Case Report: Identification of Potential Prognosis-Related TP53 Mutation and BCL6-LPP Fusion in Primary Pituitary Lymphoma by Next Generation Sequencing: Two Cases.

Background: Primary pituitary lymphoma (PPL) is an extremely rare disease with poor prognosis. Although PPL has been shown to be different from classical primary central nervous system lymphoma because of the embryological origin of structures, individual and precise treatment of PPL remains unknown. Methods: A 61-year-old man and a 65-year-old woman both diagnosed with primary pituitary diffuse large B cell lymphoma underwent genetic analysis of cerebrospinal fluid and tumor tissue by next generation sequencing. Results: In the first case, partial remission was achieved following R²-MTX chemotherapy. In the other case with TP53 mutation and BCL6-LPP fusion, disease progressed although different chemotherapy regimens were given. Conclusion: The gene mutation of TP53 and BCL6 may be identified as a marker responsible for prognostic difference in patients with PPL. Genetic analysis may provide a novel approach for precise management and prognosis prediction.

Diabetes insipidus and syndrome of inappropriate antidiuresis (SIADH) after pituitary surgery: incidence and risk factors.

Electrolyte disorders are relatively frequent and potentially serious complications after pituitary surgery. Both DI (diabetes insipidus) and SIADH (syndrome of inappropriate antidiuresis) can complicate and prolong hospital and intensive care unit stay, and the latter may even be preventable. We aim to assess the incidence of both electrolyte disorders and their risk factors. From a prospective registry of patients who underwent endoscopic transnasal transsphenoidal surgery (TSS) for pituitary adenoma, patients with postoperative DI and SIADH were identified. Univariable and multivariable statistics were carried out to identify factors independently associated with the occurrence of either DI or SIADH. A total of 174 patients were included, of which 73 (42%) were female. Mean age was 54 years (range 20-88). During postoperative hospital stay, 13 (7.5%) patients presenting with DI and 11 (6.3%) with SIADH were identified. Patients who developed DI after surgery had significantly longer hospital stays (p = 0.022), as did those who developed SIADH (p = 0.002). Four (2.3%) patients were discharged with a diagnosis of persistent DI, and 2 (1.1%) with the diagnosis of SIADH. At the last follow-up, 5 (2.9%) patients presented with persistent DI, while none of the patients suffered from SIADH. Younger age (odds ratio (OR) 0.97, 95% confidence interval (CI) 0.94-1.01, p = 0.166) and pituitary apoplexy (OR 2.69, 95% CI 0.53-10.65, p = 0.184) were weakly associated with the occurrence of DI. We identified younger age (OR 0.96, 95% CI 0.92-0.99, p = 0.045) and lower preoperative serum sodium (OR 0.83, 95% CI 0.71-0.95, p = 0.008) as independent risk factors for SIADH. Although we found a weak association among age, pituitary apoplexy, and the occurrence of DI, no independent predictor was identified for DI. For postoperative SIADH however, lower age and preoperative serum sodium were identified as significant predictors. None of these findings were sufficiently supported by preexisting literature. Both electrolyte disorders are exquisitely hard to predict preoperatively, and further research into their early detection and prevention is warranted.

Intracranial germinoma causing cerebral haemiatrophy and hypopituitarism.

A young woman presented with primary amenorrhoea, progressive haemiparesis, visual disturbance, dementia and focal motor seizures. Investigations showed hypopituitarism, unilateral cerebral atrophy and inflamed cerebrospinal fluid. A trans-sphenoidal biopsy gave a unifying diagnosis of a pituitary germinoma.

Identification of thymosins ß4 and ß 10 in paediatric craniopharyngioma cystic fluid.

BACKGROUND: Adamantinomatous craniopharyngioma is the third most recurrent paediatric brain tumour. Although histologically benign, it behaves aggressively as a malignant tumour due to invasion of the hypothalamus and visual pathways. Surgery is still the first and almost the only mode of treatment, although serious damage can occur as a consequence of tumour localization. The proteomic characterization of the intracystic tumoural fluid could contribute to the comprehension of the tumorigenesis processes and to the development of therapeutic targets to reduce cyst volume, allowing less invasive surgery and/or delay of the radical resection of the tumour mass and the collateral serious effects. METHODS: Intracystic fluid was analysed by a LC-ESI-IT-MS top-down platform after acidification, deproteinization and chloroform liquid/liquid extraction. FINDINGS: Thymosin ß4 and ß10 peptides were for the first time identified in the intracystic fluid of adamantinomatous craniopharyngioma by low- and high-resolution MS analysis coupled with LC. The two peptides showed the same distribution trend in the analysed samples. Thymosin ß4 and ß10 were present in 77 % of the analysed samples. These peptides were not found in the cerebrospinal fluid available for two patients. INTERPRETATION: The presence of ß-thymosins in the intracystic fluid of the tumour confirmed the secretion of these proteins in the extracellular environment. Due to their G-actin-sequestering activity and antiapoptotic and anti-inflammatory properties, these peptides could be strictly involved in both tumour progression and cyst development and growth.

Validation of the human chorionic gonadotropin immunoassay in cerebrospinal fluid for the diagnostic work-up of neurohypophyseal germinomas.

BACKGROUND: The measurement of human chorionic gonadotropin (hCG) in cerebrospinal fluid (CSF) is useful for the differential diagnosis of suprasellar lesions. However, the concentrations that prove diagnostic for neurohypophyseal germinoma have not been well defined. In addition, the immunoassays used for such measurements are the same as those applied in serum, and few studies have been performed regarding the validation of such techniques in CSF. The present study aims to apply the Elecsys(®) hCG + ß immunoassay from Roche Diagnostics to measure hCG in CSF, as a useful tool in the diagnosis of neurohypophyseal germinomas in children and young adults. METHODS: Validation of the immunoassay involved calculation of the functional sensitivity and reference values for hCG in CSF in 35 controls in the absence of pregnancy, trophoblastic disease or tumour pathology. For the clinical application study, three patients diagnosed with neurohypophyseal germinoma have been reviewed. RESULTS: The functional sensitivity obtained was 0.4 IU/L. The reference values for hCG in CSF ranged from undetectable values to 0.7 IU/L. The hCG concentrations in CSF in the three studied patients, with confirmed diagnosis of neurohypophyseal germinoma, were 21.1, 32.6 and 23 IU/L, respectively. CONCLUSIONS: The Elecsys® hCG + ß immunoassay from Roche Diagnostics can be used to detect hCG in CSF with high precision. According to our results, CSF-hCG concentrations that exceed the established reference interval (undetectable values to 0.7 IU/L) in the presence of suprasellar lesions and hypophyseal stalk thickening must be considered pathological, establishing the need to exclude the presence of germinoma.

Surgical outcome in 90 patients with craniopharyngioma: an evaluation of transsphenoidal surgery.

OBJECTIVE: To analyze surgical outcomes in 90 patients with craniopharyngioma treated by standard transsphenoidal surgery (TSS) or extended transsphenoidal surgery (eTSS). METHODS: From 1990-2008, 90 patients (64 adults and 26 children) underwent TSS for craniopharyngioma (34 subdiaphragmatic and 56 supradiaphragmatic). TSS was performed as the initial surgery in 62 patients and as the second procedure in 28 patients. RESULTS: Total tumor removal was achieved in 70 (77.8%) patients, subtotal removal was achieved in 17 (18.9%), and partial removal was achieved in 3 (3.3%). Total removal was more often accomplished in initial surgery (56 of 62 [90.3%]) than second surgery (14 of 28 [50.0%]). Postoperative deterioration of anterior pituitary hormones developed in 31 of 47 (66.0%) patients with preoperative normal function or partial anterior pituitary loss. New-onset postoperative diabetes insipidus (DI) developed in 35 of 67 (52.2%) patients. Of 61 patients with preoperative visual loss, 55 (90.2%) noted some degree of visual improvement after surgery. The early postoperative mortality rate was 2.2% (2 of 90 patients). Cerebrospinal fluid (CSF) leakage occurred in 11 patients (12.2%), and 5 patients required surgical repair of the leak. Tumor recurrence was observed in seven (7.8%) patients during a mean follow-up period of 4.6 years. CONCLUSIONS: Most craniopharyngiomas including the supradiaphragmatic type can be removed safely by TSS with a good outcome, although endocrine function frequently worsens after surgery. Dural fascia graft is a very effective technique to prevent CSF leaks, especially after eTSS.

Pituitary adenoma apoplexy with initial presentation mimicking bacterial meningoencephalitis: a case report.

Pituitary apoplexy is a rare but life-threatening disorder. Clinical presentation of this condition includes severe headache, impaired consciousness, fever, visual disturbance, and variable ocular paresis. Signs of meningeal irritation are very rare. However, if present and associated with headache, fever, and pleocytosis, meningeal irritation may lead to misinterpretation as infectious meningoencephalitis. To the best of our knowledge, pituitary apoplexy with an initial presentation mimicking infectious meningoencephalitis had rarely been reported in the literature. Here, we report a 57-year-old man who had acute severe headache, high fever, neck stiffness, disturbance in consciousness, and left ocular paresis. Laboratory data showed leukocytosis, an elevated C-reactive protein level, and neutrophilic pleocytosis in the cerebrospinal fluid. Because bacterial meningoencephalitis was suspected, empiric antibiotic therapy was administered but in vain. Further examinations indicated a diagnosis of pituitary adenoma with apoplexy. After the immediate administration of intravenous corticosteroid supplement and surgical decompression, the patient recovered.

Cerebrospinal fluid rhinorrhea following trans-sphenoidal pituitary macroadenoma surgery: experience from 592 patients.

OBJECTIVES: To determine the incidence, risk factors, diagnostic procedures, and management of cerebrospinal fluid (CSF) leaks following trans-sphenoidal pituitary macroadenoma surgery. METHODS: Retrospective analysis of 592 patients. RESULTS: Intra- and post-operative CSF leaks occurred in 14.2 and 4.4% of patients, respectively. Surgical revision, tumor consistency, and tumor margins were independently associated with intra-operative leaks, while the tumor size, consistency, and margins were risk factors of post-operative leaks. The intra-operative leak rate of ACTH adenomas was greater than all other types combined; the incidence of post-operative CSF leaks was highest for FSH adenomas. There were no significant differences among various techniques and we achieved an initial repair success rates of 83.3 and 92.9% for intra- and post-operative CSF leaks, respectively. Of the 26 patients with post-operative CSF leaks, five were complicated by meningitis and four by post-infectious hydrocephalus which required ventriculoperitoneal shunts. CONCLUSIONS: CSF leaks have a propensity to occur in cases with fibrous tumors or tumors with indistinct margin and may have some relationship with the tumor type. Endoscopic and microscopic repairs were shown to be effective techniques in managing these types of leaks. Post-infectious hydrocephalus may influence the outcome of the repair and ventriculoperitoneal shunts were necessary in some cases.

Elevated levels of human chorionic gonadotropin-beta, a marker of active neurohypophyseal germinoma, detected by immune complex transfer enzyme immunoassay.

We report the usefulness of a highly sensitive immune complex transfer enzyme immunoassay (ICT-EIA) to detect human chorionic gonadotropin (HCG)-beta and thereby the onset of neurohypophyseal germinoma in its active phase. A 14-year-old girl exhibiting arrested puberty was diagnosed with neurohypophyseal germinoma following observation for two years. This patient initially showed no signs of diabetes insipidus (DI). While ICT-EIA indicated concentrations of HCG-beta higher than normal in cerebrospinal fluid (CSF) and serum, the results obtained with conventional methods were negative. ICT-EIA was also useful to assess the efficacy of treatment.

Retention of dopamine 2 receptor mRNA and absence of the protein in craniospinal and extracranial metastasis of a malignant prolactinoma: a case report.

OBJECTIVES: The case presented here describes the clinical evolution of a malignant prolactinoma with occurrence of intra- and extra-cranial metastases. In this case, the presence of dopamine 2 receptor (D2R) was studied at the mRNA and protein level, in order to understand the pathological background of the resistance to treatment with different dopamine agonists. DESIGN: Together with an extensive description of the clinical history of this case, a combination of in vitro and in vivo techniques was performed to provide the basis of the dopamine resistance developed in the course of the disease. METHOD: A comparison of the D2R was performed in specimens obtained at presentation of the disease compared with autoptic specimens derived from local invasion and metastasis using in situ hybridization and immunohistochemical techniques. RESULTS: Intact D2R mRNA was found in the primitive tumor and metastatic tissues, whereas protein for the same receptor was present only in the tissues derived from neurosurgical operations and not in the metastases obtained post-mortem. CONCLUSION: This is the first report of the absence of D2R protein despite the retention of the transcript in an advanced stage of a malignant prolactinoma. The findings of this single case suggest the hypothesis that postranscriptional mechanisms may contribute to the development of dopamine resistance in prolactinomas.

Radioimmunoassay of insulin-like growth factors I and II in the cerebrospinal fluid of patients with pituitary and other central nervous system tumors.

Tumor cells are characterized by abnormalities in growth and metabolism, including the autocrine secretion of certain growth factors. On the basis of our previous demonstration of the production of insulin-like growth factors (IGFs) and their binding proteins by central nervous system (CNS) tumors, we asked whether the levels of IGFs in the CSF may be altered in patients with pituitary and other CNS tumors and may reflect autocrine secretion. We used specific radioimmuoassays for IGF-I and -II and measured these growth factors in the cerebrospinal fluid (CSF) from 26 patients with tumors located adjacent to the ventricular system. The tumors included were eight pituitary tumors (five nonsecreting, three growth hormone secreting), five gliomas, two meningiomas, five medulloblastomas, three metastases, and three other tumors. CSF from patients without tumors served as controls. For radioimmunoassay, CSF was treated with acetic acid overnight and IGF-binding proteins were separated from IGFs by C-2 solid phase cartridge extraction. The pituitary tumors were characterized by significantly elevated levels of IGFs in the CSF. In nonseceting pituitary tumors, the levels of IGF-I in the CSF were similar to normal levels, whereas IGF-II levels were significantly elevated. In acromegalic patients, levels of both IGF-I and -II in the CSF were significantly elevated compared with normal levels and compared with levels in patients with nonsecreting tumors. In contrast, the levels of IGFs in the CSF from most of the primary and metastatic CNS CNS tumors did not significantly differ from normal values. In summary, although IGFs may contribute to the regulation of cell growth in primary CNS tumors, CSF levels are not elevated.(ABSTRACT TRUNCATED AT 250 WORDS)

The cerebrospinal fluid from patients with prolactinoma promotes neurite growth of sensory neurones.

The cerebrospinal fluid (CSF) of patients with hypophysis adenomas was used to investigate its effect on organotypic cultures of dorsal root ganglia (DRG) of 10-11 day old chick embryo. Only the CSF from patients with prolactinoma showed a neurite-stimulating effect compared with other hypophysis adenomas.

[The stimulating effect of prolactin on the neurite growth of sensory neurons in an organotypic culture]. / Stimuliruiushchee vliianie prolaktina na rost neiritov chuvstvitel'nykh neironov v organotipicheskoi kul'ture.

Prolactine was found to promote neurite extension in chick embryo dorsal root ganglia in vitro. This hormone was active at the concentration 10-50 ng/ml provided extensive neurite outgrowth in the bioassay, compared to the control. The liquor from patients with prolactinoma was also found to promote neurite extension. This fact may be used for prolactinoma diagnostics.

[An autopsy case of primary intracranial squamous cell carcinoma].

An autopsied case of primary intracranial squamous cell carcinoma (PISCC) is reported, and 25 previously reported cases of PISCC, followed by the Garcia's criteria, are reviewed. A 72-year-old female was admitted to our service with chief complaints of headache and nausea on March 30, 1988. She had no neurological deficits on admission. However, CT examination revealed a round mass lesion in the left hypothalamus with dislocation of the brain stem. The cerebrospinal fluid (CSF) examination showed squamous cell carcinoma cytologically, and slightly higher levels of beta-HCG (13.0 ng/ml) and CEA (14.2 ng/ml). Because of progressive worsening in the level of her consciousness, total removal of a suprasellar tumor was performed on April 19, 1988. Gross appearance of the tumor was yellowish, soft and encapsulated. Histologically, it was squamous cell carcinoma. She did well for several days after the operation, then deteriorated. Finally she expired because of dissemination of the carcinoma on May 14, 1988. Postmortem examination revealed a large mass of squamous cell carcinoma in her right cerebellopontine angle. Except for that in the brain, no cancer was found in her body. Immunohistological study of the tumor specimen demonstrated positive for HCG in some of the large-sized neoplastic cells. Twenty-six cases of PISCC have been reported previously, so far. However, 21 cases out of the 26 PISCC were thought to have originated from intracranial epidermoid, one from the dermoid and the other one from craniopharyngioma. In the other three cases of PISCC, including the present case, the origin of the tumor was not able to be identified.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunoreactive human chorionic gonadotrophin from the cyst fluid and CSF of patients with craniopharyngioma.

A specific radioimmunoassay for the beta-chain of human chorionic gonadotrophin irHCG beta has demonstrated HCG-like material to be present in craniopharyngioma cyst fluid in nine consecutive patients with craniopharyngioma. There was no detectable LH/HCG bioactivity as assessed using testosterone production from isolated Leydig cells from rat testis in seven samples tested. One patient was also found to have measurable irHCG beta in the cerebrospinal fluid (CSF), which fell to undetectable levels following surgery; in this patient, there was clinical evidence that the cyst fluid had leaked into the CSF pre-operatively. Immunocytochemical staining for HCG beta and intact HCG was positive in five of the tumours. irHCG beta was not measurable in the serum of any of the patients.

[Metabolic pool of free amino acids in the blood and cerebrospinal fluid of patients with pituitary adenoma before and after proton therapy]. / Metabolicheskii fond svobodnykh aminokislot krovi i spinnomozgovoi zhidkosti u bol'nykh adenomoi gipofiza do i posle protonnoi terapii.

A pool of free amino acids was studied in blood and cerebrospinal fluid of 34 patients with adenoma of hypophysis before proton therapy and within 3 years after the treatment. The course of proton therapy was shown to cause a regression of the disease, a decrease in content of somatotropic hormone in blood as well as to normalize the metabolic pool of amino acids in blood and cerebrospinal fluid.