Telomere length and TERT abnormalities in pituitary adenomas.

OBJECTIVES: Pituitary adenomas (PAs) are among the most frequent intracranial tumors in humans. Abnormal telomerase activity and telomere lengthening are features of tumor cells. They may result from mutations in TERT promoter region, gene amplification or aberrant DNA methylation pattern. Such changes were found in variety of tumors including those of brain. Aim of the study was to evaluate the incidence of TERT abnormalities and to assess their role in telomere lengthening in PAs. METHODS: Study involved 101 patients with PA including both nonfunctioning and functioning subtypes. Telomerase length as well as TERT mRNA level and gene amplification were estimated using quantitative PCR (qPCR). Promoter mutations were assessed using Sanger sequencing. The results from genome-wide DNA methylation profiling with HumanMethylation 450K (Illumina) were used for the analysis of TERT locus. RESULTS: Variable telomere length was observed in patients, however no relationship with clinicopathological features was found. We observed a missense variant in TERT promoter in one patient only whereas increased TERT copy number were identified in 6 patients (5.6%). However no relationship between these results and telomere length or TERT expression was found. DNA methylation at TERT locus was not found to be changed when adenoma samples and normal tissue sections were compared. CONCLUSION: The results indicate that telomerase abnormalities do not play a role in pathogenesis of pituitary tumors.

Microsatellite instability analysis in pituitary adenomas.

OBJECTIVE: Mutator phenotypes with microsatellite instability (MSI) are observed in a subset of solid tumors including those localized in the brain. MSI arises from impaired DNA mismatch repair. It can be a potential marker of resistance to radiation and chemotherapy, as demonstrated for several cancer types. Our study aims are to investigate MSI incidence in pituitary adenomas (PA) with a currently recommended methodology. METHODS: DNA was obtained from 107 patients with PA of which 83 adenomas were nonfunctioning, 13 somatotrophic, 9 lactotrophic and 2 corticotrophic. These were examined for MSI status by PCR and capillary electrophoresis using five quasimonomorphic microsatellite markers: BAT25, BAT26, NR21, NR24 and NR27; in accordance to current Bethesda guidelines. RESULTS AND CONCLUSION: No microsatellite instability was detected in the tumor samples thus implying the lack of any clinical usefulness of MSI testing in PA cases.

Alternative splicing of iodothyronine deiodinases in pituitary adenomas. Regulation by oncoprotein SF2/ASF.

Pituitary tumors belong to the group of most common neoplasms of the sellar region. Iodothyronine deiodinase types 1 (DIO1) and 2 (DIO2) are enzymes contributing to the levels of locally synthesized T3, a hormone regulating key physiological processes in the pituitary, including its development, cellular proliferation, and hormone secretion. Previous studies revealed that the expression of deiodinases in pituitary tumors is variable and, moreover, there is no correlation between mRNA and protein products of the particular gene, suggesting the potential role of posttranscriptional regulatory mechanisms. In this work we hypothesized that one of such mechanisms could be the alternative splicing. Therefore, we analyzed expression and sequences of DIO1 and DIO2 splicing variants in 30 pituitary adenomas and 9 non-tumorous pituitary samples. DIO2 mRNA was expressed as only two mRNA isoforms. In contrast, nine splice variants of DIO1 were identified. Among them, five were devoid of exon 3. In silico sequence analysis of DIO1 revealed multiple putative binding sites for splicing factor SF2/ASF, of which the top-ranked sites were located in exon 3. Silencing of SF2/ASF in pituitary tumor GH3 cells resulted in change of ratio between DIO1 isoforms with or without exon 3, favoring the expression of variants without exon 3. The expression of SF2/ASF mRNA in pituitary tumors was increased when compared with non-neoplastic control samples. In conclusion, we provide a new mechanism of posttranscriptional regulation of DIO1 and show deregulation of DIO1 expression in pituitary adenoma, possibly resulting from disturbed expression of SF2/ASF.

Fluorescence-guided resection of primary and recurrent malignant gliomas with 5-aminolevulinic acid. Preliminary results.

BACKGROUND AND PURPOSE: Extent of resection plays a key role in the treatment of malignant gliomas (MGs). Patients with complete glioma removal, followed by chemoradiation, obtain the longest overall and progression-free survival. Fluorescence-guided resection of MGs enables intraoperative visualization of glioma tissue and increases control of the resection. The authors present preliminary results of 5-aminolevulinic acid (5-ALA) application during the resection of primary and recurrent MGs. MATERIAL AND METHODS: Six patients with either a suspected malignant glioma based on magnetic resonance imaging (MRI) or with recurrent glioblastoma multiforme were enrolled in the study. The extent of resection was calculated according to the postoperative MRI performed within 72 hours. Preoperative and early postoperative neurological status and Karnofsky Performance Scale (KPS) were compared. RESULTS: Fluorescence of tumour tissue was observed in 5/6 patients (five with the histopathological diagnosis of glioblastoma multiforme and one with neurotoxoplasmosis and AIDS). Complete tumour resection was achieved in 5 patients. Postoperative KPS and neurological status deteriorated in 2 cases. Radiotherapy and chemotherapy did not interfere with the sensitivity of the fluorescence guided tumour visualization. CONCLUSIONS: Fluorescence-guided resection of primary and recurrent MGs with 5-ALA improves control of the tumour resection. It enables the cytoreduction to be maximized but experience in neuro-oncological surgery is required to avoid serious, postoperative neurological deficits.

Statistical analysis of the intracranial procedures in Poland in 2008-2009.

BACKGROUND AND PURPOSE: Quantitative and qualitative analysis of neurosurgical procedures provides important data for assessment of the development and trends in the field of neurosurgery. The authors present statistical data on intracranial procedures (IPs) performed in Poland in 2008-2009. MATERIAL AND METHODS: Data on IPs come from reports of the National Health Fund, grouped according to the system of Diagnosis-Related Groups, group A - nervous system diseases. Data concerning the year 2009 include all IPs performed in Poland. Data from the second half of 2008 to 2009 (18 months) come from 35 neurosurgical centers in Poland, divided by provinces. We analyzed the number of IPs, the cost of procedures, duration of hospitalization and deaths. RESULTS: 20 849 IPs were performed in Poland in 2009. The most common procedure was A12 (6807; 32.65%), and the rarest was A04 (96; 0.46%). The annual cost of all IPs was 228 599 956 PLN. Average cost of the procedure ranged from 1578 PLN (A14) to 47 940 PLN (A03). Duration of the hospitalization ranged between 3 days (A14) and 12 days (A12). The highest percentage of deaths was reported for A01 (n = 1050, 19.06%). Reports from 35 neurosurgical centers in the second half of 2008 and 2009 showed the highest number of IPs per 100 000 population in Kujawsko-Pomorskie (93) and the lowest in Wielkopolskie (27) and Podkarpackie (27). The highest number of IPs (1669) was performed in neurosurgical center M1 (Malopolskie), and the lowest (99) in W1 (Wielkopolskie). CONCLUSIONS: A significant disparity in the number of IPs performed in different centers in Poland was observed.

Motor cortex stimulation in the treatment of neuropathic pain.

BACKGROUND AND PURPOSE: Despite the rapid development of neuropharmacotherapy, medical treatment of neuropathic pain (NP) still constitutes a significant socioeconomic problem. The authors herein present a group of patients treated with motor cortex stimulation (MCS) for NP of various types and aetiologies. MATERIAL AND METHODS: Our cohort included 12 female and 11 male NP patients aged 53 ± 16 treated with MCS. Eleven patients were diagnosed with neuropathic facial pain (NFP), 8 with hemi-body neuropathic pain (HNP), and 4 with deafferentation pain (DP). Prior to surgery, 16 out of 23 patients were treated with repetitive transcranial magnetic stimulation (rTMS), with a positive response in 10 cases. Pain intensity in our group was evaluated with the visual analogue scale (VAS) one month before and three months after MCS implantation. RESULTS: Improvement on the VAS was reported in the whole group of patients (p < 0.001). The best results were reported in the NFP group (p < 0.001) while the worst ones were noted in the DP group (p = 0.04). Anamnesis duration positively correlated with outcome. Infection forced the authors to permanently remove the system in one case. There were no other complications in the group. CONCLUSIONS: Minimally invasive, safe neuromodulative treatment with MCS permits neuropathic pain control with good efficacy. The type of neuropathic pain might be a prognostic factor.

Rosette-forming glioneuronal tumor of the fourth ventricle with advanced microvascular proliferation--a case report.

Rosette-forming glioneuronal tumor (RGNT) of the fourth ventricle is a recently described novel type of primary brain tumor that was included into the current WHO classification of CNS tumors. It is a very rare, slowly growing, mixed neoplasm at cerebellar localization with distinctive morphological pattern. We present an unusual case of a 20-year-old patient with RNGT of the fourth ventricle with advanced microvascular proliferation. MRI revealed the solid-cystic tumor mass largely involving the cerebellar vermis and left hemisphere with compression of the fourth ventricle. Microscopically, the tumor showed classical architectural pattern with two distinctive components. The main component consisted of neurocytic rosettes formed by round, isomorphic nuclei arranged around eosinophilic, fibrillar cores with strong synaptophysin expression. The perivascular rosettes with cell arrangement along blood vessels were observed only sporadically. The second neoplastic component consisted of spindle or stellate astroglial cells with piloid process and Rosenthal fibers, strongly resembling pilocytic astrocytoma. Focally, the astroglial cells showed increased cellularity but without marked nuclear atypia. The glial part of the tumor revealed advanced proliferation of microvessels. The vessels of glomeruloid type exhibited multilayered endothelial proliferation and marked mitotic activity. MIB1 labelling index was generally low; however, in areas exhibiting microvascular proliferation its expression was significantly increased up to 20%. This report demonstrates the unique case of RGNT with conspicuous microvascular proliferation of glomeruloid type and extensive endothelial proliferation. As there is still limited clinical experience with RGNT, further studies are necessary to evaluate the biology of this type of tumor.

Thalamic deep brain stimulation in the treatment of essential tremor.

BACKGROUND AND PURPOSE: Quality of life can be severely impaired by essential tremor (ET) being the main cause of the patient's disability. The authors present a group of ET patients treated with deep brain stimulation of the ventral intermediate nucleus of the thalamus (Vim DBS). The aim of the study was to evaluate the efficacy and safety of Vim DBS in the treatment of ET. MATERIAL AND METHODS: Between 2006 and 2009, 8 female and 10 male ET patients were treated with Vim DBS. Mean age at implantation was 63 ± 15 years. ET lasted from 4 to 30 years (mean 12 years). Clinical condition of the group was evaluated before surgery and 3 months after implantation with spirography (spiral drawings), the modified Fahn (Tremor Rating Scale, TRS) scale, and the modified ADL (Activity of Daily Living) scale. The Vim was localized with CT and MRI. The procedures of implantation were performed under local and general anaesthesia. A bilateral procedure was performed in 11 cases and a unilateral procedure was performed in 7 cases. RESULTS: The therapeutic effect of DBS was maintained at the follow-up in the third month following surgery. Mean contralateral limb tremor reduction was 79%. Head tremor reduction was reported by 75% of patients in the bilateral Vim DBS subgroup and 50% of patients in the unilateral Vim DBS subgroup. Mean ADL score improved by 61%. CONCLUSIONS: Vim DBS is a safe and effective method of ET treatment. Vim DBS improves activities of daily living of ET patients.

Subthalamic deep brain stimulation for the treatment of Parkinson disease.

BACKGROUND AND PURPOSE: The role of subthalamic nucleus deep brain stimulation (STN DBS) in the treatment of Parkinson disease (PD) is well established. The authors present a group of patients diagnosed with PD who were treated with STN DBS. MATERIAL AND METHODS: Between 2008 and 2009, 32 female and 34 male patients with PD were treated with STN DBS. Mean age at implantation was 57 ± 12 years. PD lasted from 6 to 21 years (mean 10 years). Patients were qualified for the surgery according to the CAPSIT-PD criteria. The STN was identified with direct and indirect methods. Macrostimulation and microrecording for STN identification were used in all cases. A unilateral STN DBS system was implanted in two cases and bilateral implantation was performed among rest of the group. Outcome was assessed six months after implantation. Results : The mean reduction of UPDRS III score among 51 patients who underwent follow-up was 45% (5-89%). Reduction of levodopa consumption varied from 15 to 100%. Infection forced the authors to remove the DBS system in one case four months after implantation. Skin erosion above the internal pulse generator was noted in four cases. CONCLUSIONS: Cardinal symptoms of Parkinson's disease can be safely and effectively treated with STN DBS in selected group of patients.

Invasive and Noninvasive Nonfunctioning Gonadotroph Pituitary Tumors Differ in DNA Methylation Level of LINE-1 Repetitive Elements.

PURPOSE: Epigenetic dysregulation plays a role in pituitary tumor pathogenesis. Some differences in DNA methylation were observed between invasive and noninvasive nonfunctioning gonadotroph tumors. This study sought to determine the role of DNA methylation changes in repetitive LINE-1 elements in nonfunctioning gonadotroph pituitary tumors. METHODS: We investigated LINE-1 methylation levels in 80 tumors and normal pituitary glands with bisulfite-pyrosequencing. Expression of two LINE-1 open reading frames (L1-ORF1 and L1-ORF2) was analyzed with qRT-PCR in tumor samples and mouse gonadotroph pituitary cells treated with DNA methyltransferase inhibitor. Immunohistochemical staining against L1-ORF1p was also performed in normal pituitary glands and tumors. RESULTS: Hypomethylation of LINE-1 was observed in pituitary tumors. Tumors characterized by invasive growth revealed lower LINE-1 methylation level than noninvasive ones. LINE-1 methylation correlated with overall DNA methylation assessed with HM450K arrays and negatively correlated with L1-ORF1 and L1-ORF2 expression. Treatment of αT3-1 gonadotroph cells with 5-Azacytidine clearly increased the level of L1-ORF1 and L1-ORF2 mRNA; however, its effect on LßT2 cells was less pronounced. Immunoreactivity against L1-ORF1p was higher in tumors than normal tissue. No difference in L1-ORF1p expression was observed in invasive and noninvasive tumors. CONCLUSION: Hypomethylation of LINE-1 is related to invasive growth and influences transcriptional activity of transposable elements.

Thalamic deep brain stimulation for tremor among multiple sclerosis patients.

BACKGROUND AND PURPOSE: Disabling tremor might be the main cause of disability of multiple sclerosis (MS) patients. Neuromodulation with deep brain stimulation of the thalamic nucleus ventralis intermedius (Vim DBS) is a well accepted method of neurosurgical treatment of tremor related to essential tremor or Parkinson disease. Vim DBS is not widely used to control MS tremor. MATERIAL AND METHODS: Five MS patients with tremor (3 females and 2 males) were treated with Vim DBS. Age at implantation was 37 ± 5 years. MS lasted from 5 to 12 years (mean 6) and tremor was the main cause of disability of those patients from 2 to 5 years (mean 3) before surgery. Clinical condition of the group was evaluated with spirography, the modified Fahn scale and the modified Activity of Daily Living (ADL) scale. Evaluations were performed before surgery and 3 months after surgery. MRI exclusion criteria were the presence of a thalamic hyperintense signal in T2-weight-ed images or ventricular enlargement. The procedures of implantation were performed under local and general anaesthesia. RESULTS: Intensity of contralateral limb tremor during intraoperative macrostimulation was reduced in the whole group. The therapeutic effect of DBS was maintained at three-month follow-up. Mean contralateral limb tremor reduction was 40%. Mean ADL score improved by 18%. No mortality or morbidity was reported in the group. CONCLUSIONS: The study confirms the value and safety of Vim DBS for treatment of MS-related tremor. Further study on a larger population and introduction of a qualification protocol might increase efficacy of the treatment.

Neuroendocrine tumours of rare location.

Neuroendocrine tumours (NETs) arising from dispersed endocrine system may originate from almost every location, although they are most commonly found in the gastrointestinal tract and respiratory system. NETs are considered as particularly rare if they constitute less than 1% of all neuroendocrine tumours. The aim of the paper is to present ten rare NETs from the database of the Endocrinology Department of the Jagiellonian University, Medical College: 4 NETs of the ampulla of Vater, 2 of the gallbladder, and 1 of the ovary, sphenoid sinus, Meckel's diverticulum, and epiglottis. The clinical presentation of such tumours and their management are discussed.

MRI image characteristics of materials implanted at sellar region after transsphenoidal resection of pituitary tumours.

BACKGROUND: Post-surgical evaluation of the pituitary gland in MRI is difficult because of a change in anatomical conditions. It depends also on numerous other factors, including: size and expansion of the tumour before surgery, type of surgical access, quality and volume of implanted materials and time of its resorption. The purpose was to demonstrate the characteristics of the implanted materials on MRI performed after transsphenoidal resection of pituitary tumours and to identify imaging criteria helpful in differential diagnosis of masses within the sellar region. MATERIAL/METHODS: One hundred and fifty-four patients after transsphenoidal resection of pituitary tumours were included in the study. In general, 469 MRI examinations were performed with a 1.5T scanner. We obtained T1-weighted sagittal and coronal, enhanced and unenhanced images. In 102 cases, additional T2-weighted coronal, unenhanced images with 1.5 T unit were obtained as well. RESULTS: The implanted materials appeared in 95 patient: fat in 86 and muscle with fascia in 3 patients. We could recognise implanted muscle and fascia in T2-weighted images, because of high signal intensity of the degenerating muscle and the line of low signal representing fascia. The implanted titanium mesh was found in 4 patients. Haemostatic materials were visible only in 2 patients in examinations performed at an early postoperative stage (1 month after the procedure). CONCLUSIONS: The knowledge of MRI characteristics of the materials implanted at the sellar region is very important in postoperative diagnosis of pituitary tumours and may help discriminate between tumorous and non-tumorous involvement of the sellar region. Some implanted materials, like fat, could be seen on MRI for as long as 10 years after the operation, others, like haemostatic materials, for only 1 month after surgery. T2-weighted imaging is a useful assessment method of the implanted muscle and fascia for a long time after surgery.

The Search of miRNA Related to Invasive Growth of Nonfunctioning Gonadotropic Pituitary Tumors.

PURPOSE: Nonfunctioning gonadotropic pituitary neuroendocrine tumors (PitNETs) are among the most frequent neoplasms of pituitary gland. Although PitNETs are commonly considered benign, a notable part of patients suffer from tumor recurrence after treatment. Invasive growth of pituitary tumor is among the most important prognostic factors. Since molecular features of invasiveness are of potential clinical usefulness, this study was aimed to verify whether invasive and noninvasive nonfunctioning gonadotropic PitNETs differ in the miRNA expression profile and whether the differences could provide a possible molecular classifier. METHODS: miRNA profiles were determined in 20 patients (11 invasive and 9 noninvasive tumors) using next-generation sequencing. The expression of selected miRNAs was assessed in the independent cohort of 80 patients with qRT-PCR. RESULTS: When miRNA profiles of invasive and noninvasive tumors were compared, 29 miRNAs were found differentially expressed. Hsa-miR-184, hsa-miR-181a-2-3p, hsa-miR-93-3p, hsa-miR-574-5p, hsa-miR-185-5p, and hsa-miR-3200-5p showed a potential clinical value according to ROC curve analysis. Unfortunately, differential expression of only hsa-miR-185-5p was confirmed in the validation cohort, with AUG at 0.654. CONCLUSION: Differences in miRNAs expression profiles in invasive and noninvasive gonadotropic PitNETs are slight and the level of miRNA expression seems not to be applicable as useful classifier of tumor invasiveness.

DNA Methylation Influences miRNA Expression in Gonadotroph Pituitary Tumors.

microRNAs are involved in pathogenesis of cancer. DNA methylation plays a role in transcription of miRNA-encoding genes and may contribute to changed miRNA expression in tumors. This issue was not investigated in pituitary neuroendocrine tumors (PitNETs) previously. DNA methylation patterns, assessed with HumanMethylation450K arrays in 34 PitNETs and five normal pituitaries, were used to determine differentially methylated CpGs located at miRNA genes. It showed aberrant methylation in regions encoding for 131 miRNAs. DNA methylation data and matched miRNA expression profiles, determined with next-generation sequencing (NGS) of small RNAs, were correlated in 15 PitNETs. This showed relationship between methylation and expression levels for 12 miRNAs. DNA methylation and expression levels of three of them (MIR145, MIR21, and MIR184) were determined in the independent group of 80 tumors with pyrosequencing and qRT-PCR and results confirmed both aberrant methylation in PitNETs and correlation between methylation and expression. Additionally, in silico target prediction was combined with analysis of established miRNA profiles and matched mRNA expression pattern, assessed with amplicon-based NGS to indicate putative target genes of epigenetically deregulated miRNAs. This study reveals aberrant DNA methylation in miRNA-encoding genes in gonadotroph PitNETs. Methylation changes affect expression level of miRNAs that regulate putative target genes with tumorigenesis-relevant functions.

USP8 mutations in corticotroph adenomas determine a distinct gene expression profile irrespective of functional tumour status.

OBJECTIVE: Pituitary corticotroph adenomas commonly cause Cushing's disease (CD) but part of these tumours are hormonally inactive (silent corticotroph adenomas, SCA). USP8 mutations are well-known driver mutations in corticotrophinomas. Differences in transcriptomic profiles between functioning and silent tumours or tumours with different USP8 status have not been investigated. DESIGN AND METHODS: Forty-eight patients (28 CD, 20 SCA) were screened for USP8 mutations with Sanger sequencing. Twenty-four patients were included in transcriptomic profiling with Ampliseq Transcriptome Human Gene Expression Core Panel. The entire patients group was included in qRT-PCR analysis of selected genes expression. Immunohistochemistry was used for visualization of selected protein. RESULTS: We found USP8 mutation in 15 patients with CD and 4 SCAs. USP8 mutations determine molecular profile of the tumours as showed by hierarchical clustering and identification of 1648 genes differentially expressed in USP8-mutated and USP8-wild-type tumours. Mutations affect many molecular pathways as observed in Gene Set Enrichment analysis. USP8-mutated adenomas showed higher level of POMC, CDC25A, MAPK4 but lower level of CCND2, CDK6, CDKN1B than USP8-wt tumours. Eighty-seven genes differentially expressed between CD-related adenomas and SCAs were found, including those involved in cell signalling (GLI2, DLC1, TBX2, RASSF6), cell adhesion (GJA1, CDH6), ion transport (KCNN4, KCNJ5) and GABA signalling (GABBR2, GABRD). CONCLUSION: USP8 mutations occur in functioning and silent corticotrophinomas. They have pleiotropic effect, not limited to EGFR signalling, and affect expression levels of many genes involved in different pathways. Expression of GABA-related genes GABBR2, GNAL, GABARD and KCNJ5 correspond to functional status of the tumours.

The Role of Aberrant DNA Methylation in Misregulation of Gene Expression in Gonadotroph Nonfunctioning Pituitary Tumors.

Gonadotroph nonfunctioning pituitary adenomas (NFPAs) are common intracranial tumors, but the role of aberrant epigenetic regulation in their development remains poorly understood. In this study, we investigated the effect of impaired CpG methylation in NFPAs. We determined DNA methylation and transcriptomic profiles in 32 NFPAs and normal pituitary sections using methylation arrays and sequencing, respectively. Ten percent of differentially methylated CpGs were correlated with gene expression, and the affected genes are involved in a variety of tumorigenesis-related pathways. Different proportions of gene body and promoter region localization were observed in CpGs with negative and positive correlations between methylation and gene expression, and different proportions of CpGs were located in 'open sea' and 'shelf/shore' regions. The expression of ~8% of genes differentially expressed in NFPAs was related to aberrant methylation. Methylation levels of seven CpGs located in the regulatory regions of FAM163A, HIF3A and PRSS8 were determined by pyrosequencing, and gene expression was measured by qRT-PCR and immunohistochemistry in 83 independent NFPAs. The results clearly confirmed the negative correlation between methylation and gene expression for these genes. By identifying which aberrantly methylated CpGs affect gene expression in gonadotrophinomas, our data confirm the role of aberrant methylation in pathogenesis of gonadotroph NFPAs.

DNA methylation profiling in nonfunctioning pituitary adenomas.

Nonfunctioning pituitary adenomas (NFPAs) are among the most frequent intracranial tumors but their molecular background, including changes in epigenetic regulation, remains poorly understood. We performed genome-wide DNA methylation profiling of 34 NFPAs and normal pituitary samples. Methylation status of the selected genomic regions and expression level of corresponding genes were assessed in a group of 75 patients. NFPAs exhibited distinct global methylation profile as compared to normal pituitary. Aberrant DNA methylation appears to contribute to deregulation of the cancer-related pathways as shown by preliminary functional analysis. Promoter hypermethylation and decreased expression level of SFN, STAT5A, DUSP1, PTPRE and FGFR2 was confirmed in the enlarged group of NFPAs. Difference in the methylation profiles between invasive and non-invasive NFPAs is very slight. Nevertheless, invasiveness-related aberrant epigenetic deregulation of the particular genes was found including upregulation of ITPKB and downregulation CNKSR1 in invasive tumors.

Mutational Analysis of Recurrent Meningioma Progressing From Atypical to Rhabdoid Subtype.

BACKGROUND: Rhabdoid meningioma is rare aggressive meningioma histological subtype that develops predominantly through progression from less malignant tumors. Owing to its low incidence, this tumor's biological background is unknown. The aim of this study was to profile somatic mutations in 4 meningioma samples from the same patient, derived previously from 4 subsequent tumor resections. CASE DESCRIPTION: A 58-year-old woman presented with recurrent meningioma progressing from atypical to rhabdoid subtype. Four tumor samples that represent a primary tumor (atypical GII) and 3 recurrent tumors that were subsequently removed (anaplastic GIII, rhabdoid GIII, and anaplastic/rhabdoid GIII) from this patient were subjected to mutational analysis of coding sequences of 952 tumor-related genes. Three mutations were identified in all tumor samples exhibiting a high allelic frequency: ARID1A frameshift deletion, NF2 in-frame deletion, and missense variant of SRSF2. The predicted inactivating effect of ARID1A deletion was confirmed by immunohistochemical staining of tumor sections in which a high proportion of cells lacked protein expression. Additional low-allelic-fraction mutations were observed in all tumor samples, likely representing "passenger," low-effect mutations that reflect a clonal selection of tumor cells through malignant progression of the meningioma. CONCLUSION: The mutation of ARID1A that encodes the subunit of the SWI/SNF complex represents the most likely driver of the tumor's malignant potential. It also may be involved in the acquisition of the rhabdoid phenotype, given that mutations in chromatin remodeling proteins are the hallmark of atypical teratoid/rhabdoid tumors.

Ganglion cell tumours in the sella turcica in close morphological connection with pituitary adenomas.

Ganglion cell tumours in the sellar region are uncommon. They are usually associated with pituitary adenomas, while isolated ganglion cell neoplasms are extremely rare. We report the clinicopathological studies of five cases diagnosed as ganglion cell tumours located in the intrasellar region: four mixed/collision tumours composed of gangliocytoma and pituitary adenoma, and one isolated ganglioglioma unrelated to adenoma. Clinically, two patients presented with acromegaly, while three others were initially diagnosed as non-functioning adenomas. In four cases, the histopathological examination of surgical specimens revealed intermixed lesions composed of pituitary adenoma and ganglion cell elements. The adenomas appeared to secrete growth hormone. Electron microscopy enabled identification of the sparsely granulated somatotroph cells. Neoplastic neuronal lesions were composed of mature ganglion cells, including binucleate or multinucleate cells. In all cases, boundaries between adenomatous and gangliocytic components were not clearly demarcated, and numerous gangliocytic cells were closely intermingled with adenomatous tissue. One case lacked endocrine symptoms, and no pituitary adenoma was identified in the surgically excised material; it was finally diagnosed as low-grade ganglioglioma. The etiopathogenesis of ganglion cell neoplasms in the sellar region is not clearly defined. Our study revealed that if ganglion cell neoplasms were combined with adenoma, both neoplastic components were closely related to each other, and numerous neuronal elements were strictly intermingled with adenoma cells. Such a tissue pattern indicates that these neoplastic changes, including their common respective etiopathogeneses, are closely related. The identification of both components in sellar regions may have some nosological implications.