Clinical Neuropathology最新文献

Purpose: To characterize expression of factors relevant for Ras signaling and developmental factors in a large series of peripheral nerve sheath tumors (PNST) obtained from patients with neurofibromatosis type 1 (NF1).

Materials and methods: Tissue micro-array technique was applied to study 520 PNST of 385 NF1 patients by immunohistochemistry for mTor, Rho, phosphorylated MEK, Pax7, Sox9, and periaxin expression. PNST comprised cutaneous neurofibroma (CNF) (n = 114), diffuse neurofibroma (DNF) (n = 109), diffuse plexiform neurofibroma (DPNF) (n = 108), plexiform neurofibroma (PNF) (n = 110), and malignant PNST (MPNST) (n = 22).

Results: All proteins examined showed highest expression levels/highest frequency of expression in MPNST. Benign PNF with potential for malignant dedifferentiation expressed mTor, phosphorylated MEK, Sox9, and periaxin significantly higher/more frequently than other benign neurofibroma subtypes.

Conclusion: In NF1-associated PNST, expression of proteins involved in Ras-signaling and development is upregulated not only in MPNST, but also in benign PNF with the potential for malignant dedifferentiation. The differences in protein expression may provide clues for understanding the therapeutic effects of substances applied for reduction of PNST in NF1.

Molecular characterization has become a key diagnostic tool for the classification and grading of primary brain tumors. Molecular markers, such as isocitrate dehydrogenase (IDH) mutation status, 1p/19q codeletion, methylation of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter, or CDKN2A/B homozygous deletion discriminate different tumor entities and grades, and play a crucial role for treatment response and prognosis. In recent years, magnetic resonance imaging (MRI), whose main functions has been to detect a tumor, to provide spatial information for neurosurgical and radiotherapy planning, and to monitor treatment response, has shown potential in assessing molecular features of gliomas from image-based biomarkers. As an outstanding example, numerous studies have proven that the T2/FLAIR mismatch sign can identify IDH-mutant, 1p/19q non-codeleted astrocytomas with a specificity of up to 100%. For other purposes, multiparametric MRI, often coupled with machine learning methods, seems to achieve the highest accuracy in predicting molecular markers. Relevant future applications might be anticipating changes in the molecular composition of gliomas and providing useful information about the cellular and genetic heterogeneity of gliomas, especially in the non-resected tumor parts.

Brain metastases are the most common central nervous system malignancy, and the leading cause of cancer-related deaths. Non-small cell lung carcinomas (NSCLC) comprise the most common cell of origin. Immunotherapy, particularly checkpoint inhibitors, has emerged as the standard of care for many patients with advanced lung cancer. Pannexin1 (PANX1) is a transmembrane glycoprotein that forms large-pore channels and has been reported to promote cancer metastasis. However, the roles of PANX1 in lung cancer brain metastases and tumor immune microenvironment have not been characterized. 42 patient-matched formalin-fixed paraffin-embedded tissue samples from lung carcinomas and the subsequent brain metastases were constructed into three tissue microarrays (TMAs). PANX1 and markers of tumor-infiltrating immune cells (CD3, CD4, CD8, CD68, and TMEM119) were assessed using immunohistochemistry and digital image analysis. The expression of PANX1 was significantly higher in brain metastases than in their paired primary lung carcinoma. The high levels of PANX1 in lung carcinoma cells in the brain inversely correlated with infiltration of peripheral blood-derived macrophages. Our findings highlight the role of PANX1 in the progression of metastatic NSCLC, and the potential therapeutic approach of targeting PANX1 enhances the efficacy of immune checkpoint inhibitors in brain metastasis.

There are no international guidelines for brain biopsy in neurological disease of unknown etiology, yet most practicing neurologists will encounter difficult cases in which biopsy is considered. This patient cohort is heterogenous, and it is unclear in which circumstances biopsy is most useful. We performed an audit of brain biopsies reviewed in our neuropathology department from 2010 to 2021. Of 9,488 biopsies, 331 biopsies undertaken for an undiagnosed neurological disease were identified. Where documented, the commonest symptoms were hemorrhage, encephalopathy, and dementia. 29% of biopsies were non-diagnostic. The most common clinically relevant findings on biopsy were infection, cerebral amyloid angiopathy with or without angiitis, and demyelination. Rarer conditions included CNS vasculitis, non-infectious encephalitis, and Creutzfeldt Jakob Disease. We highlight the value of brain biopsy in the workup of cryptogenic neurological disease despite recent advances in less invasive diagnostics.

Delineation of the autoimmune encephalitides with antibodies against neural surface antigens (anti-N-Methyl-D-aspartate, anti-leucine-rich glioma-inactivated protein 1, and others), autoimmune-associated epilepsies (Rasmussen encephalitis, paraneoplastic encephalitides, temporal lobe epilepsy with antibodies against glutamic acid decarboxylase), and encephalomyelitides with glial antibodies (neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein antibody disease) has been a major advance in neurology. But how do these inflammatory diseases "work"? What kind of interaction between elements of the immune system and brain cells leads to these conditions? The only direct way of answering these questions is to investigate affected brain tissue by neuropathological techniques. They provide morphological and, in part, temporal information on the elements and localization of the disease process. Molecular techniques broaden and support these data. Brain tissue becomes available through autopsies and brain biopsies, obtained for diagnostic or therapeutic interventions. The limitations of neuropathological pathogenic research are discussed. Finally, representative neuropathological findings in autoimmune encephalitides and related conditions are summarized.

We previously reported on the first neuropathological round robin trials operated together with Quality in Pathology (QuIP) GmbH in 2018 and 2019 in Germany, i.e., the trials on IDH mutational testing and MGMT promoter methylation analysis [1]. For 2020 and 2021, the spectrum of round robin trials has been expanded to cover the most commonly used assays in neuropathological institutions. In addition to IDH mutation and MGMT promoter methylation testing, there is a long tradition for 1p/19q codeletion testing relevant in the context of the diagnosis of oligodendroglioma. With the 5^th edition of the World Health Organization (WHO) classification of the central nervous system tumors, additional molecular markers came into focus: TERT promoter mutation is often assessed as a molecular diagnostic criterion for IDH-wildtype glioblastoma. Moreover, several molecular diagnostic markers have been introduced for pediatric brain tumors. Here, trials on KIAA1549::BRAF fusions (common in pilocytic astrocytomas) and H3-3A mutations (in diffuse midline gliomas, H3-K27-altered and diffuse hemispheric gliomas, H3-G34-mutant) were most desired by the neuropathological community. In this update, we report on these novel round robin trials. In summary, success rates in all four trials ranged from 75 to 96%, arguing for an overall high quality level in the field of molecular neuropathological diagnostics.