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Year : 2020  |  Volume : 68  |  Issue : 4  |  Page : 838--839

Evaluation of Surrogate Immunohistochemical Markers for Molecularly Defined Neoplasms of the Central Nervous System: Need of the Hour

Aruna Nambirajan, Mehar Chand Sharma 
 Department of Pathology, AIIMS, New Delhi, India

Correspondence Address:
Dr. Mehar Chand Sharma
M.D., F.R.C.Path, Department of Pathology, AIIMS, New Delhi

How to cite this article:
Nambirajan A, Sharma MC. Evaluation of Surrogate Immunohistochemical Markers for Molecularly Defined Neoplasms of the Central Nervous System: Need of the Hour.Neurol India 2020;68:838-839

How to cite this URL:
Nambirajan A, Sharma MC. Evaluation of Surrogate Immunohistochemical Markers for Molecularly Defined Neoplasms of the Central Nervous System: Need of the Hour. Neurol India [serial online] 2020 [cited 2020 Nov 29 ];68:838-839
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In the lead article of this issue, Dr Vani Santosh and her team report that immunohistochemistry for alpha internexin is a good surrogate marker for the presence of chromosomes 1p and 19q co-deletion in anaplastic oligodendrogliomas with immunopositivity showing high sensitivity and moderate specificity for 1p/19q co-deletion.[1] This work is especially important at this juncture in the history of neurooncology diagnostic practice where most, if not all, brain tumors are defined and prognosticated by specific molecular criteria, some with added predictive value as well,[2],[3] and neuropathology practice without molecular diagnostic set-up is becoming increasingly challenging. The 2016 update to the World Health Organization (WHO) classification of CNS tumors had, for the first time, incorporated molecular genetic criteria in addition to histology to define various tumor entities[2] and the cIMPACT-NOW guidelines published regularly thereafter have reaffirmed and refined these criteria and introduced new criteria as more clinical and molecular information comes to light.[3] While the wealth of molecular information has undoubtedly improved our understanding of various brain tumors, in particular of gliomas and embryonal tumors, and brought us closer than ever to translate this into molecular targeted therapies, it has also increased the need for evaluating and establishing robust, cost-effective, and rapid means of molecular subtyping for daily neuropathology practice, especially in resource-constrained settings. For oligodendrogliomas, in particular, chromosomes 1p and 19q co-deletion is now a defining molecular criterion in addition to the presence of IDH gene mutations.[2] Laboratories without facilities for detection of 1p/19q co-deletion (usually performed by in-situ hybridization) would now have to resort to labelling these tumors as oligodendroglioma, not otherwise specified.[2]

Immunohistochemistry is practiced even in the smallest of pathology laboratories and is a rapid, cost-effective, and robust technique for use in formalin-fixed paraffin-embedded tumor tissue, including archived tissue and does not require high technical expertise. Numerous surrogate markers are already available in neuropathology and are being widely used. These include (1) antibodies against specific mutant proteins, e.g., IDH1 p.R132H, H3.3 p.K27M, H3.3 p.G34R/V, BRAF p.V600E, etc. for the detection of mutations in the corresponding genes; (2) antibodies against normal tissue proteins whose expression is lost due to deleterious mutations in the corresponding genes, e.g., ATRX, INI-1, BRG-1, etc.; (3) antibodies against tissue proteins that are normally not expressed but overexpressed in tumor cells as a result of increased signaling downstream to the defining molecular alteration, e.g., stem cell marker Lin28A in C19MC amplified embryonal tumors, L1CAM in RELA fusion-positive ependymomas, etc.; (4) antibodies against normal tissue proteins that show altered expression due to modification of specific signaling pathways by the defining molecular alteration, e.g., H3K27me3 loss in H3K27M gliomas and PFA ependymomas. Many of these immunohistochemical markers are endorsed by the latest cIMPACT-NOW guidelines as well.[3]

Alpha internexin as a potential surrogate marker for 1p and 19q co-deletion is unique as the gene encoding for it is neither located at these chromosomal locations nor appears to be directly related to any of the candidate tumor causative genes identified at these loci.[4] It is an intermediate filament specifically expressed in neuronal cells. In 2008, Ducrayet al. first demonstrated that increased m-RNA and protein expression levels of alpha internexin strongly correlated with 1p/19q co-deletion in gliomas indicating a pro-neural phenotype in oligodendrogliomas.[5] Subsequently, the same group and a handful of other authors as reviewed in the article[1] showed that alpha internexin immunohistochemistry is highly sensitive and moderately specific for 1p/19q co-deletion. In the current article,[1] Rajmohanet al. demonstrate that alpha internexin immunopositivity correlates strongly with IDH mutations (determined by IHC and sequencing) and retained ATRX expression, both of which are molecular hallmarks of oligodendrogliomas. They further show that alpha internexin staining correlated with longer progression-free and overall survival on univariate analysis as has been observed for 1p/19q co-deletion, strengthening their argument for alpha internexin as a surrogate for the latter. Nevertheless, it is not a perfect surrogate and despite its high positive predictive value (93%), it is also expressed in a subset of non-1p/19q co-deleted gliomas reducing its specificity and limiting its value as an alternative to 1p/19q analysis. Nevertheless, it would be worthwhile exercise to introspect a larger molecularly characterized patient cohort to understand how alpha internexin independently contributes to the pathogenesis of oligodendrogliomas and the downstream mechanisms by which 1p/19q codeletion correlates with alpha internexin upregulation.


1Rajmohan KS, Sugur HS, Shwetha SD, Pandey P, Arivazhagan A, Santosh V. Alpha Internexin: A Surrogate Marker for 1p/19q Codeletion and Prognostic Marker in Anaplastic (WHO grade III) Gliomas. Neurol India 2020;68:832-7.
2Louis DN, Perry A, Reifenberger G. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A summary. Acta Neuropathol 2016;131:803-820.
3Louis DN, Wesseling P, Aldape K. cIMPACT-NOW update 6: New entity and diagnostic principle recommendations of the cIMPACT-Utrecht meeting on future CNS tumor classification and grading [published online ahead of print, 2020 Apr 19]. Brain Pathol. 2020;10.1111/bpa. 12832. doi: 10.1111/bpa.12832.
4Gladitz J, Klink B, Seifert M. Network-based analysis of oligodendrogliomas predicts novel cancer gene candidates within the region of the 1p/19q co-deletion. Acta Neuropathol Commun 2018;6:49.
5Ducray F, Mokhtari K, Crinière E, Idbaih A, Marie Y, Dehais C, et al. Diagnostic and prognostic value of alpha internexin expression in a series of 409 gliomas. Eur J Cancer 2011;47:802-8.