PRESIDENTIAL ORATION, ISNOCON 2018
Year : 2018 | Volume
: 1 | Issue : 1 | Page : 14--16
Milestones in neuropathology: Bridging morphology with molecules
Department of Neuropathology, NIMHANS, Bengaluru, Karnataka, India
Dr. Vani Santosh
Department of Neuropathology, NIMHANS, Bengaluru - 560 029, Karnataka
|How to cite this article:|
Santosh V. Milestones in neuropathology: Bridging morphology with molecules.Int J Neurooncol 2018;1:14-16
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Santosh V. Milestones in neuropathology: Bridging morphology with molecules. Int J Neurooncol [serial online] 2018 [cited 2022 Jun 29 ];1:14-16
Available from: https://www.Internationaljneurooncology.com/text.asp?2018/1/1/14/245360
Advancements in Neuropathology
Neuropathology is a highly specialized branch of pathology dealing with diseases of the nervous system, enabling the study of structural abnormalities on biopsied and autopsied material through macroscopic, microscopic and occasionally, ultrastructural examination. When compared to other branches of pathology, neuropathology has had complex origins because of its pivotal links with basic and clinical neuroscience. The beginning of neuropathology can be traced back to the year 1906, with the legendary studies on the nervous system by two great Nobel Laureates, Cajal, and Camillo Golgi. Other great contributions to neuropathology came from Rudolf Virchow and Pio del Rio-Hortega, who threw light on understanding the terms “Neuroglia” and “myelin.”, Subsequently, Paul Ehrlich, another Nobel laureate established the concept of the blood–brain barrier. These have been some of the discoveries that built the foundation for neuropathology.
If we look at the contribution of neuropathology to the field of neuro-oncology, it was Virchow who first initiated our understanding on the pathology of brain tumors. He introduced the term “glioma.” Subsequently, notable contributions in neuro-oncopathology came from Dorothy Russell and Lucien Rubinstein. Some of Russell's contributions included the identification of the entity “pinealoma” then considered as a teratomatous lesion, and another entity, “microglioma” distinctly different from gliomas, and now termed as central nervous system (CNS) lymphoma.
There have been dramatic technical advances over the decades of surgical neuropathology practice. Although it started with the humble light microscopy and the available stains, it soon progressed to electron microscopy and enzyme histochemistry followed by immunohistochemistry (IHC). At present, we are in the molecular era that is enriched with several molecular techniques such as fluorescent in situ hybridization/polymerase chain reaction, gene sequencing, next-generation sequencing, high-throughput “omics” platforms, and computational science. These techniques have provided great opportunities for diagnostic and research in neuropathology, in the context of rapid changes taking place in this scientific discipline.
Neuropathology in India
In India, it was Professors DK Dastur, Iyer, Deshpande, who first laid the foundation for neuropathology, between the years 1960–1980. Subsequently, Professors AP Desai, Sriramachari, VS Lalitha, Sarala Das, Subimal Roy, and others continued the tradition of diagnostic Neuropathology, followed by excellent contributions by Professors SK Shankar, Chitra Sarkar, C. Sundaram, and others. During the past two decades, there has been a quantum jump in diagnostic and experimental neuropathology in our country, with the introduction of molecular pathology in several centers. In particular, neuropathologists have contributed significantly for the growth of the discipline of neuro-oncology.
Progress in Brain Tumor Pathology
This is an area of primary responsibility for most practicing neuropathologists, who play a major role in bridging morphology with molecular pathology. An important example comes from the latest WHO classification, which for the very first time, uses molecular parameters in addition to histology to define several brain tumor entities. I will discuss these advancements briefly with respect to diffuse gliomas.
Diffuse Gliomas - An Enigma
For nearly a century, morphological diagnosis has been the gold standard for brain tumor classification and has formed the basis for future therapy. However, with respect to diffuse gliomas, there can be limitations in the histomorphological diagnosis due to several reasons, such as; suboptimal quantity and quality of surgically resected tissue submitted for examination, imprecise criteria used by histopathologists for typing and grading the tumors and the fact that morphology does not completely represent the biology of the tumor. Furthermore, the histopathological diagnosis of diffuse glioma has allowed for a considerable amount of inter-observer variability in interpretation, leading to being less predictive of clinical outcomes. More recently, studies have shown distinct molecular alterations in diffuse gliomas, and have helped to identify molecular and prognostic subclasses of these tumors. The three clinically relevant molecular markers, namely mutations of isocitrate dehydrogenase (IDH 1&2) genes, alpha-thalassemia/mental retardation syndrome X-linked gene mutation (with or without Tp53 mutations), and 1p/19q codeletion have been widely studied in the past few decades and shown to provide information far superior to the histological entities in diffuse lower grade gliomas. In light of this, the WHO 2016 classification has introduced revised criteria for classification coupling traditional histopathology and molecular signatures, generating the “integrated” diagnostic entities. This has brought about a major reshuffle in the classification of diffuse gliomas with the incorporation of genetically defined entities. Importantly, the revised classification has seen a tremendous growth potential in terms of diagnosis, prognosis, and therapy.
Although the updated classification, based on recent molecular insights, is clinically relevant, there are some questions that need to be addressed for better understanding. For instance, India is a very diverse country. While we do have some of the finest neuro-oncology centers where all the molecular testing facilities are available for diagnostic purposes, there are several other centers where only histology/IHC-based approach for glioma diagnosis is being carried out. Moreover, the molecular tests are expensive, not affordable by patients of lower economic strata. In view of this, we need a practical, adaptation of the WHO recommendation, suitable for a resource-limited setup. This is a pertinent question to be addressed not only in the developing but also in developed countries. In this regard, in our previous study, we have generated a simple algorithm for diagnosis, using histology and IHC for the current classification of adult diffuse glioma appropriate for a resource-limited setup.
On the other hand, throughout the globe, there have been rapid advances in molecular understanding of brain tumors. As an initiative to evaluate some of the molecular advancements and recommend proposed changes to CNS tumor classifications in the future, the “Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy” has been constituted, which is sponsored by the International Society of Neuropathology. The goal is to review novel diagnostically relevant data and to arrive at a consensus defining the optimal information that can be practically incorporated in the CNS tumor classifications to come.
Similar to diffuse lower grade gliomas, the WHO 2016 classification emphasizes diagnosing glioblastoma histomolecularly. Accordingly, two entities of glioblastoma are now recognized, namely the IDH wild-type and IDH mutant glioblastomas, and the latter is known to have a significantly better prognosis. The role of MGMT promoter mutations in GBM has been well established. Apart from its prognostic and predictive role, its association with pseudo-progression is documented. Other common molecular alterations such as EGFR amplification including EGFRvIII mutation, PTEN deletion, and TERT promoter mutation are known to confer poor prognosis in glioblastoma. During the past two decades, several studies including that of The Cancer Genome Atlas, employed high throughput molecular profiling platforms such as transcriptome profiling, genome-wide methylation profiling, comparative genomic hybridization, single-nucleotide polymorphism arrays, and others to delineate the genetic and epigenetic landscape of glioblastoma.
In our previous collaborative study, using whole genome gene expression profiling approach, we were able to identify novel diagnostic and prognostic biomarkers in glioblastoma. Our study identified two novel biomarkers, GADD45a and FSTLI which were GBM-specific and had significant prognostic value. We also showed the associations of another set of biomarkers, IGFBP-2, -3, and -5 expression with increasing grades of malignancy in astrocytomas. Among these, IGFBP-3 was identified as a novel prognostic GBM biomarker. IGFBP-3 influenced cell proliferation, migration, and invasion by regulating a downstream molecule STAT-1. We also showed that GBM tumor growth is potentiated by IGFBP-2 through the activation of β-catenin pathway by its C-terminal domain. Our high-throughput studies also identified a fourteen gene prognostic signature as well as a nine-gene DNA methylation signature and a sixteen gene classifier signature in GBM.,,
In conclusion, in this molecular era with newer discoveries, it is important to note that the role played by the neuropathologist is vital in terms of validation of molecular biomarkers and transferring research findings to routine diagnostics. This is strengthened through regular multidisciplinary team meetings and collaborative research projects.
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