18 / 154
344
classification; however, gemistocytic astrocytoma has kept its
defined place, but only as an
IDH
-mutant subtype. This once
again shows the importance of associated molecular compo-
nent in making the diagnosis. Diffuse midline glioma charac-
terized by a K27M mutation in the histone H3 genes H3F3A
or HIST1H3B/C is a newly defined entity. These tumors have a
diffuse growth pattern, have midline location, occur in both
children and adults, and are associated with a very poor prog-
nosis1. Diffuse intrinsic pontine glioma (DIPG) is considered a
part of this new entity. This molecular definition will facilitate
development of therapies directed against this mutation.
Other molecular markers in non-glioma tumors that have
now been incorporated in the new WHO classification include
RELA fusion-positive supratentorial ependymoma, mostly
occurring in children; C19MC-altered embryonal tumors
with multilayered rosettes; and restructuring of medullo-
blastomas based on WNT, SHH (sonic hedgehog), and TP53
mutations. For the purpose of this review we will focus on
molecular markers in diffuse gliomas only (Table 1).
SUMMARY OF MOLECULAR MARKERS ISOCITRATE
DEHYDROGENASE (
IDH
) MUTATIONS
IDH
is a cytosolic enzyme that catalyzes the oxidative decar-
boxylation of isocitrate into alpha-ketoglutarate and nicotin-
amide adenine dinucleotide phosphate (NADPH) in normal
cells (9). The most common mutation involves amino acid
132 of
IDH1
(R132H) in more than 70% of WHO grade II and
III astrocytomas, oligodendrogliomas, and in secondary glio-
blastomas. As a surrogate to molecular genetic testing, a
mutation-specific antibody can be used clinically to identify
R132H mutations in glioma tumor tissue by immunohisto-
chemistry (Figure 1).
IDH2
(functions in the mitochondria)
mutations noted in R172 amino acid are much less common
(
~
3%) and associated with oligodendroglial histology (2,10).
The mutated
IDH
enzymes convert isocitrate to 2-hydroxy-
glutarate, which is believed to function as an oncometabolite
and cause tumorigenesis. Although the exact mechanisms of
this process remain to be elucidated, epigenetic mechanisms
causing development of hypermethylated phenotype, thereby
WHO 2007
WHO 2016
Diffuse astrocytoma
Diffuse astrocytoma, IDH-mutant
Gemistocytic astrocytoma, IDH-mutant
Diffuse astrocytoma, IDH-wildtype
Diffuse astrocytoma, NOS
Anaplastic astrocytoma
Anaplastic astrocytoma, IDH-mutant
Anaplastic astrocytoma, IDH-wildtype
Anaplastic astrocytoma, NOS
Glioblastoma
Glioblastoma, IDH-wildtype
Glioblastoma, IDH-mutant
Glioblastoma, NOS
Oligodendroglioma
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted
Oligodendroglioma, NOS
Anaplastic
oligodendroglioma
Anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted
Anaplastic oligodendroglioma, NOS
Oligoastrocytoma
Oligoastrocytoma, NOS
Anaplastic
oligoastrocytoma
Anaplastic oligoastrocytoma, NOS
Did not exist
New
Diffuse midline glioma H3 K27M-mutant
Gliomatosis
cerebri
Deleted
Protoplasmic
astrocytoma
Fibrillary
astrocytoma
Deleted
TABLE 1. CHANGES IN CLASSIFICATION OF GLIOMAS BETWEEN 2007 AND 2016 WHO CLASSIFICATION SYSTEMS
[REV. MED. CLIN. CONDES - 2017; 28(3) 343-351]
NOS: Not otherwise specified