[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.

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.

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.

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.

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.

[Treatment of Cushing's disease. Transsphenoidal surgery and pituitary radiotherapy]. / Tratamiento de la enfermedad de Cushing. Cirugía transesfenoidal y radioterapia hipofisaria.

Transsphenoidal surgery is currently considered the treatment of choice for Cushing's disease. Initial remission is achieved in approximately 70-85%, but 10-15% of patients with remission will suffer a recurrence months or years later. Pituitary irradiation has been used as a therapeutic tool for many years. Nowadays, this option is considered a second-line treatment, to be used when there is postsurgical persistence or recurrence of the disease. The present article reviews the surgical approaches, remission rates reported by different groups, prognostic factors, and the most frequent complications after transsphenoidal surgery. We also review the different techniques that can be used for pituitary irradiation, as well as the efficacy and morbidity reported for each of these techniques in patients with Cushing's disease.

Evaluation of the effect of radiotherapy for pituitary tumours on cognitive function and quality of life.

AIMS: Pituitary tumours are often treated with radiotherapy, which can cause cognitive impairment when given in high doses. It is assumed that current regimens do not cause damage, but this has not been established. The aim was to determine whether radiotherapy given to people with pituitary tumours was associated with cognitive impairment and reduced quality of life. MATERIAL AND METHODS: We retrospectively compared two outcome groups (patients with pituitary tumours who had undergone radiotherapy and surgery and patients with pituitary tumours who had surgery alone), and carried out standardised tests of cognitive function and quality of life. RESULTS: The data suggested that patients with pituitary tumours treated with surgery, with or without radiotherapy, had cognitive impairment compared with the normal population. Patients receiving radiotherapy performed significantly worse than those receiving only surgery on the Stroop test, a measure of executive function. They also scored significantly lower on the Physical Health composite of the SF36, although this difference was no longer significant when account was taken of baseline differences between the groups. There were no significant differences in other cognitive functions, mood, general well-being or the Mental Health Composite of the SF36. CONCLUSIONS: Patients treated for pituitary disease may have cognitive impairment. A decrease in cognitive function was found regardless of treatment type. The decrease seemed to be greater in the radiotherapy group and was mainly on executive function. This impairment of executive function could affect daily life. Further prospective studies are required to assess the effect of pituitary disease on cognitive function and the safety of radiotherapy.

Acquired narcolepsy in an acromegalic patient who underwent pituitary irradiation.

The authors report the case of a 60-year-old man with acromegaly, who developed narcolepsy 2 weeks after completing radiotherapy for a pituitary adenoma. Cataplexy and sleepiness were predominant symptoms. Onset of narcolepsy is unusual at this age and the temporal relationship following radiotherapy suggests this treatment was implicated. His CSF hypocretin levels were normal, indicating other factors may be important in his narcolepsy.

Adult height after cranial irradiation for optic pathway tumors: relationship with neurofibromatosis.

OBJECTIVE: Optic pathway tumors decrease adult height by central precocious puberty (PP) or hypothalamic-pituitary disorders, particularly growth hormone (GH) deficiency caused by the tumor, management of the tumor, or associated neurofibromatosis 1. The objective of this study was to evaluate the respective roles of these factors on disorders and adult height. STUDY DESIGN: Thirty-five patients with optic pathway tumors diagnosed at 6.4 +/- 0.6 years treated by cranial irradiation (30-56 Gy) reached adult height after treatment with GH alone (n = 16), gonadotropin hormone-releasing hormone analogue alone (n = 2), or both (n = 16). RESULTS: Central precocious puberty occurred before irradiation in four cases and after irradiation in 18. Eleven of the 17 patients with neurofibromatosis 1 had PP. Before irradiation, five of 21 patients lacked GH, zero of 21 lacked thyroid-stimulating hormone, and zero of 13 lacked adrenocorticotropin. After irradiation, 35 of 35 lacked GH, 28 of 35 lacked thyroid-stimulating hormone, and six of 35 lacked adrenocorticotropin; puberty was delayed in 15 patients. Adult height was -0.8 +/- 0.2 SD, below target height (0.2 +/- 0.2 SD, P <.0001), similar in patients with and without PP, but lower in those with neurofibromatosis 1 (-1.4 +/- 0.4 SD) than in those without (-0.3 +/- 0.3 SD, P =.04). CONCLUSIONS: Optic pathway tumors cause PP, but cranial irradiation causes most of the other hypothalamic-pituitary disorders. Adult height of patients given GH or gonadotropin hormone-releasing hormone analogue seems to depend on neurofibromatosis 1.

Radiation-induced cerebral aneurysm successfully treated with endovascular coil embolization.

In a 30-year-old male, multiple cerebral aneurysms developed 19 years after receiving 60 Gy of irradiation for craniophariginoma. Angiogram revealed right IC-PC and upper basilar trunk aneurysms in addition to atherosclerotic change. The right IC-PC aneurysm was wrapped and the basilar trunk aneurysm located between the origins of SCA and AICA was treated by endovascular coil embolization. The packing of the aneurysm was complete, but stenosis of the basilar artery appeared. The patient was discharged uneventfully and follow-up angiogram 6 months later demonstrated that the aneurysm had disappeared and the patency of the basilary artery had been preserved. Radiation-induced intracranial vasculopathy is a well-recognized phenomenon, but aneurysm formation is less common than arterial occlusive lesion. However, the mortality rate after bleeding is so high that immediate diagnosis and treatment by direct surgery or coil embolization are necessary.

[Clinical recurrence of Cushing syndrome without evidence of tumor recurrence: radical hypophysectomy?]. / Les récurrences cliniques de la maladie de Cushing sans récidive tumorale documentée: hypophysectomie radique.

Outcome following radiation therapy for hormonally-active Cushing adenoma is reported. Conventional radiation using 20 to 30 grays improved mass and hormone level in 30 to 80% of the patient. Gamma-knife radiosurgery was at least as effective. These results are discussed in this review.

Histological changes in the pituitary gland and adenomas following radiotherapy.

To elucidate histological changes in the pituitary gland and adenomas following radiotherapy, two irradiated pituitary glands and seven irradiated non-functioning adenomas were studied. The latter included four cases with conventional radiation (CR) and three cases with radiosurgery: two with gamma knife radiosurgery (GKR) and one with stereotactic fractionated radiotherapy (SRT). The specimens were obtained 10 months to 10 years (mean 58 months) after the radiotherapy. Irradiated pituitary glands showed diffuse fibrosis in the adenohypophysis, whereas irradiated adenomas showed either mild or no fibrosis in five CR/SRT cases and diffuse thick hyaline deposits in two GKR cases. No necrosis was observed. Stellate-shaped S-100 protein-positive cells were greater in number in the irradiated pituitary glands than in the normal glands. Pituitary cells with dense granular reactivity for mitochondrial protein, cytochrome oxidase, and Mn-SOD, mimicking oncocytes, were greater in number in the irradiated adenohypophysis but did not show any change in cell size. Many irradiated pituitary cells and some irradiated adenoma cells were densely positive with anticytokeratin 1,5,10,14 antibody whereas non-irradiated counterparts were negative. In adenomas, MIB-1 labeling index remained unchanged after the radiation. The results may indicate that radiation-induced fibrosis was associated with an increased number of folliculo-stellate cells, mitochondrial dysfunction, and squamous metaplasia. These findings were prominent in irradiated pituitary cells and may participate in delayed pituitary hypofunction following radiotherapy. In irradiated adenoma cells, similar findings were observed but diffuse fibrosis was absent. The histological changes were more intensive in adenomas following GKR than those following CR.

Fractionated stereotactically guided radiotherapy and radiosurgery in the treatment of functional and nonfunctional adenomas of the pituitary gland.

PURPOSE: We evaluated survival rates and side effects after fractionated stereotactically guided radiotherapy (SCRT) and radiosurgery in patients with pituitary adenoma. METHODS AND MATERIALS: Between 1989 and 1998, 68 patients were treated with FSRT (n = 63) or radiosurgery (n = 5) for pituitary adenomas. Twenty-six had functional and 42 had nonfunctional adenomas. Follow-up included CT/MRI, endocrinologic, and ophthalmologic examinations. Mean follow-up was 38.7 months. Seven patients received radiotherapy as primary treatment and 39 patients received it postoperatively for residual disease. Twenty-two patients were treated for recurrent disease after surgery. Mean total dose was 52.2 Gy for SCRT, and 15 Gy for radiosurgery. RESULTS: Overall local tumor control was 93% (60/65 patients). Forty-three patients had stable disease based on CT/MRI, while 15 had a reduction of tumor volume. After FSRT, 26% with a functional adenoma had a complete remission and 19% had a reduction of hormonal overproduction after 34 months' mean. Two patients with STH-secreting adenomas had an endocrinologic recurrence, one with an ACTH-secreting adenoma radiologic recurrence, within 54 months. Reduction of visual acuity was seen in 4 patients and partial hypopituitarism in 3 patients. None of the patients developed brain radionecrosis or radiation-induced gliomas. CONCLUSION: Stereotactically guided radiotherapy is effective and safe in the treatment of pituitary adenomas to improve local control and reduce hormonal overproduction.