Editorial

The 2016 World Health Organization classification of tumours of

the Central Nervous System: what the paediatric neuroradiologist
needs to know
Sahil Chhabda1, Olivia Carney2, Felice D’Arco2, Thomas S. Jacques3, Kshitij Mankad2
1
Department of Radiology, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK; 2Developmental Biology and Cancer
Programme, UCL Great Ormond Street Institute of Child Heath, London, UK; 3Department of Pathology, Great Ormond Street Hospital NHS
Foundation Trust, London, UK

Correspondence to: Dr. Kshitij Mankad. Department of Paediatric Neuroradiology, Great Ormond Street Hospital NHS Foundation Trust, Great
Ormond Street, London, WC1N 3JH, UK. Email: [email protected].

Abstract: The recently published 2016 World Health Organization (WHO) classification of tumours of the
Central Nervous System (CNS) introduces a number of significant changes from the previous edition. Based
on an improved understanding of the genetic and molecular basis of tumorigenesis there has been a shift
towards defining tumours by means of these characteristics in addition to their histological features, thus
providing an integrated diagnosis. In this article, we will provide a concise overview of the salient changes in
the 2016 WHO classification of tumours of the CNS that are of relevance to the paediatric neuroradiologist
when it comes to day-to-day reporting.

Keywords: Central nervous system neoplasms; classification, diagnostic imaging; paediatric; World Health
Organization (WHO)

Submitted Sep 25, 2016. Accepted for publication Oct 02, 2016.
doi: 10.21037/qims.2016.10.01
View this article at: http://dx.doi.org/10.21037/qims.2016.10.01

Background As a result of this new method of classification, a number

of new tumour entities have been described in this updated
The 2007 World Health Organization (WHO) classification
edition. There has also been significant restructuring of the
of the central nervous system (CNS) tumours was primarily
classification of pre-existing tumour categories including
based on histological features which presented a number
the diffuse gliomas, medulloblastomas and other embryonal
of issues and limitations. In comparison, the 2016 WHO
CNS tumour classification builds on developments and tumours. Entities such as gliomatosis cerebri have been
research in the molecular and genetic basis of tumorigenesis downgraded to a pattern of spread rather than a distinct
and aims to incorporate these characteristics alongside biological entity from the diffuse gliomas.
histological findings in tumour classification. The aim is to The nomenclature of tumours has subsequently changed
provide an integrated phenotypic and genotypic diagnosis and now for several tumours consists of the histopathological
thus more accurately defining real biological entities. name followed by the genetic determinant e.g.,
By means of an integrated approach to tumour medulloblastoma, SHH-activated, TP53-mutant. The not
classification, narrower diagnostic criteria can be applied otherwise specified or NOS suffix is reserved for situations
resulting in improved diagnostic accuracy and a reduction where there is either insufficient material or the facilities for
in inter-observer variability. This in turn will hopefully testing for the specific genotype are not available.
improve the reproducibility of results and better guide In cases where there is discordance between the histology
prognostication and treatment of CNS tumours. and molecular genetic features the pathologist needs to

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Quantitative Imaging in Medicine and Surgery, Vol 6, No 5, October 2016 487

judge the relevance of each piece of evidence but in an SHH-activated and TP53 mutant. It is defined by the
increasing number of tumours it is the genotype that will be WHO as: ‘A poorly differentiated embryonal tumour of
the primary determinant of the tumour type. An example the cerebellum with evidence of SHH pathway activation
of this would be a diffuse glioma that is histologically and either germline or somatic TP53 mutation’ (4). The
astrocytic but is also found to have IDH mutation and clinical outcomes for this subgroup of medulloblastomas are
1p/19q codeletion. Under the new classification this will fall very poor. These patients carry a significant risk of having
under the diagnosis of oligodendroglioma, IDH-mutant and a germline TP53 mutation and should be offered genetic
1p/19q codeleted. counselling.
A recent review by Louis et al. provides a comprehensive
overview of the changes that that 2016 classification brings
Diffuse gliomas
with it (1).
Whilst a large majority of changes relate to histological This group has been restructured and now includes all the
and molecular diagnostic criteria, an understanding of the diffusely infiltrating gliomas regardless of whether they are
new classification and nomenclature will be vital for the astrocytic or oligodendroglial in origin. The restructuring is
paediatric neuroradiologist when it comes to reporting. based on the genetic understanding of adult tumours, which
are largely determined based on IDH gene mutations and
the presence or absence of 1p/19q codeletions (3). This is
New entities, variants and patterns that the of limited value in paediatrics as both genetic changes are
paediatric neuroradiologist should be aware of rare in paediatric tumours even when they are of the similar
including reclassifications and deletions histological type to their adult counterparts.
Neuronal and mixed neuronal-glial tumours
Paediatric diffuse gliomas
A new tumour entity of neuronal-glial origin commonly There has been separation of paediatric diffuse gliomas from
presenting in childhood and adolescence is the diffuse adult diffuse gliomas based on the presence of molecular
leptomeningeal glioneuronal tumour. These tumours markers thus allowing for more targeted therapies. A new
are characterized by predominant and widespread entity in this group is diffuse midline glioma, H3 K27M-
leptomeningeal growth with or without a parenchymal mutant. These midline tumours (typically of the thalamus,
component. Histologically these tumours frequently pons or spinal cord) with a diffuse pattern encompass many
have oligodendroglial cytology with evidence of neuronal of the tumours recognized as diffuse intrinsic pontine glioma
differentiation on immunohistochemistry; whilst IDH (DIPG) and many high-grade gliomas of the thalamus in
mutations are typically absent, molecular findings may children. These tumours have a poor prognosis (5).
include BRAF fusion, isolated 1p deletions or combined
1p/19q codeletions (2). Diffuse astrocytoma and anaplastic astrocytoma
The terms protoplasmic astrocytoma and fibrillary
Medulloblastomas astrocytoma are no longer in the 2016 classification.
Gliomatosis cerebri is no longer considered a distinct entity
The commonest malignant brain tumours in childhood but is regarded as a growth pattern of other glial tumours (4).
are now defined by integrated diagnoses which accounts
for the genetic and histological features of the tumour. Glioblastomas
The histological classification is already well defined and Glioblastomas are classified based on IDH mutations into
includes classic, anaplastic/large cell, desmoplastic/nodular glioblastoma, IDH-wild-type, glioblastoma, IDH-mutant
and extensive nodular variants. In terms of molecular and glioblastoma, NOS (4).
classification, the subtypes of include WNT-activated, One particular new entity of relevance to the paediatric
SHH-activated and non-WNT/non-SHH (group 3 and neuroradiologist is the epithelioid glioblastoma. These
group 4) (3). Providing an integrated diagnosis is of clinical tumours typically present as diencephalic or superficial
value as both the histological and molecular variants have cerebral masses. Histologically they are characterized
distinct therapeutic and prognostic implications. by large epithelioid cells, vesicular chromatin and
An entity of particular relevance is the medulloblastoma, prominent nucleoli. Rhabdoid cells may also be present.

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488 Chhabda et al. 2016 WHO classification of CNS tumours

Immunohistochemistry or sequencing often reveals a BRAF Atypical teratoid/rhabdoid tumour (AT/RT) is now
V600E mutation (6). characterized by alterations in SMARCB1 (INI1) or rarely
SMARCA4 (BRG) CNS embryonal tumour with rhabdoid
Other astrocytomas features is used for tumours that have histological features
Anaplastic pleomorphic xanthoastrocytoma has been added of AT/RT without the specific genetic alterations (4,8,9).
as a distinct entity as opposed to the previously applied There remain a group of embryonal tumours of the
descriptive title of pleomorphic xanthoastrocyomta with nervous system that do not have one of these characteristic
anaplastic features (4). features and these are described as CNS neuroblastoma,
CNS ganglioneuroblastoma or embryonal tumour, NOS
depending on the histological findings. However, it should
Ependymomas
be noted that some of the tumours historically described
These are the third commonest neuroepithelial tumours in this group can be reclassified into other tumour entities
of childhood, after astrocytomas and medulloblastomas. based on current diagnostic techniques (e.g., high grade
There is increasing data suggesting that ependymomas can glioma, ETMR, AT/RT and ependymoma) and these
be divided into several subtypes on the basis of molecular alternative diagnoses need to be actively excluded before a
profiling (particularly DNA methylation profiling). diagnosis of embryonal tumour is accepted.
With regards to the 2016 classification, one of the new There are some exciting new molecular data that
molecularly defined entities in this category is ependymoma, indicate that there are new tumour entities that account
RELA fusion-positive. RELA fused ependymomas constitute for a number of the embryonal tumours and it is likely that
most of the supratentorial ependymomas encounterd in future classifications will take account of these new CNS
children and have a poor prognosis (4). tumours (10).
Cellular ependymoma has been deleted in the 2016
classification.
Conclusions

The 2016 WHO classification of CNS tumours introduces

Other embryonal tumours
a number of significant changes, a large proportion of which
The term CNS-primitive neuroectodermal tumour (PNET) relate to an improved understanding of the molecular and
and supratentorial PNET have been removed from the genetic basis of tumorigenesis. It is vital that the paediatric
diagnostic lexicon. This will avoid confusion with the neuroradiologist is familiar with the new nomenclature,
peripheral-type PNET or Ewing’s sarcoma that can still classification, patterns of spread and reclassification of
present with the skull or occasionally the CNS (1). entities that are no longer considered relevant as all
There has been a major restructuring of the classification these factors have implications with regards to patient
of non-medulloblastoma embryonal tumours particularly management and prognostication. Whilst diagnoses can
taking account of a subgroup that display amplification still be made for tumour variants that fall into a NOS
of the C19MC region encoding an miRNA cluster of category, ongoing research will hopefully enable further
chromosome 19 (19q.13.42). characterization of these entities which are not yet fully
The entity previously recognized as embryonal tumour defined.
with abundant neuropil and true rosettes (ETANTR) or
embryonal tumour with multilayered rosettes (ETMR),
Acknowledgements
ependymoblastoma and most cases of medulloepithelioma
have been reclassified based on the presence or absence of K Mankad has funding from the Brain Tumour Charity,
C19MC amplification (7). Children with Cancer, Great Ormond Street Children’s
In cases of confirmed C19MC amplification, the term Charity and NIHR.
ETMR, C19MC-altered should be applied. Most of the
tumours previously described as medulloepithelioma will
Footnote
now be classified as ETMR, C19MC-altered. Tumours
without the C19MC alteration will be classified under the Conflicts of Interest: The authors have no conflicts of interest
category of medulloepthelioma (1). to declare.

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Quantitative Imaging in Medicine and Surgery, Vol 6, No 5, October 2016 489

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