Editorial
Molecular Diagnosis of Glial Neoplasms: A New Era
Gokden M*
Department of Pathology, University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, USA
*Corresponding author: Murat Gokden, Department of Pathology, University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, 4301 West Markham Street, #517, Little Rock, Arkansas 72205, USA
Published: 31 Aug, 2016
Cite this article as: Gokden M. Molecular Diagnosis of Glial
Neoplasms: A New Era. Clin Oncol.
2016; 1: 1067.
Editorial
Although genetic alterations involved in the development and progression of central nervous
system (CNS) tumors and especially gliomas have long been recognized, identification of a number
of molecular markers in these tumors has taken the center stage with the turn of this century due
to the recognition of their role as diagnostic, prognostic and/or predictive markers. This not only
allowed us to add molecular findings to our existing armamentarium, which largely consisted of
morphology and special stains, but resulted in the recognition of specific entities characterized by
specific molecular alterations, determination of the prognoses of some of these tumors based on the
alterations they had, and development of specific therapies targeting certain tumors with particular
molecular features. The impact of all these developments is reflected most recently in the revised 4th
edition of World Health Organization (WHO) Classification of Tumours of the Central Nervous
System [1]. This discussion is not meant to be an in-depth review of these discoveries, but rather, a
reminder of the recent exciting changes in our approach to the biology, diagnosis and treatment of
the tumors of the CNS.
One of the first of this group of genetic alterations that made its way into the diagnostic arena
and had an impact in diagnostic neuropathology and neuro-oncology is codeletion of 1p and
19q in oligodendroglioma [2]. Although the diagnosis of typical oligodendroglial and astrocytic
tumors by light microscopy had been straightforward, many of these tumors also had ambiguous
cytohistomorphologic features that made accurate classification difficult, if not impossible, resulting
in the diagnosis of oligoastrocytoma (the so-called intermingled histology), which admittedly, over
time, turned into a wastebasket category for many cases. The histologic classification of these diffuse
gliomas had a low diagnostic reproducibility among neuropathologists [3]. In spite of the recognition
that codeletions of 1p and 19q were associated with oligodendrogliomas, much debate took place in
the transition period over whether a subpopulation of oligoastrocytomas and astryctomas also could
have this alteration, resulting in the realization that there are molecular subsets of these tumors [4],
leading to the molecular classification of diffuse gliomas [5,6]. These and other studies now form the
basis for the integrated diagnosis of CNS tumors emphasized in the current WHO classification [1].
Along similar lines, there has been a relatively recent explosion of additional markers, some of
which also had an impact similar to and alongside 1p/19q codeletions. Isocitrate dehydrogenase 1
and 2 (IDH-1 and IDH-2, respectively) mutation analysis results have now been recognized as a
must-have finding to report when a diagnosis of diffuse glioma is made, owing to their importance
in the diagnosis and prognosis of these tumors [7]. IDH 1 and 2 mutations not only indicate a
better prognosis, but they are useful to the neuropathologist for the dreaded differential diagnosis
of neoplastic versus reactive glial proliferations and other well-circumscribed, low-grade glial
or glioneuronal tumors such as pilocytic astrocytoma, ganglioglioma and dysempbroplastic
neuroepithelial tumor in small tissue samples due to their presence exclusively in diffuse gliomas.
Loss of nuclear alpha thalassemia/mental retardation syndrome/X-linked (ATRX) expression
by immunohistochemistry has been associated with astrocytic lineage in diffuse gliomas [8]
and this parameter has been incorporated into the molecular classification of these tumors [6].
Testing for mutations in the BRAF gene brings to the table a useful tool to aid in the differential
diagnosis of well-circumscribed gliomas from diffuse gliomas [9] due to its higher frequency
in pleomorphic xanthoastrocytoma and ganglioglioma in contrast to diffuse astrocytomas. In
addition, a smaller percentage of supratentorial pilocytic astrocytomas show the mutation in BRAF
V600E, while cerebellar pilocytic astrocytomas have a higher frequency of BRAF/KIAA fusion.
Immunohistochemistry is now available to identify BRAF V600E mutation on paraffin sections
[10]. Additional recently-identified alterations applicable to glial neoplasms and their diagnosis
are H3 K27M mutation, associated with the midline gliomas, leading to the specific diagnosis of
“diffuse midline glioma, H3 K27M-mutant”, imparting a grim prognosis [11]. This replaces the
former designations of brain stem glioma and diffuse intrinsic pontine glioma. Although ependymal
neoplasms have been classified more definitively according to their
location and age, along with their genetic alterations, “ependymoma,
RELA fusion-positive” is currently the only well-established
ependymoma in this group. RELA fusion is a supratentorial
ependymoma, which can be WHO grade II or III (anaplastic) and has
a worse prognosis [12].
Many advances have also been made and integrated into the
diagnostic practice with subsequent prognostic and predictive
implications in other tumor categories and will not be further
discussed here. Most notable ones are the molecular classification
of medulloblastomas by incorporating sonic hedgehog and WNT
pathways. A new entity called embryonal tumor with multilayered
rosettes, C19MC-altered, has taken its place in the new WHO
Classification [1]. With these and other similar advances, the concept
of “integrated diagnosis” of the tumors of the CNS has also emerged.
The diagnostic line will now not only mention the usual histological
appearance (such as diffuse astrocytoma), WHO grade (such as WHO
grade II), but also the ancillary test results (such as IDH-mutant).
These improvements and their integration into the diagnosis
and differential diagnosis of these tumors, leading to their refined
classification, bring along potential drawbacks, most notably the
issues of availability of these techniques in pathology laboratories and
access to them by the practicing pathologists. Given the differences
and many times large gaps among various institutions’ technical
capabilities and the availability of expertise in the performance and
interpretation of these tests, as well as the availability of diagnostic
neuropathology expertise, it can be argued that the consistency
and reproducibility of the final diagnoses may be low. On the other
hand, better defined and stricter diagnostic criteria, such as in the
differentiation of gliomas of oligodendroglial and astrocytic lineage
based on their molecular profiles, should more than compensate for
these differences, especially with the availability of these molecular
tests in many large medical centers and in commercial laboratories.
As mentioned before, immunohistochemical staining techniques are
also emerging as surrogate markers for these molecular alterations,
rendering their identification more feasible, cost- and time-efficient.
In more complicated situations, the time-honored practice of
consultation should clarify many, if not all, of the remaining nontechnical,
expertise-related issues.
Overall, the accumulation of data in all aspects of neuro-oncology
has necessitated this integration of molecular and genetic findings
into what we already have known and practiced, leading us to this
new era of molecular diagnostics and targeted therapies. All these, in
a way, are reminiscent of the times when immunohistochemistry was
emerging as the state of the art, sophisticated diagnostic tool about
four decades ago. Likewise, we will soon become very well-familiar
with all the intricacies of molecular test selection and relevance, as
well as interpretation and incorporation of their results into patient
care.
References
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