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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

Date of Web Publication14-Nov-2018

Correspondence Address:
Dr. Vani Santosh
Department of Neuropathology, NIMHANS, Bengaluru - 560 029, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJNO.IJNO_13_18

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How to cite this article:
Santosh V. Milestones in neuropathology: Bridging morphology with molecules. Int J Neurooncol 2018;1:14-6

How to cite this URL:
Santosh V. Milestones in neuropathology: Bridging morphology with molecules. Int J Neurooncol [serial online] 2018 [cited 2019 May 19];1:14-6. Available from: http://www.Internationaljneurooncology.com/text.asp?2018/1/1/14/245360




  Advancements in Neuropathology Top


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[1],[2] 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.”[3],[4] Subsequently, Paul Ehrlich, another Nobel laureate established the concept of the blood–brain barrier.[5] 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.”[6] 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.[7]

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 Top
[8]

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 Top


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 Top


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.[9] 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.[10] 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.[11]

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.[12]


  Glioblastoma Top


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 More Details, 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.[13] 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.[14] IGFBP-3 influenced cell proliferation, migration, and invasion by regulating a downstream molecule STAT-1.[15] We also showed that GBM tumor growth is potentiated by IGFBP-2 through the activation of β-catenin pathway by its C-terminal domain.[16] 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.[17],[18],[19]

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.





 
  References Top

1.
Allen IV. The Changing Face of Neuropathology. Available from: https://www.pathsoc.org/files/history/c16.pdf.  Back to cited text no. 1
    
2.
Cajal SR. Histology of the Nervous System of Man and Vertebrates. Translated by Swanson N, Swanson LW, Azoulay L. Paris, New York: Maloine, Oxford University Press; 1995.  Back to cited text no. 2
    
3.
Virchow R. Cellular Pathology as Based upon Physiological and Pathological Histology. London: John Churchill; 1860.  Back to cited text no. 3
    
4.
Boullerne AI. The history of myelin. Exp Neurol 2016;283(Pt B): 431-45.  Back to cited text no. 4
    
5.
Dyrna F, Hanske S, Krueger M, Bechmann I. The blood-brain barrier. J Neuroimmune Pharmacol 2013;8:763-73.  Back to cited text no. 5
    
6.
Martin-Villalba A, Okuducu AF, von Deimling A. The evolution of our understanding on glioma. Brain Pathol 2008;18:455-63.  Back to cited text no. 6
    
7.
Rubinstein LJ. Microgliomatosis. In: Zülch KJ, Woolf AL, editors. Classification of Brain Tumours. Acta Neurochirurgica Supplementum. Vol. 10. Vienna: Springer; 1964.  Back to cited text no. 7
    
8.
Sarkar C, Shankar SK. Professor Subimal Roy (1933-2015): Our teacher in neuropathology. Neurol India 2015;63:295-6.  Back to cited text no. 8
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9.
van den Bent MJ. Interobserver variation of the histopathological diagnosis in clinical trials on glioma: A clinician's perspective. Acta Neuropathol 2010;120:297-304.  Back to cited text no. 9
    
10.
Louis DN, Ohgaki H, Weistler OD, Cavenee WK, Ellison DW, Figarella-Branger D, et al., editors. WHO Classification of Tumors of Central Nervous System. 4th ed. Lyon, France: IACR Press; 2016.  Back to cited text no. 10
    
11.
Rajeswarie RT, Rao S, Nandeesh BN, Yasha TC, Santosh V. A simple algorithmic approach using histology and immunohistochemistry for the current classification of adult diffuse glioma in a resource-limited set-up. J Clin Pathol 2018;71:323-9.  Back to cited text no. 11
    
12.
Louis DN, Aldape K, Brat DJ, Capper D, Ellison DW, Hawkins C, et al. Announcing cIMPACT-NOW: The consortium to inform molecular and practical approaches to CNS tumor taxonomy. Acta Neuropathol 2017;133:1-3.  Back to cited text no. 12
    
13.
Reddy SP, Britto R, Vinnakota K, Aparna H, Sreepathi HK, Thota B, et al. Novel glioblastoma markers with diagnostic and prognostic value identified through transcriptome analysis. Clin Cancer Res 2008;14:2978-87.  Back to cited text no. 13
    
14.
Santosh V, Arivazhagan A, Sreekanthreddy P, Srinivasan H, Thota B, Srividya MR, et al. Grade-specific expression of insulin-like growth factor-binding proteins-2, -3, and -5 in astrocytomas: IGFBP-3 emerges as a strong predictor of survival in patients with newly diagnosed glioblastoma. Cancer Epidemiol Biomarkers Prev 2010;19:1399-408.  Back to cited text no. 14
    
15.
Thota B, Arimappamagan A, Kandavel T, Shastry AH, Pandey P, Chandramouli BA, et al. STAT-1 expression is regulated by IGFBP-3 in malignant glioma cells and is a strong predictor of poor survival in patients with glioblastoma. J Neurosurg 2014;121:374-83.  Back to cited text no. 15
    
16.
Patil SS, Gokulnath P, Bashir M, Shwetha SD, Jaiswal J, Shastry AH, et al. Insulin-like growth factor binding protein-2 regulates β-catenin signaling pathway in glioma cells and contributes to poor patient prognosis. Neuro Oncol 2016;18:1487-97.  Back to cited text no. 16
    
17.
Arimappamagan A, Somasundaram K, Thennarasu K, Peddagangannagari S, Srinivasan H, Shailaja BC, et al. A fourteen gene GBM prognostic signature identifies association of immune response pathway and mesenchymal subtype with high risk group. PLoS One 2013;8:e62042.  Back to cited text no. 17
    
18.
Shukla S, Pia Patric IR, Thinagararjan S, Srinivasan S, Mondal B, Hegde AS, et al. A DNA methylation prognostic signature of glioblastoma: Identification of NPTX2-PTEN-NF-κB nexus. Cancer Res 2013;73:6563-73.  Back to cited text no. 18
    
19.
Rao SA, Srinivasan S, Patric IR, Hegde AS, Chandramouli BA, Arimappamagan A, et al. A 16-gene signature distinguishes anaplastic astrocytoma from glioblastoma. PLoS One 2014;9:e85200.  Back to cited text no. 19
    




 

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