27-61). Ten patients had a magnetic resonance evidence of macroadenoma, three with slight visual field impairment. In the majority of patients, thyroid ultrasonography showed the presence of goiter and/or increased gland vascularization. Median TSH value at diagnosis was 3.29 mU/L (normal ranges 0.2-4.2 mIU/L), with median fT4 2.52 ng/dL (0.9-1.7 ng/dL). RESULTS: Three patients (two microadenoma) were primarily treated with NCH and achieved disease remission, whereas ten patients (nine macroadenomas) were initially treated with SSA. Despite the optimal biochemical response observed during medical treatment in most patients (mean TSH decrease -72%), only two stayed on medical therapy alone, achieving stable biochemical control at the end of the follow-up. The remaining patients (n = 7) underwent NCH later on during their clinical history, followed by radiotherapy or adjuvant SSA treatment in two cases. Noteworthy, five of them developed hypopituitarism. All patients reached a biochemical control, after a multimodal therapeutic approach. CONCLUSIONS: Neurosurgery ultimately led to complete disease remission or to biochemical control in majority of patients, whereas resulting in a considerable percentage of post-operative complications (mainly hypopituitarism, 50%). In the light of the optimal results unanimously reported for medical treatment with SSA, our experience suggests that a careful evaluation of risk/benefit ratio should be taken into consideration when directing the treatment approach in patients with TSHoma.

Treatment paradigms for pituitary adenomas: defining the roles of radiosurgery and radiation therapy.

Pituitary adenomas represent one of the most common types of intracranial tumors. While their macroscopic appearance and anatomical location are relatively homogeneous, pituitary tumors have the potential to generate a wide variety of clinical sequelae. Treatment options for pituitary tumors include medical therapy, microscopic or endoscopic surgical resection, radiosurgery, radiation therapy, or observation depending on the biochemical profile and clinical status of the patient. Radiosurgery and external beam radiation therapy (EBRT) are most commonly as adjunctive treatments following incomplete surgical resection leaving residual tumor, tumor recurrence, or failure of medical therapy. We present a comprehensive literature review of the radiosurgery series for pituitary tumors including nonfunctioning adenomas, ACTH- and GH-secreting adenomas, and prolactinomas. While postradiosurgery radiographic tumor control for nonfunctioning adenomas is excellent, typically around 90 %, the rates of biochemical remission for functioning adenomas are lower than the tumor control rates. The highest endocrine remission rates are achieved patients with Cushing's disease and the lowest in those with prolactinomas. Although EBRT has been largely supplanted by radiosurgery for the vast majority of pituitary adenomas cases, there remains a role for EBRT in select cases involving large tumor volumes in close proximity to critical neural structures. By far the most common complication after radiosurgery or EBRT is delayed hypopituitarism followed by cranial neuropathies. The effect of suppressive medications on radiosurgery outcomes remains controversial. Due to the rare but well-documented occurrence of late recurrence following endocrine remission, long-term and rigorous clinical and radiographic follow-up is necessary for all pituitary adenoma patients treated with radiosurgery or EBRT.

Baseline characteristics and effects of ten years of growth hormone (GH) replacement therapy in adults previously treated with pituitary irradiation.

CONTEXT: Little is known of the importance of previous irradiation therapy for baseline characteristics and responsiveness to GH replacement in GH deficient (GHD) adults. OBJECTIVE/DESIGN/PATIENTS: In this prospective, single-centre, open-label study, the effects of 10-year GH replacement were determined in 18 GHD adults that had previously received conventional external fractionated pituitary irradiation therapy (IRR group) and 18 non-irradiated GHD patients (non-IRR group). All patients had adult onset disease and complete deficiency of anterior pituitary hormones and both groups were comparable in terms of age, gender, body mass index (BMI), and waist:hip ratio. RESULTS: At baseline, IRR patients had higher serum triglyceride (TG) and insulin levels and lower high density lipoprotein (HDL)-cholesterol (HDL-C) level than non-IRR patients (all p<0.05). The 10-year GH replacement improved body composition, bone mass and serum lipid profile without any between-group differences, except for a marginally more beneficial response in serum TG level in the IRR patients. After 10 years, there was no between-group difference in any variable after correction for a higher replacement dose of glucocorticoids in the IRR patients at study end using an analysis of covariance. During the 10-year GH replacement, 5 IRR patients suffered from vascular events (2 fatal) whereas only one non-fatal vascular event occurred in the non-IRR patients. CONCLUSIONS: IRR patients with GHD display a more severely impaired cardiovascular risk profile at baseline, which was reversed by the 10-year GH replacement after correction for the higher glucocorticoid dose at study end. However, vascular events occurred more frequently in the IRR patients.

Multiple head and neck tumors following treatment for craniopharyngioma.

To report a unique case of a patient with multiple head and neck tumors following treatment for craniopharyngioma. Retrospective review of the medical record. There is an association between radiation treatment for primary intracranial malignancies and the subsequent development of other intracranial tumors. At the same time, reports regarding the association between thyroid cancer and radiation exposure are abundant within the literature. We present a unique case of a young female who underwent resection and radiation treatment for a craniopharyngioma in 1988. With the exception of bitemporal visual loss and panhypopituitarism requiring hormone replacement therapy, the patient had a relatively uneventful course until 2005. At that time, she developed hearing loss and incapacitating vertigo, which was ultimately attributed to a temporal bone Langerhans histiocytosis. A year and a half later, she was noted to have a thyroid nodule, the pathology of which revealed papillary carcinoma. Seven months after that, she developed new auditory and vestibular symptoms attributable to an acoustic neuroma. This case is remarkable because neither Langerhans histiocytosis following radiation of a craniopharyngioma nor this distinctive combination of head and neck tumors in general have ever been previously reported.

Possible role of a radiation-induced p53 mutation in a Nelson's syndrome patient with a fatal outcome.

Nelson's syndrome (NS) is characterized by the appearance and/or progression of ACTH-secreting pituitary macroadenomas in patients who had previously undergone bilateral adrenalectomy for the treatment of Cushing's disease. Such corticotroph macroadenomas respond poorly to currently available therapeutic options which include surgery, radiotherapy and chemotherapy. P53 protein accumulation may be detected by immunohistochemistry in pituitary corticotroph adenomas and it has been suggested that it might be causally related to tumor development. Wild type P53 protein plays an important role in the cellular response to ionizing radiation and other DNA damaging agents and is mutated in many human tumors. In this study we report an adult male patient with NS who underwent both transsphenoidal and transcranial pituitary surgeries, conventional and stereotaxic radiotherapy and brachytherapy. Despite of the efforts to control tumor mass and growth, this macroadenoma displayed relentless growth and aggressive behavior. DNA extracted from the first two surgical samples, as well as DNA from peripheral blood leukocytes disclosed normal p53 sequence. DNA extracted from tumor samples obtained at surgeries performed after pituitary irradiation carried a somatic heterozygous mutation, consisting of a deletion of four cytosines between nucleotides 12,144-12,149 in exon 4 of the p53 gene. This frameshift mutation creates a stop codon in exon 4 excluding the expression of a functional protein from the defective allele. These data demonstrate a possible association between the P53 protein loss of function induced by radiotherapy and the aggressive course of the disease in this patient.

Radiation therapy for pediatric craniopharyngioma.

OBJECT: The treatment of craniopharyngioma is highly controversial. Continued advances in limited surgery and radiation therapy have maintained excellent local disease control while minimizing treatment-related sequelae. Further analyses of outcomes are necessary to characterize the long-term effects of radiation therapy. METHODS: An extensive literature review was performed for all studies including radiation therapy, with or without surgery, for pediatric craniopharyngioma. RESULTS: The authors identified 32 papers describing radiation therapy for treatment of pediatric craniopharyngioma, with disease control ranging from 44 to 100%. Modern studies report at least 90% disease control with 5-year follow-up. Fifteen studies reported outcomes, demonstrating that more than two-thirds of patients treated with surgery and radiation therapy have favorable outcomes, and this rate is more than 85% in the modern era. CONCLUSIONS: Conservative surgery and radiation therapy results in long-term disease control in pediatric patients with craniopharyngioma that is comparable to results obtained with radical surgery alone. However, children with craniopharyngioma remain vulnerable to late treatment failures and side effects from radiation therapy, including endocrinopathies, vasculopathies, and secondary tumors, which may be detrimental to the quality of life. Long-term follow-up beyond 5-10 years is necessary to assess tumor control relative to functional outcomes.

Craniopharyngioma: a comparison of tumor control with various treatment strategies.

OBJECT: Craniopharyngiomas have a propensity to recur after resection, potentially causing death through their aggressive local behavior in their critical site of origin. Recent data suggest that subtotal resection (STR) followed by adjuvant radiotherapy (XRT) may be an appealing substitute for gross-total resection (GTR), providing similar rates of tumor control without the morbidity associated with aggressive resection. Here, the authors summarize the published literature regarding rates of tumor control with various treatment modalities for craniopharyngiomas. METHODS: The authors performed a comprehensive search of the English language literature to identify studies publishing outcome data on patients undergoing surgery for craniopharyngioma. Rates of progression-free survival (PFS) and overall survival (OS) were determined through Kaplan-Meier analysis. RESULTS: There were 442 patients who underwent tumor resection. Among these patients, GTR was achieved in 256 cases (58%), STR in 101 cases (23%), and STR+XRT in 85 cases (19%). The 2- and 5-year PFS rates for the GTR group versus the STR+XRT group were 88 versus 91%, and 67 versus 69%, respectively. The 5- and 10-year OS rates for the GTR group versus the STR+XRT group were 98 versus 99%, and 98 versus 95%, respectively. There was no significant difference in PFS (log-rank test) or OS with GTR (log-rank test). CONCLUSIONS: Given the relative rarity of craniopharyngioma, this study provides estimates of outcome for a variety of treatment combinations, as not all treatments are an option for all patients with these tumors.