PL1
Evolving concepts of glioblastoma: 1863–2014
Burger P
Johns Hopkins University School of Medicine, USA
The glioblastoma was well known, in the 1860s, to Virchow who appreciated the lesion's infiltrative nature and relation to lower grade astrocytoma in some cases. Other seemingly more discrete types would, presumably, today be considered “primary.” It remained until 2008 for a molecular correlation, mutations in IDH1 or IDH2, to become clear. Later, Scherer was instrumental in refining the “secondary” subtype. Vascular proliferation was recognized and presciently presumed by Scherer to result from vasostimulatory factors released by the tumor. Decades later, Bevacizumab was created to block VEGF, unsuccessfully thus far insofar as overall survival is concerned. Discovery of tumor suppressor genes and oncogenes began with the first description of EGFR overexpression in 1984. Gains of chromosome 7 and losses of 10 were recognized at about the same time. The EGFRvIII variant was identified, and clinical attempts to target EGFR abnormalities continue today. Epigenetic influences on tumor development became apparent first in the role of MGMT and its interaction with effects alkylating agents. The pervasive influence of epigenetic mechanisms is increasingly appreciated. The role of micro RNAs, some of the latter with multiple targets, adds another layer of complexity. A lesion long known to be complex is thus even more so at closer and closer inspection. Glioblastomas now can be divided into subgroups on the basis of genetics, epigenetics, methylation profiles, micro RNAs, etc. Inter‐ and intratumoral heterogeneity is now well known. Recognition of therapeutic opportunities, and obstacles, continues to evolve.
PL2
The neuropathology of C9ORF72 mutations
Mackenzie I
Department of Pathology, University of British Columbia, Vancouver, Canada
In 2011, abnormal expansion of a GGGGCC hexanucleotide repeat in a non‐coding region of the chromosome 9 open reading frame 72 gene (C9ORF72) was identified as the most common genetic abnormality in familial and sporadic forms of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) and the cause in most families where both conditions occur. The associated FTD phenotype is most often the behavioral variant and the motor neuron disease is usually classical ALS; however, a wide range of neurological features are now recognized, including aphasia, memory deficits, extrapyramidal dysfunction, psychosis and learning disability. The neuropathology of C9ORF72 mutation carriers includes a combination of frontotemporal lobar degeneration with TDP‐43 immunoreactive (ir) neuronal and glial cytoplasmic inclusions and neurites (FTLD‐TDP) and typical ALS with TDP‐43‐ir inclusions in motor neurons. The specific FTLD‐TDP subtype is most often type B. Two additional pathological changes are highly characteristic of cases with the C9ORF72 mutation, each of which may play a pathogenic role. Aggregates of RNA, composed of the massively expanded GGGGCC repeat, can be demonstrated in neuronal nuclei using fluorescent in situ hybridization. These RNA foci are thought to bind and sequester specific RNA binding proteins, leading to the abnormal splicing of other genes. Another absolutely sensitive and specific pathological change is the presence of neuronal inclusions in the cerebellar granular layer, hippocampal pyramidal neurons and other neuroanatomical sites, that immunostain for markers of the ubiquitin proteasome system (i.e. ubiquitin and p62) but that are negative for TDP‐43. It has recently been shown that these inclusions are composed of dipeptide repeat (DPR) proteins that result from the unconventional translation of the expanded GGGGCC repeats in both sense and antisense direction and in all reading frames (poly‐GA, ‐GP, ‐GR and poly‐PA, ‐PG, ‐PR respectively). Clinicopathological correlative studies have shown that the anatomical distribution of TDP‐43 pathology correlates closely with the pattern of neurodegeneration and clinical phenotype. In contrast, the distribution of DPR pathology is highly consistent among cases, with no clinical correlation, suggesting that DPR inclusions may be a useful pathological marker for the presence of the C9ORF72 mutation but are of uncertain pathogenic significance.