|Year : 2018 | Volume
| Issue : 5 | Page : 147-148
The times they are a-changin' – How molecular pathology will change practice
Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
|Date of Web Publication||25-Oct-2018|
Prof. Ho-Keung Ng
Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Ng HK. The times they are a-changin' – How molecular pathology will change practice. Glioma 2018;1:147-8
When I was a freshman resident in pathology, we had only available to us a couple of stains in neuropathology that were none too specific and the names of which, such as phosphotungstic acid-hematoxylin, cresyl violet, Palmgren, and Bodian, residents of the modern day look at with the curiosity, they normally reserve for museum displays. However, back then there was not much else one could use other than your eyeballs and dyes or silver precipitates. Immunohistochemistry came along around that time, and the monoclonal antibodies and the brown stains radically changed the way we practiced pathology. For the first time, we were able to look at tissues under the microscope with scientific means in addition to mere colors and patterns. Hence, immunohistochemistry changed the practice of pathology completely.
We are now at the doorsteps of another era of tumor pathology practice − the era of molecular pathology. This is certainly true for tumors of the central nervous system (CNS). The WHO 2016 panel should be congratulated to have made the big leap in recognizing the classification of some of the tumor groups by molecular criteria, for example, isocitrate dehydrogenase gene (IDH) for the gliomas, molecular groups for medulloblastomas, and INI-1 for atypical teratoid/rhabdoid tumor. We fancy that one day molecular pathology will be like what immunohistochemistry is today, machine-standardized, specific and sensitive and yet adding on top of our current scientific methods with genes and RNA. But for molecular pathology, a bridge remains, albeit not too far.
The aims of all pathology reporting are two-tiered for oncologic practice:First, to confirm tumor is present or to refute its presence and secondly, to categorize or classify a tumor. These basic aims have not changed over the years. It is often said that the aims of modern molecular pathology diagnosis are first to classify tumor, for example, according to the WHO 2016, second to give a prognostic indicator by biomarker like IDH, and third, where possible, to predict response to therapy, like 1p19q codeletion. While these are well said, in fact, the fundamental aims of pathology reporting as I outlined at the beginning of this paragraph are the same. Even in the old days, when we made a diagnosis of CNS germinoma, we were categorizing by morphology, made a speculation about its prognosis based on morphology and predicted in most instances its response to radiotherapy by the term germinoma because we recognized its special histological features. So to me, the aims of molecular pathology are not new. They merely add to the precision of what we have been trying to say as pathologists for decades. With only color, patterns, and brown stains, we were not delivering with reproducibility, precision, or scientific explanations. Molecular pathology potentially offers the diagnostic process vast improvement in all three departments.
The advent of molecular pathology has changed practice in many areas of CNS tumor diagnostics already. It is unimaginable in most modern laboratories except those in the less developed parts of the world, to diagnose a glioma these days without IDH genotype or an oligodendroglioma without 1p19q status. Increasingly, in most places in the world, pediatric oncologists will not accept a diagnosis of medulloblastoma without molecular group as a full diagnosis. Yet, for me, the potentials of molecular diagnostics in CNS tumors are yet to be fulfilled completely, and the publication of the WHO 2016 was merely the end of a beginning.
To start with, for one of the key aims of pathology reporting, to diagnose or refute the presence of tumor cells, neither immunohistochemistry nor the commonly used brain tumor molecular diagnostics will help. This remains a judgment by one's eyeballs. Neurosurgeons continue to experience the daily frustration of trying to “completely” resect a glioma because pathologists cannot be certain about individual infiltrating cells. They need to resort to other means like intraoperative fluorescence, as alluded to by Danny Chan in an article in this special issue or radiologic methods like the RANO criteria as mentioned in the February issue of this journal.
For classification, there remains a lot of work beyond WHO 2016 so molecular pathology diagnostics are not fully there yet. The c-IMPACT-NOW group already made two updates of WHO 2016 and more will be expected., WHO 2016 made IDH genotype the overarching classifier for gliomas but did not make sufficient reference to the fact that this has little relevance for pediatric gliomas. Our experience and those of others are that pediatric low-grade gliomas need their own prognostic and possibly diagnostic biomarker panel. For oligodendrogliomas, WHO 2016 defined as IDH mutant AND 1p19q codeleted. It did not tackle the question of only one of them being present. It is hard to imagine that in all the clinical trials involving oligodendrogliomas where 1p19q codeletion was only 50%–70%, there have been errors in the diagnosis in up to 30%–40% of cases., In fact, all 1p19q codeleted tumors are IDH mutant but not vice versa, and there does exist a small group of oligodendroglial-looking IDH mutated gliomas which are 1p19q nondeleted., Another contentious point was IDH wild-type astrocytic tumors which could be dismissed as mere glioblastomas. Again, the experience of a few groups suggested that they can be further “graded” by molecular means namely 10q, epidermal growth factor receptor and telomerase reverse transcriptase and those IDH wild-type astrocytomas devoid of these markers have a more indolent clinical course and do not behave like glioblastomas.,, The list for potential improvements goes on.
Naturally, literature and evidence have moved on since the WHO panel met in Haarlem in 2014 and Heidelberg in 2015, where the basic framework of WHO 2016 was decided on. New information continues to appear on a weekly basis. Aden Chan in this special issue highlighted the potential use of BRAF in prognostication of gliomas of diverse age groups. Qing Chang's group reviewed the potential use of biomarkers outside DNA and RNA, the exosomes, and their potential use in liquid biopsies. Danny Chan gives a more clinical view of how to make use of all these biomarkers in day-to-day patient management, as in spite of all the advances in understanding, we have not translated the latter to major improvement in survival yet. The urgency to find effective agents for glioblastoma goes on, especially in the setting of temozolomide resistance, as shown by Gilbert Leung's group in this issue.
And very central to this theme of molecular diagnostics, Kay Li gave a summary of the potential use of a next-generation sequencing (NGS) targeted gene panel for diagnosis of brain tumors. Clearly, this is an evolving field as yet, we do not have a standardized way of doing NGS, how we report on the relevant findings and how to translate those findings to the clinics. Latter-day prophets now readily proclaim the demise of microscopy in brain tumor diagnosis or that methylation genomics are better than histology in designating a brain tumor group. The task which surely remains is to how to marry the genomics with the epigenomics and how to accommodate them in the regular diagnostic laboratories. The methodology of molecular diagnostics continues to be diverse, and we are far from what I described earlier on for immunohistochemistry-standardized, sensitive, and specific.
Bob Dylan, a prophet of an earlier generation, said “the times they are a-changin'……” The articles contained in this special issue confirm that they surely are for molecular diagnostics. I remain optimistic that molecular pathology of brain tumors will change the practice of diagnostic pathology in due course.
I thank Shaz Cheng, a medical student of the Chinese University of Hong Kong for editorial assistance for this issue.
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