A patológus szerepe a központi idegrendszer tumorainak diagnosztikájában, a terápiatervezésben. Prognosztikus és prediktív markerek vizsgálata

Despite advances in imaging methods, the standard of diagnosis and treatment of the tumours of the nervous system remains the histological report issued by a neuropathologist. For reliable, definitive diagnosis, close collaboration with other medical professions is essential, correlation of histological findings with clinical and imaging results is necessary. Neuropathology became a subspecialty because of the specific knowledge and experience it requires. In more complex cases consultation with neuropathologists is important to ensure adequate diagnosis and subsequent treatment. In both establishing the diagnosis and treatment planning, the molecular testing of brain tumors becomes more and more important. These tests are reliably available only in larger centers. Out of the molecular markers, in current practice the investigation of codeletion at 1p/19q, IDH mutations, beta-katenin nuclear positivity and MGMT methylation gained acceptance. Besides these tests already in practice, a vast array of potential diagnostic and prognostic markers are being investigated, which in the future may assist in delivering better and more individualized therapy

Prostate-specific membrane antigen expression in the vasculature of primary lung carcinomas associates with faster metastatic dissemination to the brain

Glioblastomas and brain metastases (BM) of solid tumours are the most common central nervous system neoplasms associated with very unfavourable prognosis. In this study, we report the association of prostate-specific membrane antigen (PSMA) with various clinical parameters in a large cohort of primary and secondary brain tumours. A tissue microarray containing 371 cases of ascending grades of gliomas pertaining to astrocytic origin and samples of 52 cases of primary lung carcinomas with matching BM with follow-up time accounting to 10.4 years was evaluated for PSMA expression using immunohistochemistry. In addition, PSMA expression was studied in BM arising from melanomas and breast carcinomas. Neovascular expression of PSMA was evident alongside with high expression in the proliferating microvasculature of glioblastomas when compared to the tumour cell expression. This result correlated with the results obtained from the in silico (cancer genome databases) analyses. In gliomas, only the vascular expression of PSMA associated with poor overall survival but not the tumour cell expression. In the matched primary lung cancers and their BM (n = 52), vascular PSMA expression in primary tumours associated with significantly accelerated metastatic dissemination to the brain with a tendency towards poor overall survival. Taken together, we report that the vascular expression of PSMA in the primary and secondary brain tumours globally associates with the malignant progression and poor outcome of the patients.Peer reviewe

Next generation sequencing for characterization of mitochondrial genome in pituitary adenomas

Introduction Disrupted mitochondrial functions and genetic variations of mitochondrial DNA (mtDNA) have been observed in different tumors. Regarding pituitary adenomas mtDNA was evaluated only in oncocytic type using PCR based methods and it showed high prevalence of Complex I variants. Next generation sequencing (NGS) allows high throughput sequencing and it is useful for accurate identification of heteroplasmy of mitochondrial genome as well. Aim We aimed to investigate the entire mitochondrial genome in different adenoma types. Material and methods We collected 22 gonadotroph (GO), 11 growth hormone producing (GH) and 11 null-cell (NC) adenoma specimens from samples removed by transsphenoidal surgery. From fresh frozen tissues DNA extraction was performed using QIAamp Fast DNA Tissue Kit. For library preparation VariantPro™ Amplicon Mitochondrion Panel kit was used. The total mtDNA (16569 bp) was sequenced on Illumina MiSeq Instrument. Following complex bioinformatic analysis Revised Cambridge Reference Sequence (rCRS) of the human mitochondrial DNA was used as reference. Heteroplasmy was determined using 3% cutoff. Results. The whole mitochondrial genome were covered by 630±370 (avg±SE) reads per base. 496 variants were identified in adenomas compared to reference sequence. Overall a low (7.22%) heteroplasmy prevalence was found. Based on mitochondrial sequence variants by hierarchical cluster analysis we could not discriminate different adenoma types. No association between Ki-67 index or recurrent-nonrecurrent status of adenomas and mitochondrial variants were detected. Four variants appeared more often in null-cell adenomas compared to gonadotroph adenomas (chrM_188: 18% vs. 0%, chrM_16093: 18% vs. 0%, chrM_185: 27% vs. 0% and chrM_14798: 36% vs. 5%; Padj=0.0246, 0.0246, 0.01542 and 0.01829, respectively). Of these variants chrM_14798, chrM_4216 and chrM_15452 are non-synonymous polymorphisms leading to amino acid change in MT-CYB (mitochondrially encoded cytochrome b) and in MT-ND1 (mitochondrially encoded NADH dehydrogenase 1) genes. We identified chrM_16189 variant (non-protein coding variant) in 40% (6/15) of nonrecurrent adenomas compared to recurrent ones where this variant was not present (0/11) (p=0.0209). Conclusions Next-generation sequencing is a reliable method for investigating mitochondrial genome and heteroplasmy in pituitary adenomas. In pituitary adenomas the prevalence of heteroplasmy of mitochondrial genome is low suggesting that these alterations may not influence mitochondrial function considerably. Of pituitary tumours only null cell adenomas possess alterations of mitochondrial genome with potential functional consequences suggesting that during the development of this subtype of pituitary tumours mitochondrial function-associated mechanisms may have role

Region Specific Differences of Claudin-5 Expression in Pediatric Intracranial Ependymomas: Potential Prognostic Role in Supratentorial Cases

Ependymomas are common pediatric brain tumors that originate from the ependyma and characterized by poor prognosis due to frequent recurrence. However, the current WHO grading system fails to accurately predict outcome. In a retrospective study, we analyzed 54 intracranial pediatric ependymomas and found a significantly higher overall survival in supratentorial cases when compared to infratentorial tumors. Next we performed region-specific immunohistochemical analysis of the ependyma in neonatal and adult ependyma from the central canal of spinal cord to the choroid plexus of lateral ventricles for components of cell-cell junctions including cadherins, claudins and occludin. We found robust claudin-5 expression in the choroid plexus epithelia but not in other compartments of the ependyma. Ultrastructural studies demonstrated distinct regional differences in cell-cell junction organization. Surprisingly, we found that 9 out of 20 supratentorial but not infratentorial ependymomas expressed high levels of the brain endothelial tight junction component claudin-5 in tumor cells. Importantly, we observed an increased overall survival in claudin-5 expressing supratentorial ependymoma. Our data indicates that claudin-5 expressing ependymomas may follow a distinct course of disease. The assessment of claudin-5 expression in ependymoma has the potential to become a useful prognostic marker in this pediatric malignancy