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Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 46-51

What the eyes cannot see—Limitations of current molecular neuropathological interpretations: A primer

Department of Neurosurgery, Apollo Hospitals, Hyderabad, Telangana, India; Exsegen Research Pvt Ltd, Hyderabad, Telangana, India

Date of Submission17-Oct-2021
Date of Acceptance16-Feb-2022
Date of Web Publication20-Apr-2022

Correspondence Address:
Dr. Amitava Ray
Third Floor, Nirvanaz, 8-2-293/82/A/240, Road 36, Jubilee Hills, Hyderabad 500033, Telangana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJNO.IJNO_22_21

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Background: Molecular testing has now been incorporated into the mainstream of neuropathological diagnosis, especially in gliomas. There are multiple molecular markers that determine prognosis, and a few are of therapeutic importance. Currently, a number laboratory techniques are being used to test these molecular markers, with an ever increasing number making the transition from being a research tool to use in day-to-day clinical practice.Objective: The objective of this article is to inform the practicing clinicians of the various molecular markers that may be used in neuropathological practice and to highlight the various laboratory methods that are used and the strengths and drawbacks of each test.Materials and Methods: Using intracranial gliomas as an example of the recent changes, this article highlights the different laboratory methods used for the testing of the most popular molecular markers that are used in clinical practice, namely, 1p19q, IDH, P53, H3K27M, EGFR, ATRX, and TERT and details the strengths and pitfalls of each one of them when compared with the current gold standard.Results: The results of traditional immunohistochemistry are compared to the modern molecular biology techniques, and the differences in interpreting the results are discussed.Conclusion: This article highlights the different ways of molecular testing in neuropathology and their differing interpretations. This knowledge is vital in clinical practice.

Keywords: Molecular techniques, neuropathology, pitfalls

How to cite this article:
Ray A. What the eyes cannot see—Limitations of current molecular neuropathological interpretations: A primer. Int J Neurooncol 2021;4:46-51

How to cite this URL:
Ray A. What the eyes cannot see—Limitations of current molecular neuropathological interpretations: A primer. Int J Neurooncol [serial online] 2021 [cited 2023 Mar 25];4:46-51. Available from: https://www.Internationaljneurooncology.com/text.asp?2021/4/2/46/343567

  Key message Top

As molecular testing moves away from immunohistochemistry alone, it has become imperative for the practicing clinicians to be able to interpret these various modalities and understand what the shortcomings are. As testing gets more and more complex, this understanding will form an integral part of management of patients.

  Introduction Top

It was almost one hundred years ago that Dr A. C. Broders published a series of 256 squamous cell carcinomas of the lip—divided into four grades based on its similarity to the parent tissue—Grade 1 being least aggressive with maximal similarity to the normal lip histology and Grade 4 being the most malignant with least resemblance.[1] As the story unfolded, it became clear that the grade of the tumor dictated outcome; the lesser the resemblance to the parent tissue, the worse the prognosis. Starting in the 1920s, close on the heels of this study was Percival Bailey, who, while working with Cushing, demonstrated that if tumors arising from glial tissue were graded using the outcome as the primary endpoint, the pathological features would broadly match the previous classification.[2] The Bailey–Cushing classification has formed the bedrock of all modern attempts in classifying glial tumors; the poorer the outcome, the higher the grade. Modified and enhanced subsequently by Kernohan and Mabon in the 1920s[3] and later by Dumas-Duport et al. in the 1980s,[4] there was a temporary shift to a grading system with an emphasis on the tissue architecture of the lesion, but for all practical purposes the two systems largely overlapped. Gliomas were divided into four grades with the “circumscribed” or largely surgical gliomas being in grade 1 with a normal life expectancy following surgical removal and grades 2–4 forming an increasing continuum of malignancy with grade 4 tumors or glioblastomas having a dismal mean survival of between 12 and 14 months.[5]

This simple classification still holds true, for the majority of glial tumors. However, with time it became clear that there are a number of prediction failures, with pathologically lower-grade tumors having abysmal outcomes and vice versa. Research was further driven by a concerted effort to improve poor outcomes that seem to be invariable in all high-grade glial lesions with a few exceptions. Late in the 20th century, while studying oligodendroglial tumors, Cairncross et al.[6] found that a subset did better with chemotherapy leading to the discovery of “1p19q”—the loss of 1p and 19q. But that was really the only prognostic marker till the advent of Next Generation Sequencing (NGS) provided an opportunity to study glial lesions in depth. In 2008, sequencing the genetic mutations of gliomas found that missense isocitrate dehydrogenase (IDH) mutations resulted in improved survival.[7] This study was soon followed by a plethora of similar works that placed IDH mutations at the heart of classifying infiltrative astrocytic and oligodendroglial tumors. The discovery of a whole host of other genetic markers followed including H3K27M, EGFR, BRAFv600E or the KIAA1549–BRAF fusion, which are now used to classify glial tumors. Not only did these molecular markers help emphasize the different molecular signatures of high and low grade tumors, but they were able to differentiate, to a degree, the lower grade tumors that would have a poor outcome.[8] Thus in 2016, the World Health Organization (WHO), in keeping pace with the growing body of evidence, started integrating some of these markers into everyday neuropathological practice. This was further boosted by a series of position papers by the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT) that outlined the nuances of such an integration. The world of traditional neuropathology was being radically modified as the new classification required the interpretation of a number of new molecular tests. This article scrutinizes the current neuropathological practice, using the commonly used molecular markers in gliomas as an illustrative example, and highlights the possible strengths and shortcomings in the interpretation of these tests.

  Commonly used markers in gliomas Top


Initially described as a prognostic marker in oligodendroglial tumors, 1p19q is now the diagnostic test for oligodendroglial tumors.[9] Multiple prospective randomized trials have demonstrated a significant survival benefit with the addition of procarbazine, lomustine, and vincristine (PCV) chemotherapy to the standard radiotherapy regime.[10] The loss of the short arm of chromosome 1 and the long arm of chromosome 19, commonly referred to as LOH (loss of heterozygosity) 1p19q, is usually detected by a reliable and validated laboratory technique called fluorescent in-situ hybridization (FISH). FISH uses dual fluorescent-labeled DNA probes that localize targets within the nucleus of individual cells. Test probes are labeled with red for 1p and 19q and control probes in green fluorochrome that map to 1q and 19p regions of the chromosome that are left untouched by this deletion. Assessments of 1p:1q and 19p:19q are done on separate slides on 50–100 non-overlapping interphase nuclei. The test is positive if 25–30% of the cells show co-deleted signals. Normal chromosomes have two copies of each chromosome and return a 2R2G (two red test probes and two green control probes) signal: a complete LOH yields a 1R2G signal pattern. Ratios are calculated for each chromosome by dividing the total number of test probes by the total number of controls—and a number less than or equal to 0.8 is taken as positive,[11] although there may be a slight variation in this interpretation, as in some laboratories, each of the chromosomal arms is weighted separately.[12] This result, however, must be interpreted with caution; if deletion is specific to the probe site alone and not to the entire arm (most commercial probes bind to 1p36 and 19q13), it will not result in the survival benefit conferred to the patient due to the loss of the entire chromosomal arm. Loss of the entire chromosome (aneuploidy) or multiple copies of the same chromosome (polysomy) or gain of the whole chromosomal set (polyploidy) that are commonly observed in malignancies may further complicate the interpretation.

Multiple technologies are now available to confirm FISH findings. Polymerase chain reaction (PCR)-LOH has greater specificity than FISH as it tests multiple loci in a single assay, but the quantitative data still need categorization.[13] PCR is considered to be a more labor-intensive process which requires more tissues (practically excluding all stereotactic biopsies) and a negative control. Array CGH (comparative genomic hybridization)[14] and single nucleotide polymorphism (SNP)[15] array assess copy number variations at all chromosomal loci on a microarray. Though polysomies are not detected, genome-wide high throughput techniques may identify additional genetic alterations of clinical importance.[16]

Isocitrate dehydrogenase

IDH forms the backbone of the classification of infiltrative gliomas. Missense mutations at position arginine 132 and less commonly at arginine 172 constitute almost 80–90% of all mutations seen. The R132H mutation, also known as IDH1, can be reliably detected by a specific and sensitive antibody on immunohistochemistry (IHC) with almost 100% accuracy.[17] In a paper published in 2013, Agarwal et al.[18] showed cross reactivity in a small proportion of cases with the R132L mutation, using the H09-mAb specific for R132H. This finding was in contrast to the western blot study[17] by Capper et al., who found no cross reactivity between the two distinct mutations. Although all IDH-mutated tumors have a more favorable outcome, data seem to be emerging which suggest that genomic hypermethylation may vary depending on the nature and site of the exact mutation.[19] Non-canonical mutations are especially common in the younger patients with gliomas and carry the same survival benefits as the effect of these mutations in genomic hypermethylation remains the same.[20] It may also be possible that IDH-1 is not the only mutation that exists, with secondary mutations significantly altering the protein structure and its effects on hypermethylation. Though these findings are of mere theoretical significance now, these may be of vital clinical relevance as targeted therapies come to the fore and treatment based on specific mutations become commonplace.

The other problem with IHC in the detection of IDH mutations remains the variability in terms of strength and distribution. Nearly 50% of the tumors in the study mentioned earlier had marked heterogeneity in terms of the taking up the stain. There were also marked differences in the pattern of staining that were dependent on the type of the cell in question: astrocytic tumors highlighted the unipolar and bipolar astrocytic processes, gemistocytes had peripheral accentuation with a central halo, whereas oligodendrogliomas showed strong staining of the cytoplasm. In addition, nuclear staining with the IDH antibody has also been widely reported but not completely explained, though IDH is located exclusively in the cytoplasm.[17],[18],[21] Preferential staining of the oligodendroglial component in mixed oligo-astrocytic tumors has also been documented by several authors.[17],[18] While experienced neuropathologists with years of clinical training and experience may find interpretation a routine matter, this may not be so to the inexperienced neuropathologists or pathologists with a more general practice, as is the case with the overwhelming majority of pathologists in India.

In spite of these drawbacks, IDH IHC remains the backbone of molecular testing of gliomas, with IDH1 immunohistochemistry being sensitive and specific enough to detect the majority of mutant tumors. Non-canonical mutations, however, are seen in younger patients and have the same effects of genome-wide hypermethylation and better survival. Sequencing of the IDH gene is therefore advised in this age group but not above the age of 54 where non-canonical mutations are rare.[22]


TP53 has been known to us for nearly 40 years. It was initially known to be an oncogene, until Suzy Baker joined the Bert Vogelstein Laboratory and started to examine a portion of chromosome 17 that was lost in a majority of colonic cancers. The rest, as they say, is history and papers on TP53 as a tumor suppressor changed the way cancer is managed today.[23]TP53 is now often referred to as the “Guardian of the Genome” and is the most mutated tumor suppressor gene across all cancers. P53 IHC has now been established as the definitive way to establish TP53 mutations: missense mutations of TP53 that result in the accumulation of p53 protein in the nucleus are detected. In a series of 157 cases, Takami et al.[24] showed that a strong nuclear p53 reactivity in more than 10% of tumor nuclei had a positive predictive value of 94.5% and a negative predictive value of 86.3% in determining the TP53 mutation status. But it must also be noted that p53 immuno-reactivity can also be seen in non-neoplastic conditions, especially in demyelinating processes such as progressive multifocal leukoencephalopathy, a condition marked by significant astrocytic atypia.[25] Thus, the significance of p53 immunopositivity lies not in the immunostain alone, but its holistic interpretation in the context of morphological and other molecular findings of the tumor as well.

The absence of p53 IHC does not exclude a mutation either. Splice variants and/or truncating mutations will lead to a loss of p53 immunoreactivity by either grossly changing the protein structure or by radically decreasing the amount of p53 protein produced.[26] Thus, in cases in which there is significant clinical and pathological suspicion of deregulation of the p53 pathway, sequencing is recommended to rule out pathway dysfunction.

Histone mutant gliomas

Histones are an octamer complex comprising H2A, H2B, H3, and H4 proteins that form a DNA–protein complex to maintain chromatin structure. Each of these octamers is encoded by different genes. The H3 family of proteins includes the canonical H3.1, which is expressed only during DNA replication, encoded by HIST1H3B and HIST1H3C and the variant histone H3.3 that is expressed throughout the cell cycle and is encoded by H3F3A and H3F3B.[27] H2 is encoded by HIST2H3C.[28] A number of post-translational modifications occur that affect the epigenetic regulation of gene transcription and the underlying chromatin structure. One such modification is the trimethylation of lysine 27 on histone 3 which normally acts as a gene repressor. The H3K27M mutation replaces lysine for methionine, which essentially stops the trimethylation and post-transcriptional silencing of the gene. The K27M mutation can be detected on both H3.1 and its variant H3.3 by a very specific antibody on IHC[29] as can the presence or absence of methylation, which is largely absent when the mutation is present. However, the epitope fails to distinguish between the canonical H3.1 and the variant H3.3 mutations, as the mutation occurs on the highly conserved portion of the gene that is common to both the variants. Though this difference in semantics was initially thought to be of little clinical interest, it is now becoming clear that tumorigenesis may vary with the type of H3 mutation, H3.1K27M, co-occurring with activin-receptor type 1 (ACVR1) and phosphoinositide 3-kinase (PI3K), whereas the H3.3 mutations commonly occur with deletions of tumor suppressor 53 (TP53) and amplification of platelet-derived growth factor. H3.3K27M diffuse intrinsic pontine gliomas have been shown to be more aggressive, more invasive, and less differentiated than their H3.1K27M counterparts.[30] As targeted therapies and personalized medicine become more popular and acceptable, it may be critical that this differentiation is made for prognostication and treatment.

Genes affecting telomere length: TERT and ATRX

Telomeres are DNA–protein complexes that protect the chromosome ends. The length of the telomere shortens with each mitosis till there is cell cycle arrest due to telomere length limitation. Cancer cells preserve telomere length by telomerase activation or in a telomerase-independent manner called ALT.[31] Telomerase consists of telomerase reverse transcriptase (TERT) and an associated telomerase RNA molecule (TERC). Mutations in TERT occur upstream of the TERT ATG gene code start site (also known as the promoter region) and result in an increase in TERC, which helps maintain telomere length. This mutation of the promoter is not reliably detected by any IHC test.[32] TERT promoter mutations are almost exclusively seen in the IDH-mutated 1p19q co-deleted oligodendroglioma or IDH-wt glioblastomas.[33] The ALT phenotype is dependent on a homologous recombination DNA repair mechanism to maintain telomere length and is most often seen in the IDH-mutant astrocytic phenotype. Addition of ATRX suppresses the ALT phenotype, and hence the ATRX mutations are commonly associated with these tumors. ATRX mutations are usually detected by a loss of ATRX nuclear staining, quite opposite to that of p53. ATRX immunostain can be patchy as it is very sensitive to fixation, so internal positive controls are essential, usually found in the endothelial or inflammatory cells within the same area of the tumor. In addition, all ATRX mutations may not be accompanied by a loss of nuclear stain, and hence a negative result in the presence of a classical astrocytic histology must be treated with caution.[26]

EGFR amplification and over-expression

Epidermal growth factor receptor (EGFR) is one of the most commonly dysregulated genes in cancer, which generally take the form of mutations like EGFRvIII, involving deletion from exons 2 to 7 or in the form of an increase in the DNA copy numbers. An increase in the copy numbers or EGFR amplification is usually shown by FISH, which has, historically, been the gold standard. IHC has been compared with FISH and found to be sensitive but less than 50% specific. Lee et al.[34] in a study of 76 patients of whom 67 were IDH (wt) and 9 were IDH mutant, and 4 were secondary GBMs; it was found that EGFR amplification was seen in 30/76 tumors, and in 23 it was a part of high polysomy cases. When these results were compared with IHC, the sensitivity was 87.9% in cases of EGFR amplification alone and approached 100% in those tumors with high polysomy. However, the specificity was less than 50%, which has been the case with a large number of studies. However, in a study with contrasting results, Shinojima et al.[35] found remarkable concordance between IHC and FISH and went on to suggest that the tumors that were EGFR-amplified on FISH and expressed EGFR on IHC had the worst outcome, although this study has not been universally replicated. Using DNA methylation profiling as a tool to classify tumors, The German Cancer Research Group recently published data in which EGFR amplification as detected by FISH was the most specific but least sensitive marker with 99.8% and 36%, respectively,[36] leaving even the “gold standard” with enough room for improvement. Targeted gene or as a part of whole exome/genome sequencing using Next Generation Sequencing protocols when paired with RNA-seq studies provides the most comprehensive answers to the mechanisms of increased gene expression. Though limited by cost and infrastructure at present, this technology may just represent the future of molecular neuropathology.

  Conclusion Top

The start of the 21st century has sparked a revolution in the study and understanding of malignant brain tumors, especially gliomas. Malignant gliomas still remain one of the last frontiers of cancer care survival improving only marginally and in tiny increments over the last 100 years. This is disappointing when compared with the revolutionary treatments that have transformed the prognosis of some of the other malignancies, which had equally dismal prognosis at the turn of the 20th century. Accurate neuropathological examination still remains the foundation of the diagnosis, which is now aided by molecular markers to improve prognostication and help guide treatment. In the rare event, a druggable target is found as a result of molecular testing, and survival rates are dramatically revised upward. As we become ever more reliant on molecular markers to make a diagnosis and target therapy, it becomes imperative for us to understand the pitfalls in the interpretation of such tests. The same result may be obtained by different tests as it examines different parts of the same pathway: some testing the mutations in the DNA structure, some tests studying the effects of the mutations at the RNA level, or perhaps interrogating the presence of the protein using IHC. Interestingly, different tests interrogating the same part of the pathway may yield different results: FISH, PCR, and aCGH are known to produce different results. As more and more tests become commonplace, it will become even more important for clinicians to understand these nuances that affect clinical decision-making. This review aims to increase awareness among clinicians that it is time that they equip themselves with this knowledge.

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Conflicts of interest

There are no conflicts of interest.

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