Advances in Adult Brain Tumor Classification Using
Molecular Neuropathology
Brain neoplasms (tumors) can be separated
into those which arise primarily in the
brain and its coverings, versus those
which metastasize from a systemic organ
(such as lung, breast, kidney, skin or colon).
Primary brain tumors often resemble
the supporting cells (”glia”) of the brain,
especially astrocytes and oligodendrocytes,
and are collectively known as
gliomas. Tumors arising from the coverings
of the brain and spinal cord are most
often meningiomas. Radiographic studies,
particularly contrast-enhanced magnetic
Robert Macaulay, MD
resonance imaging (MRI) can strongly suggest the diagnosis.
Surgical biopsy or resection provides tissue for confirmation
of the diagnosis, and for ancillary studies which may provide
prognostic information.
Gliomas can be subdivided into diffusely infiltrative versus
circumscribed varieties; the radiographic, microscopic and
genetic findings are distinct for the different tumor types.
The most commonly encountered glioma is glioblastoma (GbM),
although this term is no longer used as a stand-alone diagnostic
category. Most glioblastomas lack a mutation in the IDH1 or
IDH2 gene (wildtype); such tumors are therefore designated
GbM-IDH-wt. This is a highly aggressive tumor and requires a
thorough diagnostic workup including molecular classification
to enable prognostication and selection of adjuvant therapy.
Of the many additional molecular tests which can be conducted,
the most informative is methylation (or ”silencing”) of the
MGMT promoter, which tends to confer predictive benefit.
IDH-mutated tumors can show morphology similar to astrocytes,
or to oligodendrocytes (which normally produce myelin to
insulate nerve axons); many examples have mixed or ambiguous
morphology. The characteristic chromosomal aberration of
oligodendroglioma is loss of portions of chromosome 1 and 19
(codeletion of 1p/19q). Oligodendrogliomas are either Grade 2
(indolent) or Grade 3 (anaplastic).
By exclusion, any IDH-mutated glioma lacking 1p/19q codeletion is
designated as an astrocytoma; if it appears indolent, it is placed
in the WHO Grade 2 category, if mitotically active it is designated
“anaplastic” and assigned WHO Grade 3, and if highly aggressive
it is designated “glioblastoma-IDH-mutated, WHO grade 4.”
Unfortunately, there is a tendency for low grade tumors to
progress to higher grades, but the pace of progression varies
unpredictably between patients.
Rarely, a GbM-IDH-wt arising in an adult will have genetic changes
more similar to pediatric cases. The most common of these are
mutations in a histone gene. Histones are proteins which attach
to and stabilize DNA, and regulate expression of particular genes.
Alterations in histones have been linked to a variety of cancers.
One type of diffuse astrocytoma which arises in the midline of
the brain, brainstem and spinal cord has a tendency to exhibit
a mutation at the 27 amino acid position; the new WHO system
has grouped such tumors under the new name “diffuse midline
glioma, H3 K27M, WHO Grade4”. The personalized medicine
group at Moffitt provides expertise in deciphering the myriad
genetic alterations which can be detected in various cancers.
Another tumor which is more common in pediatric patients
but which also affects adults is pilocytic astrocytoma. This is
a circumscribed glioma, and can often be resected with
excellent long term outcomes. Although it is generally
straightforward to identify, demonstration of a characteristic
genetic change can help in difficult cases; most have a fusion
between the BRAF gene and the KIAA1549 gene.
Amongst the tumors arising from the coverings of the brain,
meningioma is by far the most common; however, they arise
as several subtypes and in varying grades of aggressiveness.
Most meningiomas are indolent (WHO grade 1), lacking
proliferative activity or brain invasion, but certain subtypes
have a propensity for recurrence and may require closer
monitoring and/or additional therapy. Genetic changes
under-pinning meningiomas correlate closely with the subtype,
but are not yet used for official subclassification. Grading of
meningioma is algorithmic, requiring subtype, proliferative activity,
other morphologic features, and brain invasion to be assessed.
Hemangiopericytoma/Solitary Fibrous Tumor (HPC/SFT) can
mimic meningioma radiographically, but pathologic examination
is typically distinctive. Immunohistochemical tests routinely
performed at Moffitt include STAT6, which is altered in HPC/
SFT but not in meningioma, and SSTR2a which is expressed in
meningioma but not in HPC/SFT. Other tumors which may mimic
meningioma include schwannoma, lymphoma, melanocytic
neoplasms, craniopharyngioma, metastasis, and non-neoplastic
inflammatory (infectious or non-infectious) tumefactions.
Advances in molecular pathology have greatly contributed to
classification of tumors arising in every organ. Hopefully this
diagnostic “granularity” will lead to greater clarity in clinical trial
design and the development of targeted therapies to deliver the
most effective agents to the most susceptible tumor types.
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MOFFITT.org 2018 ISSUE | NEURON NEWS 7
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