Professional Documents
Culture Documents
2016 WHO Classification PDF
2016 WHO Classification PDF
WHO
World Health Organization Classification of Tumours
WHO OMS
Edited by
Wiestler Webster K.
Cavenee
Printed by Maestro
38330 Saint-lsmier, France
The WHO Classification of Tumours of the Central Nervous System presented in this
book reflects the views of a Working Group that convened for Consensus and
Editorial Meeting at the German Cancer Research Center,
Heidelberg, 21-24 June 2015.
Distributed by
WHO Press, World Health Organization, 20 Avenue Appla, 1211 Geneva 27, Switzerland Tel.: +41 22
791 3264; Fax: +41 22 791 4857; email: bookorders@who.int
Publications of the World Health Organization enjoy copyright protection in accordance with the
provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved.
The designations employed and the presentation of the material in this publication do not imply the
expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization
concerning the legal status of any country, territory, city, or area or of Its authorities, or concerning the
delimitation of Its frontiers or boundaries.
The mention of specific companies or of certain manufacturers’ products does not Imply that they are
endorsed or recommended by the World Health Organization in preference to others of a similar nature
that are not mentioned. Errors and omissions excepted, the names of proprietary products are
distinguished by initial capital letters.
The authors alone are responsible for the views expressed In this publication.
Combined histological-molecular molecular genetic alterations suggest a genetic finding is present, leaving that
classification that such challenges will be readily over- to individual practitioners and institutions,
For nearly a century, the classification of come in the near future {2105}. Many of but the commentary sections do clarify
brain tumours has been based on con- the genetic parameters included in the the implication of certain genetic features;
cepts of histogenesis, hinging on the idea 2016 WHO classification can be as- for example, in what situations IDH status
that tumours can be classified according sessed using immunohistochemistry can be designated as wildtype.
to their microscopic similarities with puta- or FISH, but it is recognized that some
tive cells of origin and their developmental Histological grading
centres may not have the ability to carry
differentiation states. These histological Histological grading is a means of pre-
out molecular analyses and that some
similarities have been characterized pri- dicting the biological behaviour of a
molecular results may not be conclusive.
marily on the basis of the light microscop- neoplasm. In the clinical setting, tumour
With this in mind, an NOS diagnostic des-
ic appearance of H&E-stained sections, grade is a key factor influencing the
ignation has been included in the 2016
the immunohistochemical expression of choice of therapies. Since its first pub-
WHO classification wherever such issues
proteins, and the electron microscopic lication in 1979, the WHO classification
may apply. The NOS designation indi-
assessment of ultrastructural features. of tumours of the central nervous system
cates that there is insufficient informa-
The 2000 and 2007 WHO classifications has included a grading scheme that es-
tion to assign a more specific code. In
considered histological features along sentially constitutes a malignancy scale
this context, the NOS category includes
with the rapidly increasing knowledge (ranging across a wide variety of neo-
both tumours that have not been tested
of the genetic changes that underlie the plasms) rather than a strict histological
for the genetic parameter(s) and tumours
tumorigenesis of CNS tumours. Many grading system {1290,1291,2878}. WHO
that have been tested but did not show
of the canonical genetic alterations had grading is widely used, and it has incor-
the diagnostic genetic alterations. In
been identified by the time the 2007 porated or largely replaced other previ-
other words, the NOS designation does
WHO classification was published, but at ously published grading systems for
not refer to a specific entity; instead, it
the time the consensus opinion was that brain tumours. Although grading is not
designates the lesions that cannot be
such changes could not yet be used to a requirement for the application of the
classified into any of the more precisely
define neoplasms; instead, genetic sta- WHO classification for some tumours,
defined groups.
tus served as supplementary information including gliomas and meningiomas,
within the framework of diagnostic cat- Definitions, disease summaries, and numerical WHO grades are useful addi-
egories established by standard, histolo- commentaries tions to the diagnoses. The WHO Work-
gy-based means. In contrast, the present Each entity-specific section in the 2016 ing Group responsible for this update of
update (the 2016 classification) breaks WHO classification begins with a short the 4th edition has expanded the classifi-
with this nearly century-old tradition and disease definition that describes the es- cation to include additional entities; how-
incorporates well-established molecular sential diagnostic criteria. This initial ever, since the number of cases of some
parameters into the classification of dif- definition is followed by a description of of these newly defined entities is limited,
fuse gliomas. characteristic associated findings; for the assignment of grades to such entities
Changing the classification to include example, although a delicate branching is still provisional, pending publication of
diagnostic categories that depend on vasculature and calcospherites are not additional data and long-term follow-up.
genotype may create certain challenges essential for the diagnosis of oligoden-
Histological grading across tumour
with respect to testing and reporting. droglioma, they are highly characteristic.
entities
These challenges include the availability The diagnostic criteria and characteris-
Grade I lesions are generally tumours
and choice of genotyping and surrogate tic features are then followed by the rest
with low proliferative potential and the
genotyping assays, the approaches that of the disease summary, in which other
possibility of cure after surgical resec-
may need to be taken by centres without notable clinical, pathological, and mo-
tion alone. Grade II lesions are usually
genotyping (or surrogate genotyping) ca- lecular findings are described. Finally,
infiltrative in nature and often recur, de-
pabilities, and the actual formats used to for some entities, there is also additional
spite having low levels of proliferative
report these integrated diagnoses {1535}. commentary that provides information on
activity. Some grade II entities tend to
However, an important consideration for classification, clarifying the nature of the
progress to higher grades of malignancy;
the 2016 WHO classification was that the genetic parameters to be evaluated and
for example, grade II diffuse astrocytoma
implementation of combined phenotyp- providing genotyping information on pos-
tends to transform to grade III anaplas-
ic-genotypic diagnostics in some large sibly overlapping histological entities. The
tic astrocytoma and glioblastoma. The
centres and the increasing availability classification does not specify the type
grade III designation is applied to lesions
of immunohistochemical surrogates for of testing required to establish whether
WHO grades of select CNS tumours Desmoplastic infantile astrocytoma and ganglioglioma I
Papillary glioneuronal tumour I
Diffuse astrocytic and oligodendroglial tumours Rosette-forming glioneuronal tumour I
Diffuse astrocytoma, IDH-mutant II Central neurocytoma II
Anaplastic astrocytoma, IDH-mutant III Extraventricular neurocytoma II
Glioblastoma, IDH-wildtype IV Cerebellar liponeurocytoma II
Glioblastoma, IDH-mutant IV Tumours of the pineal region I
Diffuse midline glioma, H3 K27M-mutant IV Pineocytoma II or III
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted II Pineal parenchymal tumour of intermediate differentiation
Anaplastic oligodendroglioma, IDH-mutant and Pineoblastoma IV
1p/19q-codeleted III Papillary tumour of the pineal region II or III
Other astrocytic tumours Embryonal tumours
Pilocytic astrocytoma I Medulloblastoma (all subtypes) IV
Subependymal giant cell astrocytoma I Embryonal tumour with multilayered rosettes, C19MC- IV
Pleomorphic xanthoastrocytoma II altered
Anaplastic pleomorphic xanthoastrocytoma III Medulloepithelioma IV
Ependymal tumours CNS embryonal tumour, NOS IV
Subependymoma I Atypical teratoid/rhabdoid tumour IV
Myxopapillary ependymoma I CNS embryonal tumour with rhabdoid features IV
Ependymoma II Tumours of the cranial and paraspinal nerves
Ependymoma, RELA fusion-positive II or III Schwannoma I
Anaplastic ependymoma III Neurofibroma I
Perineurioma I
Other gliomas
Malignant peripheral nerve sheath tumour (MPNST) I I, III or IV
Angiocentric glioma I
Chordoid glioma of third ventricle II Meningiomas
Meningioma I
Choroid plexus tumours
Atypical meningioma II
Choroid plexus papilloma I
Anaplastic (malignant) meningioma III
Atypical choroid plexus papilloma II
Choroid plexus carcinoma III Mesenchymal, non-meningothelial tumours
Neuronal and mixed neuronal-glial tumours Solitary fibrous tumour / haemangiopericytoma I, II or III
Haemangioblastoma I
Dysembryoplastic neuroepithelial tumour I
Gangliocytoma I Tumours of the sellar region I
Ganglioglioma I Craniopharyngioma I
Granular cell tumour I
Anaplastic ganglioglioma III
Pituicytoma I
Dysplastic gangliocytoma of cerebellum (Lhermitte-Duclos) I
Spindle cell oncocytoma I
16 Diffuse gliomas
of diffuse gliomas, in the setting of deep-
er and broader genomic capabilities, will
require less histological evaluation - per-
haps only an initial diagnosis of diffuse
glioma. For the time being, the current
WHO classification is predicated on the
concept of combined phenotypic and
genotypic classification, and on the gen-
eration of so-called integrated diagnoses
{1535}.
It is important to acknowledge that
changing the classification to include
diagnostic categories that depend on
genotype may create certain challenges
with respect to testing and reporting,
which have been discussed elsewhere
{1535}. These challenges include the Fig. 1.02 IDH1 and IDH2 mutations in human gliomas, histologically diagnosed according to the 2007 WHO classi-
availability and choice of genotyping and fication. Reprinted from Yan H et al. {2810}.
surrogate genotyping assays, the ap-
proaches that may need to be taken by prognostic information in addition to that or morphology. The finding of a solitary
centres without genotyping (or surrogate provided by histological grade. Never- mitosis in an ample specimen is not suf-
genotyping) capabilities, and the actual theless, in the 2016 WHO classification, ficient proof of WHO grade III behaviour,
formats used to report these integrated diffuse astrocytomas are graded using but the separation of grade II tumours
diagnoses {1535}. However, the imple- a three-tiered system similar to the Ring- from grade III tumours may be facilitated
mentation of combined phenotypic-gen- ertz system {2130}, the St. Anne-Mayo by determination of the Ki-67 proliferation
otypic diagnostics in some large centres system {533}, and the previously pub- index {1056}. Microvascular proliferation
{2105} and the increasing availability of lished WHO schemes {1293,1534}. Ac- is defined as apparent multilayering of
immunohistochemical surrogates for mo- cording to the WHO’s current histological endothelium (rather than simple hyper-
lecular genetic alterations suggest that definition, tumours with cytological atypia vascularity) or glomeruloid vasculature.
such challenges will be readily overcome alone (i.e. diffuse astrocytomas) are con- Necrosis may be of any type; perinecrotic
in the near future {2510A). sidered grade II, those that also show an- palisading need not be present. Simple
aplasia and mitotic activity (i.e. anaplas- apposition of cellular zones with interven-
Histological grading of diffuse
tic astrocytomas) are considered WHO ing pallor suggestive of incipient necrosis
astrocytic tumours
grade III, and tumours that additionally is insufficient. The aforementioned crite-
In neuro-oncology, histological grading
show microvascular proliferation and/or ria make their appearance in a predict-
has been most systematically evaluated
necrosis are grade IV. Atypia is defined able sequence: atypia is followed in turn
and successfully applied to diffusely in-
as variation in nuclear shape or size with by mitotic activity, then increased cellu-
filtrative astrocytic tumours, although
accompanying hyperchromasia. Mitoses larity, and finally microvascular prolifera-
recent studies suggest that molecu-
must be unequivocal, but no special sig- tion and/or necrosis.
lar parameters may provide powerful
nificance is accorded to their number
18 Diffuse gliomas
pathways). Local mass lesions may
be present in either grey or white mat-
ter, but they have indistinct boundaries,
and changes such as smaller or larger
cysts, granular areas, and zones of firm-
ness or softening may be seen. Cystic
change most commonly presents as a
focal spongy area, with multiple cysts of
various sizes. Extensive microcyst forma-
tion may cause a gelatinous appearance.
Occasionally, a single large cyst filled Fig. 1.04 A Large diffuse astrocytoma occupying the left temporal lobe, with extension to the Sylvian fissure. Note the
with clear fluid is present. Tumours with homogeneous surface and the enlargement of local anatomical structures. B Large diffuse astrocytoma originating
prominent gemistocytes sometimes have from the pericallosal cortex of the right hemisphere. The tumour extends into the interhemispheric fissure and shifts the
single, large, smooth-walled cysts. Focal midline towards the left hemisphere. Macroscopically, this lesion is well delineated and still shows structures resembling
cortical architecture.
calcification may also be present, and a
more diffuse grittiness may be observed.
Extension into contralateral structures, filaments. The pattern may vary markedly for R132H-mutant IDH1 (sometimes in
particularly in the frontal lobes, is rarely in different regions of the neoplasm. His- combination with p53 immunohistochem-
observed. tological recognition of neoplastic astro- istry and rarely with assessment for tri-
cytes using H&E staining on sectioned somy 7) is a powerful means to distinguish
Microscopy
material depends mainly on nuclear neoplastic from reactive astrocytes {347}.
Diffuse astrocytoma is composed of
characteristics. The normal astrocytic nu- In other situations, however, the differen-
well-differentiated fibrillary astrocytes in
cleus is oval to elongated, but on section- tial diagnosis can be challenging and may
a background of a loosely structured, of-
ing, occasional round cross-sections are rely on standard histological differences.
ten microcystic tumour matrix. Fibrillary
seen. The nucleus is typically vesicular, Diffuse astrocytoma contains astrocytes
astrocytoma is the classic type of diffuse
with intermediate-sized masses of chro- that are increased in number and usually
astrocytoma and is no longer listed as a
matin and often with a distinct nucleolus. in size, but are otherwise difficult to distin-
variant {1533}.
Normal human astrocytes show no H&E- guish on an individual basis from normal
The cellularity is moderately increased
stainable cytoplasm that is distinct from or reactive cells. In minor degrees of ana-
compared with that of normal brain, and
the background neuropil. Reactive as- plasia, it is the number of astrocytes and
nuclear atypia is a characteristic feature.
trocytes are defined by enlarged nuclei (most commonly) the uniformity of their
Mitotic activity is generally absent, but a
and the presence of stainable, defined morphology that is most helpful in recog-
single mitosis does not justify the diagno-
cytoplasm, culminating in the gemisto- nizing their neoplastic nature. Reactive
sis of anaplastic astrocytoma unless ob-
cyte, which has a mass of eosinophilic astrocytes are rarely all in the same stage
served in a small biopsy or in the setting
cytoplasm, often an eccentric nucleus, of reactivity at the same time, so reac-
of obvious nuclear anaplasia. The pres-
and cytoplasm that extends into fine tions reveal mixtures of astrocytes; some
ence of necrosis or microvascular prolif-
processes. with enlarged nuclei, others with varying
eration is incompatible with the diagnosis
amounts of cytoplasm, most often on a
of diffuse astrocytoma. Phenotypically, Differential diagnosis
somewhat rarefied background. In diffuse
neoplastic astrocytes may vary consider- The major entity in the differential diagno-
astrocytoma, almost all of the nuclei look
ably with respect to their size, the promi- sis is reactive astrocytosis. Because most
identical, and the background is of at least
nence and disposition of cell processes, IDH-mutant diffuse astrocytomas have
normal density or shows increased num-
and the abundance of cytoplasmic glial R132H mutations, immunohistochemistry
bers of cellular processes. Microcystic
Fig. 1.05 Diffuse astrocytoma. A Moderately cellular tumour composed of uniform neoplastic fibrillary astrocytic cells. B Extensive microcyst formation.
Fig. 1.08 Diffuse astrocytoma. A Cytoplasm and cell processes show a variable extent of GFAP immunoreactivity. B The Ki-67 proliferation index is low.
20 Diffuse gliomas
astrocytomas, IDH-mutant anaplastic protein, and its deficiency has been as- which also predisposes patients to chon-
astrocytomas, and IDH-mutant glioblas- sociated with epigenomic dysregulation drosarcoma {734,1027}.
tomas develop from a distinct population and telomere dysfunction {473}. In par-
Prognosis and predictive factors
of precursor cells that differ from the pre- ticular, ATRX mutations seem to induce
cursor cells of IDH-wildtype glioblastoma an abnormal telomere maintenance Clinical prognostic factors
{870,1830}. mechanism known as alternative length-
ening of telomeres {977}. ATRX mutations In the pre-IDH era, the median survival
Genetic profile time was reported to be in the range of
and alternative lengthening of telomeres
Diffuse gliomas of WHO grades II and 6-8 years, with marked individual vari-
are mutually exclusive with activating mu-
III, including diffuse astrocytoma, are ation. The total length of disease is in-
tations in the TERT gene, which encodes
nearly all characterized by mutations in fluenced mainly by the dynamics of
the catalytic component of telomerase.
IDH genes: either IDH1 or /DH2{118,953, malignant progression, which had been
Interestingly, TERT mutations are found
1895,2810}. Diffuse gliomas that occur in in the vast majority of oligodendroglio- reported to occur after a median time
adults and that do not harbour IDH muta- of 4-5 years {254,1826,1834}. The Eu-
mas and most IDH-wildtype glioblasto-
tion, regardless of their WHO grade, tend ropean Organisation for Research and
mas {349,622,1270}. Distinct telomere
to exhibit more aggressive clinical behav- Treatment of Cancer (EORTC) trials
maintenance mechanisms, mediated by
iour {870,2238}. 22844 and 22845 showed that patient
either activated telomerase or alternative
Glioma-associated IDH1 and IDH2 muta- age > 40 years, astrocytoma histology,
lengthening of telomeres, seem to be re-
tions impart a gain-of-function phenotype quired for the pathogenesis of all diffuse largest tumour diameter > 6 cm, tumour
to the respective metabolic enzymes crossing the midline, and neurological
gliomas.
IDH1 and IDH2, which overproduce deficits prior to surgery were associated
ATRX deficiency has also been associ-
the oncometabolite 2-hydroxyglutarate with inferior outcome {1975}. However,
ated with generalized genomic instability,
{523}. The physiological consequences these prognostic estimates must be re-
which can induce p53-dependent cell
of 2-hydroxyglutarate overproduction are evaluated in the context of IDH mutation
death in some contexts {488}. Therefore,
widespread, including profound effects TP53 mutations in diffuse astrocytoma status; one study that included 683 IDH-
on cellular epigenomic states and gene mutant diffuse astrocytoma cases from
may enable tumour cell survival in the
regulation. Specifically, IDH mutations in- three series showed a median survival of
setting of ATRX loss. The genomic insta-
duce G-CIMP, by which widespread hy- 10.9 years {2103}.
bility of IDH-mutant diffuse astrocytomas
permethylation in gene promoter regions
is reflected in characteristic DNA copy Proliferation
silences the expression of several impor-
number abnormalities, which include Low to absent proliferation rates as esti-
tant cellular differentiation factors {1540, low-level amplification events involv-
2589}. In this way, IDH mutation and mated by mitotic count or the Ki-67 prolif-
ing the oncogenes MYC and CCND2 in eration index have traditionally been con-
G-CIMP are thought to maintain glioma
mutually exclusive subsets {349}. Copy sidered a diagnostic criterion for grading
cells of origin in stem cell-like physiologi-
number events typically associated with a diffuse astrocytoma as WHO grade II.
cal states inherently more prone to self-
IDH-wildtype glioblastoma, such as Among histologically diagnosed diffuse
renewal and tumorigenesis. In particular,
EGFR amplification and homozygous astrocytomas, the level of proliferation
it appears that IDH mutations promote CDKN2A deletion, are rarely encoun-
glioma formation by disrupting chromo- has not been associated with outcome.
tered, emphasizing the biological differ-
somal topology and allowing aberrant Histopathological factors
ences between IDH-mutant and IDH-
chromosomal regulatory interactions that Gemistocytic astrocytoma has been
wildtype astrocytomas {349,622,870}.
induce oncogene expression, including associated with early progression and
On the basis of expression profiling,
glioma oncogenes such as PDGFRA inferior outcome {1834}, but data on
multiple diffuse astrocytoma subclasses
{713A}. Consistent with this concept, IDH have been designated, stratified by IDH larger contemporary patient cohorts with
mutations seem to be among the first ge- known IDH mutation status are lacking.
mutation status as well as neuroglial lin-
netic alterations that occur in WHO grade Other histological factors associated with
eage markers {349,870}. The transcrip-
II diffuse glioma {2709}. MGMT promoter outcome have not yet been identified.
tional profiles of diffuse astrocytomas
methylation was reported in about 50%
indicate distinct cells of origin in addition Genetic alterations
of diffuse astrocytomas in the pre-IDH
to specific genomic features. IDH1/2 mutations distinguish astrocyto-
era, but this proportion may be higher
among IDH-mutant diffuse astrocytomas Genetic susceptibility mas with a more favourable course from
and does not correlate consistently with Diffuse astrocytoma can occur in pa- IDH-wildtype tumours, which have a less
G-CIMP {1753,2589}. tients with inherited TP53 germline mu- favourable course {951}. Among IDH-
The vast majority of IDH-mutant dif- tations / Li-Fraumeni syndrome (see wildtype tumours, a genotype of 7q gain
fuse astrocytomas, as well as the WHO Li-Fraumeni syndrome, p. 310), although and 10q loss is associated with a par-
grade III anaplastic astrocytomas and affected family members more frequently ticularly poor outcome {2731}. However,
grade IV glioblastomas that evolve from develop anaplastic astrocytoma and glio- as noted earlier (see Clinical prognostic
them, also harbour class-defining loss- blastoma. Lower-grade astrocytoma has factors), a study that included 683 IDH-
of-function mutations in TP53 and ATRX been diagnosed in patients with inherited mutant diffuse astrocytomas from three
{1160,1215,1834,2092,2704}. ATRX en- Ollier-type multiple enchondromatosis, series reported a median survival of
codes an essential chromatin-binding
10.9 years. IDH mutations may be use- For a diagnosis of gemistocytic astro- Localization
ful as a predictive biomarker when IDH- cytoma, gemistocytes should constitute Gemistocytic astrocytomas can develop
targeted therapies such as small-mole- more than approximately 20% of all tu- in any region of the CNS, but they most
cule inhibitors {2685} or vaccines {2301} mour cells. The presence of occasional commonly develop in the frontal and tem-
become available. Comprehensive gen- gemistocytes in a diffuse astrocytoma poral lobes.
otyping studies have shown correlations does not justify the diagnosis {1533}. Re-
Macroscopy
between IDH mutation status and other ports have suggested that gemistocytic
Macroscopically, gemistocytic astrocy-
molecular parameters; in particular, there astrocytoma may progress more rapidly
tomas are not substantially different from
are strong associations between IDH mu- than standard diffuse astrocytoma to
other low-grade diffuse gliomas. They
tation and TP53 mutation (present in 94% anaplastic astrocytoma and secondary
are often characterized by expansion of
of cases) and ATRX inactivation (present glioblastoma, but these reports are from
the infiltrated brain areas without clear
in 86% of cases) {349}. the pre-IDH era and it remains unclear
delineation of the neoplasm. The involved
whether IDH-mutant gemistocytic astro-
Mutant IDH catalyses the formation of areas may show greyish discolouration,
cytomas have an increased tendency for
2-hydroxyglutarate, which could poten- granularity, firmer or softer consistency,
anaplastic progression {319,1533}.
tially be monitored by MR spectroscopy and microcystic change {1533}.
{449} or in body fluids {358}. However, ICD-0 code 9411/3
Microscopy
the clinical value of these approaches
Grading The histopathological hallmark of gemis-
has yet to be validated.
IDH-mutant gemistocytic astrocytoma cor- tocytic astrocytoma is the presence of a
responds histologically to WHO grade II. conspicuous proportion of gemistocytic
Gemistocytic astrocytoma, neoplastic astrocytes. Gemistocytes
Epidemiology
IDH-mutant should account for more than approxi-
Gemistocytic astrocytomas account for
mately 20% of all tumour cells; the pres-
Definition approximately 10% of all WHO grade II
ence of occasional gemistocytes in a
A variant of IDH-mutant diffuse astrocy- diffuse astrocytomas {981}. The mean
diffuse astrocytoma does not justify the di-
toma characterized by the presence of reported patient age at diagnosis is
agnosis of gemistocytic astrocytoma. The
a conspicuous (though variable) propor- 40 years {2703}, the median age is
mean proportion of gemistocytes is ap-
tion of gemistocytic neoplastic astrocytes 42 years {1377}, and the male-to-female
proximately 35% {2703}. The cut-off point
(gemistocytes). ratio is 2:1 {2703}.
of 20% is somewhat arbitrary, but a useful
Fig. 1.10 Gemistocytic astrocytoma. A Tumour cells have enlarged, glassy, eosinophilic cytoplasm and eccentric nuclei. B Immunostaining shows a marked and consistent
accumulation of GFAP in the cytoplasm of neoplastic gemistocytes. Interspersed are small tumour cells with little cytoplasm; proliferation is largely restricted to this inconspicuous cell
population. C p53 accumulation is present in nuclei of small and gemistocytic tumour cells.
22 Diffuse gliomas
Paediatric diffuse astrocytoma Genetic aspects remains to be determined whether the
Although the histopathology of paedi- Diffuse astrocytomas in children and prognosis of IDH-mutant gemistocytic
atric diffuse astrocytoma resembles adults have distinct genetic profiles. astrocytoma differs significantly from that
that of adult diffuse astrocytoma, there However, diffuse astrocytomas with ge- of IDH-mutant diffuse astrocytoma.
are many important distinctions be- netically defined so-called adult-type
tween the disease in children and in disease can present in adolescents,
adults. and so-called paediatric-type disease
can present in young adults. Paediatric Diffuse astrocytoma,
Clinicopathological aspects diffuse astrocytomas are characterized
The annual incidence of paediatric dif- IDH-wildtype
mainly by alterations in MYB and BRAF. Definition
fuse astrocytoma (defined by patient
Amplification or rearrangements of MYB A diffusely infiltrating astrocytoma without
age < 20 years at diagnosis) is 0.27 cas-
are detected in approximately 25% of mutations in the IDH genes.
es per 100 000 population; lower than paediatric diffuse astrocytomas {2518,
that of adult diffuse astrocytoma, which IDH-wildtype diffuse astrocytoma is rare.
2855}. Rearrangements of MYBL1 have Most gliomas with a histological appear-
is 0.58 per 100 000 {1863}. Most pae-
also been described {2068}. Other pae- ance resembling that of diffuse astrocy-
diatric diffuse astrocytomas are located
diatric diffuse astrocytomas harbour toma but without IDH mutation can be re-
in the cerebral hemispheres, but a sig-
BRAF V600E mutations, FGFR1 altera- classified in adults as other tumours with
nificant proportion present in the thala-
tions, or KRAS mutations {2855}. Rare additional genetic analyses. Tumours
mus, which is an unusual site for adult paediatric diffuse astrocytomas contain
diffuse astrocytoma. Anaplastic pro- that conform to this diagnosis most likely
the H3 K27M mutation usually found in constitute a variety of entities, and can
gression occurs in approximately 75%
paediatric high-grade gliomas {2855}. therefore follow a broad range of clini-
of adult lesions, but is rare in paediatric
The mutations in IDH1, IDH2, TP53, cal courses. Thus, IDH-wildtype diffuse
tumours {284}.
and ATRX that are frequently found in astrocytoma is considered a provisional
adult diffuse astrocytomas are not entity.
present in the paediatric tumours
{2443}. Gliomatosis cerebri growth pattern
Like other diffuse gliomas, diffuse astro-
criterion in borderline cases {1377,2556}. displacement of nuclei to the periphery of cytoma can manifest at initial clinical pre-
The gemistocytes are characterized by the cell body. Expression of p53 protein sentation with a gliomatosis cerebri pat-
plump, glassy, eosinophilic cell bodies of is also frequently seen in gemistocytes tern of extensive involvement of the CNS,
angular shape. Stout, randomly oriented {2706}. with the affected area ranging from most
processes form a coarse fibrillary of one cerebral hemisphere (three lobes
Genetic profile or more) to both cerebral hemispheres
network. These processes are often
Gemistocytic astrocytoma is a variant of with additional involvement of the deep
useful in distinguishing the tumour cells
IDH-mutant diffuse astrocytoma. Reports grey matter structures, brain stem, cer-
from the mini-gemistocytes found in
have noted that gemistocytic astrocyto- ebellum, and spinal cord. See Anaplastic
oligodendroglioma. Gemistocytic neo-
mas are characterized by a particularly astrocytoma, IDH-wildtype (p. 27) for ad-
plastic astrocytes consistently express
high frequency of TP53 mutations, which ditional detail.
GFAP in their perikarya and cell
are present in > 80% of all cases {1834,
processes. The nuclei are usually
2703}, and likely in nearly all cases of
eccentric, with small, distinct nucleoli and
IDH-mutant gemistocytic astrocytoma.
densely clumped chromatin. Perivascular
The fact that TP53 mutations are present
lymphocyte cuffing is frequent {322}.
in both gemistocytes and non-gemis-
Electron microscopy confirms the
tocytic tumour cells indicates that the
Diffuse astrocytoma, NOS
presence of abundant, compact glial
gemistocytes are neoplastic and not re- Definition
filaments in the cytoplasm and in cell
active in nature {2094}. This interpretation A tumour with morphological features of
processes. Enlarged mitochondria have
is also supported by Immunoreactivity to diffuse astrocytoma, but in which IDH
also been noted {609}.
mutant IDH1 protein {359}. mutation status has not been not fully
Proliferation assessed.
Prognosis and predictive factors
The gemistocytic neoplastic astrocytes Full assessment of IDH mutation status in
Gemistocytic astrocytomas have been
show a significantly lower rate of diffuse astrocytomas involves sequence
reported to undergo progression to
proliferation than in the intermingled analysis for IDH1 codon 132 and IDH2
anaplastic (gemistocytic) astrocytoma
smallcell component {1046,1372,1377, codon 172 mutations in cases that are
and IDH-mutant glioblastoma more com-
2706}. However, microdissection has immunohistochemically negative for the
monly than do other diffuse astrocytomas
revealed identical TP53 mutations in both IDH1 R132H mutation.
{1377,1834,1929,1930}. However, these
gemistocytes and non-gemistocytic
data pertain to histologically diagnosed ICD-O code 9400/3
tumour cells {2094}.
gemistocytic astrocytomas irrespective
Immunophenotype of the presence of an IDH mutation. It
The cytoplasm of neoplastic gemisto-
cytes is filled with GFAP, causing
Fig. 1.11A Anaplastic astrocytoma in the right frontotemporal region. Note the ill-defined borders with the adjacent brain structures and focal cysts. B Frontotemporal anaplastic
astrocytoma containing a large cyst but no macroscopically discernible necrosis. C Anaplastic astrocytoma with diffuse, bilateral infiltration of the corpus callosum, the caudate
nucleus, and the fornices. The fornices are grossly enlarged and show petechial haemorrhages.
24 Diffuse gliomas
Macroscopy astrocytomas (i.e. gliomas that lack IDH
Like WHO grade II diffuse astrocytoma, mutations) {953}.
anaplastic astrocytomas tend to infiltrate
Genetic profile
the surrounding brain without causing
The molecular features of anaplastic as-
frank tissue destruction. This often leads
trocytoma largely recapitulate those of
to a marked enlargement of invaded
WHO grade II IDH-mutant diffuse astro-
structures, such as adjacent gyri and
cytoma. By definition, mutations in IDH1
basal ganglia. On cut surface, the higher
or IDH2 are present in all tumours, and
cellularity of the anaplastic astrocytoma
TP53 and ATRX alterations are found in
results in a discernible tumour mass,
the majority of tumours {118,953,1160,
which in some cases is distinguished Fig. 1.12 Anaplastic astrocytoma. Smear preparations 1215,1834,1895,2092,2704,2810}.
more clearly from the surrounding brain show various degrees of nuclear atypia.
Robust molecular correlates of anaplastic
structures than is seen in WHO grade II
progression within diffuse astrocytoma
diffuse astrocytomas. Macroscopic cysts astrocytoma at one end of the range and
lineages have yet to be established, be-
are uncommon, but there are often areas with glioblastoma at the other {492,1137,
cause the biological distinctions between
of granularity, opacity, and soft consist- 1223,2059}. The index may vary con-
IDH-mutant and IDH-wildtype tumours
ency. It is often difficult to grossly dis- siderably, however, even within a single
have emerged only recently. However,
tinguish between a WHO grade III ana- tumour.
compared with WHO grade II IDH-mutant
plastic astrocytoma and a WHO grade II
Immunophenotype astrocytomas, WHO grade III tumours
diffuse astrocytoma.
In general, the immunohistochemical have higher frequencies of chromosome
Microscopy features of anaplastic astrocytoma re- arm 9p and 19q losses {349,1269}.
The principal histopathological features capitulate those of WHO grade II diffuse
astrocytoma, consistent with their shared Prognosis and predictive factors
are those of a diffusely infiltrating astro-
cytoma with increased mitotic activity histogenetic and molecular foundations. Clinical prognostic factors
compared with the WHO grade II equiva- IDH-mutant anaplastic astrocytomas are
lent, usually accompanied by distinct nu- typically positive for GFAP and frequently Historically, median survival has been in
clear atypia and high cellularity. Mitotic exhibit strong and diffuse nuclear expres- the range of 3-5 years, but with marked
activity should be evaluated in the con- sion of p53. The majority express R132H- differences in cases with older patient
text of sample size. In small specimens, mutant IDH1 (reflecting their underlying age and low performance status, both
such as those obtained at stereotactic IDH mutation status) and display nega- of which are associated with inferior
biopsy, a single mitosis suggests signifi- tive immunostaining for nuclear ATRX. outcome {2740}. In the era of subtyping
cant proliferative activity; in such cases, anaplastic astrocytomas by IDH mutation
Cell of origin status, survival estimates now vary more
Ki-67 labelling may be helpful. In large
The cell of origin is unknown. The fact widely (see Genetic alterations). The ex-
resection specimens, a few mitoses are
that diffuse WHO grade II and III astro- tent of surgical resection at diagnosis
not sufficient for WHO grade III designa-
cytomas, IDH-mutant glioblastomas, also seems to impact outcome {2740}.
tion {826}. Regional or diffuse hypercellu-
and oligodendrogliomas all carry an IDH
larity is an important diagnostic criterion; Proliferation
mutation suggests that they may share a
but even in the setting of low cellularity, Proliferative activity, as estimated by
cell of origin different from those of IDH-
the diagnosis is still appropriate if there mitotic count or the Ki-67 proliferation
wildtype glioblastomas and pilocytic
is significant mitotic activity. With pro- index, is not prognostic for anaplastic
gressive anaplasia, nuclear morphology astrocytomas.
becomes more atypical, with increasing
variation in nuclear size, shape, coarse- Histopathological factors
ness, and dispersion of chromatin and Histological factors are not associated
increasing nucleolar prominence and with outcome of anaplastic astrocytoma,
quantity. Additional signs of anaplasia but they have not yet been carefully eval-
include multinucleated tumour cells and uated within the context of IDH-mutant
abnormal mitoses, but these are not ob- anaplastic astrocytoma.
ligatory for WHO grade III. By definition,
Genetic alterations
microvascular proliferation (multilayered IDH1/2 mutations are associated with
vessels) and necrosis are absent. better outcome, whereas IDH-wildtype
Proliferation anaplastic astrocytoma has an outcome
Unlike WHO grade II diffuse astrocy- similar to that of IDH-wildtype glioblasto-
toma, anaplastic astrocytoma displays ma {952}. A study that included 562 IDH-
mitotic activity. The growth fraction as de- mutant anaplastic astrocytomas from
termined by the Ki-67 proliferation index three series showed a median survival
is usually in the range of 5-10%, but can of 9.3 years {2103}. EGFR amplification
overlap with values for low-grade diffuse Fig. 1.13 Anaplastic astrocytoma. Moderate cellularity,
marked nuclear atypia, and mitoses.
Fig. 1.15 IDH-mutant anaplastic astrocytoma. A Well-delineated focus with higher cellularity, mitotic activity, and a lack of GFAP expression (left). Such foci are encountered in
anaplastic astrocytomas and glioblastomas and may represent new clones resulting from the acquisition of additional genetic alterations, indicating progression to a higher grade of
dedifferentiation and malignancy {750}. B GFAP Immunoreactivity. C Immunoreactivity for the proliferation marker MIB1, including a cell in mitosis.
Fig. 1.16 Mutations in ‘lower-grade’ (i.e. WHO grade II and III) gliomas (LGGs), detected in The Cancer Genome
Atlas (TCGA) series {349}. Note that the mutational pattern in LGG with wildtype IDH is similar to that of glioblastoma
(GBM) with wildtype IDH. LGGs with IDH mutation are divided into oligodendroglial tumours with 1p/19q codeletion and
astrocytic tumours with frequent TP53 and ATRX mutations but no 1p/19q codeletion. SNV, single nucleotide variant;
SV, structural variant. Reprinted from: Brat DJ et al., Cancer Genome Atlas Research Network {349}.
26 Diffuse gliomas
Anaplastic astrocytoma, Gliomatosis cerebri growth pattern Anaplastic astrocytoma, NOS
IDH-wildtype Like other diffuse gliomas, anaplastic
astrocytoma can manifest at initial clini- Definition
Definition
cal presentation with a gliomatosis cer- A tumour with morphological features
A diffusely infiltrating astrocytoma with
ebri pattern of extensive involvement of of anaplastic astrocytoma, but in which
focal or dispersed anaplasia and signif-
the CNS, with the affected area ranging IDH mutation status has not been fully
icant proliferative activity but without mu-
from most of one cerebral hemisphere assessed.
tations in the IDH genes.
(three lobes or more) to both cerebral Full assessment of IDH mutation status
IDH-wildtype anaplastic astrocytoma is
hemispheres with additional involvement in anaplastic astrocytomas involves se-
uncommon and accounts for about 20%
of the deep grey matter structures, brain quence analysis for IDH1 codon 132 and
of all anaplastic astrocytomas. Nonethe-
stem, cerebellum, and spinal cord. A IDH2 codon 172 mutations in cases that
less, histologically defined anaplastic
similar extensive, diffuse involvement of are immunohistochemically negative for
astrocytomas have the highest incidence
the deep grey matter structures (i.e. ba- the IDH1 R132H mutation.
of wildtype IDH1 and IDH2 among the
WHO grade II and III diffuse glioma vari- sal ganglia and thalamus), brain stem,
ICD-0 code 9401/3
ants {1269,2810}. Most gliomas with a cerebellum, and spinal cord can also be
histological appearance resembling that seen in the absence of cerebral corti- Grading
of anaplastic astrocytoma but without cal involvement. Gliomatosis was once Anaplastic astrocytoma, NOS, corre-
IDH mutation share molecular features thought to be a distinct nosological en- sponds histologically to WHO grade III.
with IDH-wildtype glioblastoma, and tity, but is now considered to be a pat-
sometimes with H3 K27M-mutant glio- tern of exceptionally widespread involve-
mas if located preferentially in midline ment of the neuraxis. It can be seen in
locations. Tumours in this category are any of the diffuse glioma subtypes, but
more clinically aggressive than are IDH- is most common in anaplastic astrocy-
mutant anaplastic astrocytomas and may toma. There are no unique molecular
follow a clinical course more similar to signatures that distinguish gliomatosis
that of glioblastoma. from the well-characterized subtypes of
diffuse glioma, but IDH mutations seem
Grading to be restricted to tumours with distinct
IDH-wildtype anaplastic astrocytoma solid tumour components {2313}.
corresponds histologically to WHO
grade III.
Epidemiology
Incidence
Glioblastoma is the most frequent malig-
nant brain tumour in adults, accounting
for approximately 15% of all intracranial
neoplasms and approximately 45-50%
of all primary malignant brain tumours
{1826,1863}. In most European and North
American countries and in Australia, the
annual incidence is about 3-4 cases per
100 000 population {1863}, whereas the
Age at diagnosis —— Female — Male
incidence is relatively low in eastern Asia,
with 0.59 cases per 100 000 population Fig. 1.17 Cumulative age distribution of patients with IDH-wildtype glioblastoma. There is a tendency for an earlier
per year in the Republic of Korea, for manifestation in women. Based on 371 cases from Nobusawa S et al. {1797}.
28 Diffuse gliomas
example {1861}. The annual incidence A series of environmental and genetic rostral lateral ventricles {1417}. In general,
of glioblastoma in the USA, adjusted to factors have been studied as potential tumour infiltration extends into the adja-
the United States Standard Population, causes of glioblastoma. To date, these cent cortex and through the corpus cal-
is 3.19 cases per 100 000 population investigations have yielded inconclusive losum into the contralateral hemisphere.
{1863}. The corresponding rate in a popu or negative results, including results on Glioblastoma of the basal ganglia and
lation-based study in Switzerland (adjust- the potential influence of non-ionizing ra- thalamus is common, especially in chil-
ed to the European Standard Population) diation (e.g. from mobile phones) and oc- dren. Glioblastoma of the brain stem
was 3.55 cases per 100 000 population cupational exposures. The only validated is uncommon and most often affects
{1826}. Significantly lower rates have risk factor associations are an increased children {595} (see also Diffuse midline
been reported in Asian and African coun- risk after ionizing radiation to the head glioma, H3 K27M-mutant, p. 57). The
tries, but this may be due in large part to and neck and a decreased risk among cerebellum and spinal cord are rare sites.
underascertainment. individuals with a history of allergies and/
or atopic disease(s) {1861}. Genome- Clinical features
Age and sex distribution Glioblastomas develop rapidly. The
wide association studies have identified
symptoms depend largely on the tumour
Glioblastoma can manifest in patients some specific heritable risk variants as-
location, primarily manifesting as focal
of any age, but preferentially affects sociated with glioblastoma (see Genetic
neurological deficits (e.g. hemiparesis
older adults, with peak incidence occur- susceptibility, p. 42). As our understand-
and aphasia) and tumour-associated
ring in patients aged 55-85 years. Glio- ing of the heterogeneity of glioblastoma
increases with the use of genomic tech- oedema with increase in intracranial
blastoma is the second most common
pressure. As many as half of all patients
type of intracranial neoplasm in adults nologies, our ability to discover and vali-
are diagnosed after an inaugural seizure.
aged > 55 years {1863}. Glioblastomas date glioblastoma subtype-specific risk
Other common symptoms are behaviour-
are rare in individuals aged < 40 years. factors will probably improve.
al and neurocognitive changes, nausea
In the USA, the median age of patients
Localization and vomiting, and occasionally severe
with glioblastoma is 64.0 years, and the
Glioblastoma is most often centred in pulsating headaches {557,2640,2733}. In
annual incidence rate in the 0-19 years
the subcortical white matter and deeper a study of 677 patients with IDH-wildtype
age group, adjusted to the United States
grey matter of the cerebral hemispheres. glioblastoma, the time from first symp-
Standard Population, is 0.14 new cases
In a series of 987 glioblastomas from toms to diagnosis was < 3 months in 68%
per 100 000 population. The median
the University Hospital Zurich, the most of cases and < 6 months in 84% {1827}.
patient age at diagnosis of IDH-wildtype
frequently affected sites were the tem- In patients with a significantly longer
glioblastomas is 62 years. The male-to-
poral lobe (affected in 31% of cases), duration of symptoms, the possibility of
female ratio for glioblastoma is 1.60:1 in
the parietal lobe (in 24%), the frontal an IDH-mutant glioblastoma that has
the USA {1863} and 1.28:1 in Switzerland
lobe (in 23%), and the occipital lobe (in evolved from a lower-grade astrocytoma
{1825}.
16%). Similar location trends are seen in should be considered.
Etiology the USA {1863}. Whereas primary, IDH-
Imaging
A very small proportion of glioblastomas wildtype glioblastomas have a wide-
Glioblastomas are irregularly shaped and
are inherited as part of specific Mende- spread anatomical distribution, second-
have a ring-shaped zone of contrast en-
lian syndromes (see Genetic suscep- ary, IDH-mutant glioblastomas have a
hancement around a dark, central area
tibility, p. 42) {1861}, but the etiology of striking predilection for the frontal lobe,
of necrosis. They may extend widely
most glioblastomas remains unknown. particularly in the region surrounding the
Fig. 1.18 IDH-wildtype glioblastoma. A This tumour appears multifocal on postcontrast T1-weighted MRI. B The corresponding FLAIR image of this ‘multifocal’ glioma shows an
abnormal signal connecting the seemingly separate foci of contrast enhancement. C This postcontrast T1 -weighted image shows the typical features of a ‘butterfly glioblastoma’ with
extensive involvement of the corpus callosum leading to bihemispheric spread.
Glioblastoma, IDH-wildtype 29
treated with antiangiogenic therapies,
presumably due to vascular normaliza-
tion {542}.
Gliomatosis cerebri growthpattern
Like other diffuse gliomas, glioblastoma
can manifest at initial clinical presenta-
tion with a gliomatosis cerebri pattern of
extensive involvement of the CNS, with
the affected area ranging from most of
one cerebral hemisphere (three lobes
or more) to both cerebral hemispheres
with additional involvement of the deep
grey matter structures, brain stem, cer-
ebellum, and spinal cord. See Anaplastic
astrocytoma, IDH-wildtype (p. 27) for ad-
ditional detail.
Fig. 1.19 Rare case in which the rapid development of a primary glioblastoma, IDH-wildtype, could be followed by Metastasis
neuroimaging. After a seizure, the 79-year-old man was hospitalized and MRI showed a small cortical lesion of 1 cm Despite its rapid, infiltrative growth, glio-
in diameter. Only 2 months later, the patient presented with a full-blown glioblastoma with ring enhancement, central blastoma does not commonly extend
necrosis, and perifocal oedema {1533,1822}. into the subarachnoid space or spread
through the cerebrospinal fluid, although
into adjacent lobes, the opposite hemi- Other infiltrative patterns give rise to
this may be more frequent in children {90,
sphere, and the brain stem. In the set- secondary structures of Scherer, includ-
880} Similarly, penetration of the dura,
ting of a ring-enhancing mass, biopsies ing perineuronal satellitosis, perivascular
venous sinus, and bone is exceptional
showing high-grade astrocytoma but not aggregation, and subpial spread {2838}.
{812,2002}. Although extension within
demonstrating frank histological features Infiltrative cells are located both inside
and along perivascular spaces is typi-
of glioblastoma should be suspected to and outside of the contrast-enhancing
cal, invasion of the vessel lumen is not a
have been inadequately sampled. rim of glioblastoma and generally create
frequent histological finding. Extracranial
a gradient of decreasing cell density with
Spread metastasis of glioblastoma is uncommon
increasing distance from the tumour cen-
Infiltrative spread is a defining feature of in patients without previous surgical in-
tre. Individual infiltrating tumour cells can
all diffuse gliomas, but glioblastoma is tervention, but has been documented in
be histologically identified several centi-
particularly notorious for its rapid invasion patients who have undergone interstitial
metres from the tumour epicentre, both in
of neighbouring brain structures {316}. therapies and in patients with ventricular
regions that are T2-hyperintense on MRI
Infiltration occurs most readily along shunts {935,1546,2676}. More recently,
and in regions that appear uninvolved.
white matter tracts, but can also involve circulating tumour cells have been found
These infiltrating cells are the most likely
cortical and deep grey structures. When in the blood of some patients with glio-
source of local recurrence after initial
infiltration extends through the corpus blastoma, suggesting that immune mech-
therapy, because they escape surgi-
callosum, with subsequent growth in the anisms or inhospitable environments of
cal resection, do not receive the highest
contralateral hemisphere, the result can distant organs suppress metastatic im-
dose of radiotherapy, and involve regions
be a bilateral, symmetrical lesion (so- plantation and growth {2454}. The find-
with an intact blood-brain barrier (which
called butterfly glioma). Similarly, rapid ing that immunosuppressed recipients of
diminishes chemotherapeutic bioavail-
spread is observed along white matter organ transplants from donors with glio-
ability) {834}. Interestingly, a pattern of
tracts of the internal capsule, fornix, an- blastoma have developed glioblastoma
increased infiltration has been observed
terior commissure, and optic radiation. in their transplanted organ suggests that
in a subset of patients with glioblastoma
the immune system normally suppresses
the metastatic potential of circulating tu-
mour cells {1161}.
Mechanisms of invasion
Mechanisms that promote the invasive
properties of glioblastoma cells include
those involved with cell motility, cell-ma-
trix and cell-cell interactions, and remod-
elling of the extracellular matrix, as well
as microenvironmental influences {160,
573}. Tumour cells produce migration-
enhancing extracellular matrix compo-
Fig. 1.20 A Glioblastoma with bilateral, symmetrical invasion of the corpus callosum and adjacent white matter of the nents and secrete proteolytic enzymes
cerebral hemispheres (butterfly glioblastoma). B Unusual case of a glioblastoma with focal infiltration of the cerebral
cortex and the adjacent subarachnoid space, macroscopically presenting as greyish thickening of the meninges.
30 Diffuse gliomas
tumours and that in approximately 3%
of these, the tumour foci differ in histo-
logical appearance {128}. True multifocal
glioblastomas are most likely polyclonal if
they occur infratentorially and supratento-
rially (i.e. outside easily accessible routes
such as the cerebrospinal fluid pathways
or the median commissures) {2228}. By
definition, multiple independently arising
gliomas must be of polyclonal origin, and
their existence can only be proven by ap-
plication of molecular markers, which in
informative cases enable the distinction
between tumours of common or inde-
pendent origin {175,197,1359}.
Macroscopy
Despite the short duration of symptoms
in many cases, glioblastomas are often
surprisingly large at the time of presenta-
tion, and can occupy much of a lobe. The
lesions are usually unilateral, but those in
Fig. 1.21 A Glioblastoma of the right frontotemporal region with infiltration of the basal ganglia, compression of the the brain stem and corpus callosum can
right lateral ventricle, and midline shift towards the contralateral (left) cerebral hemisphere. B Large, diffusely infiltrating be bilaterally symmetrical. Supratentorial
glioblastoma of the left frontal lobe with typical coloration: whitish-grey tumour tissue in the periphery, yellow areas bilateral extension occurs as a result of
of necrosis, and extensive haemorrhage. Note the extension through the corpus callosum into the right hemisphere.
growth along myelinated structures, in
C Symmetrical glioblastoma infiltrating the lateral ventricles and adjacent brain structures. D Large glioblastoma of
particular across the corpus callosum
the brain stem (pons), causing compression of the fourth ventricle. This location is typical of H3 K27M-mutant diffuse
and the commissures. Most glioblas-
midline gliomas.
tomas of the cerebral hemispheres are
clearly intraparenchymal with an epicen-
that permit invasion, including the matrix angiogenic mechanisms and direct ef- tre in the white matter. Infrequently, they
metalloproteinases MMP2 and MMP9, fects that enhance glioma cell migra- are largely superficial and in contact with
uPA and its receptor uPAR, and cath- tion {1239,2840}. Hypoxic tumour cells the leptomeninges and dura and may
epsins. Gliomas also express a variety display elevated expression of extracel- be interpreted by the neuroradiologist or
of integrin receptors that mediate interac- lular matrix components and intracellu- surgeon as metastatic carcinoma, or as
tions with molecules in the extracellular lar proteins associated with cell motility an extra-axial lesion such as meningi-
space and lead to alterations of the cel- {264,2170}. Activation of a pro-migration oma. Cortical infiltration may produce a
lular cytoskeleton and activation of intra- transcriptional programme seems to be preserved gyriform rim of thickened grey
cellular signalling networks such as the associated with a decrease in prolifera- cortex overlying a necrotic zone in the
AKT, mTOR, and MAPK pathways. Many tion, which may have therapeutic conse- white matter.
growth factors expressed in glioblasto- quences {834,835}. Glioblastomas are poorly delineated;
ma, such as hepatocyte growth factor, fi- the cut surface is variable in colour, with
Multifocal glioblastoma peripheral greyish tumour masses and
broblast growth factor, epidermal growth
Although multifocality is not unusual when central areas of yellowish necrosis from
factor, and VEGF, also stimulate migra-
defined radiologically, the incidence of myelin breakdown. The peripheral hyper-
tion by activation of corresponding re-
truly multiple, independent gliomas oc- cellular zone presents macroscopically
ceptor tyrosine kinases and downstream
curring outside the setting of inherited
mediators that more directly promote mi-
neoplastic syndromes is unknown. Even
gration, including FAK and the Rho fam-
careful postmortem studies on whole-
ily GTPases Rac, RhoA, and CDC42. In
brain sections do not always reveal a
EGFR-amplified glioblastomas, cells with
connection between apparently multifo-
amplification are preferentially located at
cal gliomas, because the cells infiltrat-
the infiltrating edges, suggesting a role in
ing along myelinated pathways are often
peripheral expansion {2385}. The overall
small, polar, and largely undifferentiated.
mass migration of glioblastoma is radially
One careful histological analysis {143}
outward, away from central necrosis and
concluded that 2.4% of glioblastomas
associated severe hypoxia, with rates
are truly multiple independent tumours,
substantially greater than those of pre-
a value similar to that reported by others
necrotic gliomas {2170,2467}. Hypoxia
{2.3%) {2204}. A postmortem study found
promotes invasion through the activa- Fig. 1.22 IDH-wildtype glioblastoma. This intraoperative
that 7.5% of gliomas (including oligoden-
tion of HIF1 and other hypoxia-inducible smear preparation shows small, elongated bipolar cells,
drogliomas) are multiple independent
transcription factors, due to both pro- a characteristic component of glioblastomas {1956}.
Glioblastoma, IDH-wildtype 31
The presence of highly anaplastic glial
cells, mitotic activity, and microvascular
proliferation and/or necrosis is required.
The distribution of these key features
within the tumour is variable, but large
necrotic areas usually occupy the tumour
centre, whereas viable tumour cells tend
to accumulate in the periphery. The cir-
cumferential region of high cellularity
and abnormal vessels corresponds to
the contrast-enhancing ring seen radio-
logically, and is an appropriate target for
needle biopsy. Microvascular prolifera-
tion is seen throughout the lesion, but is
usually most marked around necrotic foci
and in the peripheral zone of infiltration.
Cellular composition and histological
patterns
Few human neoplasms are as heteroge-
neous in composition as glioblastoma.
Fig. 1.23 Diagnostic hallmarks of IDH-wildtype glioblastoma. A focus of ischaemic necrosis (NE) is surrounded by Poorly differentiated, fusiform, round, or
palisading tumour cells and hyalinized vascular proliferation (VP). pleomorphic cells may prevail, but bet-
ter-differentiated neoplastic astrocytes
are usually discernible, at least focally
{317}. This is particularly true of glioblas-
tomas resulting from the progression of
WHO grade II diffuse astrocytomas, but
these are typically IDH-mutant glioblas-
tomas. The transition between areas that
still have recognizable astrocytic differ-
entiation and highly anaplastic cells may
be either continuous or abrupt. In the
case of gemistocytic lesions, anaplas-
Fig. 1.24 Glioblastoma, IDH-wildtype. A Microvascular proliferation in glioblastomas often have a glomeruloid tic tumour cells may be diffusely mixed
appearance. B Palisading necrosis is characterized by irregular zones of necrosis surrounded by dense accumulations
with the differentiated gemistocytes. An
of tumour cells.
abrupt change in morphology may reflect
the emergence of a new tumour clone
as a soft, grey to pink rim or a grey band tumour cells with nuclear atypia and brisk
through the acquisition of one or more
of tumour tissue. However, necrotic tissue mitotic activity. Prominent microvascular
additional genetic alterations (see Primi-
may also border adjacent brain structures proliferation and/or necrosis is an essen-
tive neuronal cells and glioblastoma with
without an intermediate zone of macro- tial diagnostic feature.
a primitive neuronal component, below)
scopically detectable tumour tissue. The As the outdated term ‘glioblastoma mul-
{750}. Cellular pleomorphism includes
central necrosis can occupy as much as tiforme’ suggests, the histopathology of
the formation of small, undifferentiated,
80% of the total tumour mass. Glioblas- this tumour is extremely variable. Some
lipidized, granular, and giant cells. There
tomas are typically stippled with red and lesions show a high degree of cellular
are also often areas where bipolar, fusi-
brown foci of recent and remote haem- and nuclear polymorphism with numer-
form cells form intersecting bundles,
orrhage. Extensive haemorrhages can ous multinucleated giant cells; others
and fascicles prevail. The accumulation
occur and cause stroke-like symptoms, are highly cellular but relatively mono-
of highly polymorphic tumour cells with
which are sometimes the first clinical sign morphic. The astrocytic nature of the
well-delineated plasma membranes and
of the tumour. Macroscopic cysts, when neoplasms is easily identifiable (at least
a lack of cell processes may mimic meta-
present, contain a turbid fluid and con- focally) in some tumours, but difficult to
static carcinoma or melanoma.
stitute liquefied necrotic tumour tissue, in recognize in tumours that are poorly dif-
Several cellular morphologies appear
contrast to the well-delineated retention ferentiated. The regional heterogeneity
commonly in glioblastomas. Some glio-
cysts present in WHO grade II diffuse of glioblastoma is remarkable, making
blastomas have well-recognized pat-
astrocytomas. histopathological diagnosis difficult on
terns that are characterized by a great
specimens obtained by stereotaxic nee-
Microscopy predominance of a particular cell type.
dle biopsies {317}.
Glioblastoma is typically a highly cellu- These morphologies are discussed in
The diagnosis of glioblastoma is often
lar glioma, usually composed of poorly the following subsections, along with the
based on the identification of the tissue
differentiated, sometimes pleomorphic corresponding glioblastoma patterns that
pattern rather than of specific cell types.
32 Diffuse gliomas
Fig. 1.25 Small cell glioblastoma. A Central portion of an EGFR-amplified, IDH-wildtype, 1p/19q-intact small cell glioblastoma showing a highly cellular monomorphic population
of small tumour cells with frequent mitoses despite only mild nuclear atypia. B Delicate processes are evident on a GFAP immunostain. C The Ki-67 labelling index is very high.
can be established if a particular cellu- mitotic activity. In the zone of infiltration, IDH mutations are absent {1183,1937}.
lar morphology predominates. Because tumour cells can be difficult to identify In one series, mutations of TP53 were
most of these glioblastoma patterns are as neoplastic, given their small size and found to be slightly less common in this
found in IDH-wildtype glioblastomas, bland cytology. GFAP immunoreactivity subtype, but the difference did not reach
they are discussed here, but it is recog- variably highlights delicate processes, statistical significance {1031}. The clini-
nized that some of these variants (e.g. and the Ki-67 proliferation index is typi- cal behaviour of the small-cell subtype is
gemistocytic astrocytomas progressing cally high. Due to their nuclear regular- similar to that of other primary glioblas-
to glioblastoma) are more characteristic ity, clear haloes, microcalcifications, tomas in general, with a median survival
of IDH-mutant glioblastoma. and chicken wire-like microvasculature, time of 11 months in one series {1937}.
these tumours overlap with anaplastic In the same series, about a third of the
Small cells and small cell glioblastoma oligodendroglioma {1937}. But unlike cases presented as non-enhancing or
This subtype features a predominance oligodendrogliomas, small cell glioblas- minimally enhancing masses with no
of highly monomorphic small, round to tomas frequently have EGFR amplifi- evidence of microvascular proliferation or
slightly elongated, hyperchromatic nu- cation (present in -70% of cases) and necrosis on histology. However, follow-up
clei with minimal discernible cytoplasm, chromosome 10 losses (in > 95%). As in imaging 2-3 months later often showed
little nuclear atypia, and (often) brisk other primary glioblastomas in general, ring enhancement, and survival times
were shorter for these cases (median:
6 months), suggesting that these cases
constitute early presentations of WHO
grade IV glioblastoma rather than WHO
grade III anaplastic astrocytoma {1937}.
Primitive neuronal cells and glioblastoma
with a primitive neuronal component
This subtype constitutes an otherwise
classic diffuse glioma with one or more
solid-looking primitive nodules showing
neuronal differentiation. The glioma com-
ponent is typically astrocytic, although
rare primitive neuronal foci have also
been reported in oligodendrogliomas
{1946}. The primitive foci are sharply
demarcated from the adjacent glioma and
display markedly increased cellularity and
a high nuclear-to-cytoplasmic ratio and
mitosis-karyorrhexis index. More variable
features include Homer Wright rosettes,
cell wrapping, and anaplastic cytol-
ogy similar to that of medulloblastoma or
other CNS embryonal neoplasms. Addi-
tional primitive neuronal features include
immunoreactivity for neuronal markers
such as synaptophysin, reduction or loss
of GFAP expression, and a markedly ele-
Fig. 1.26 Glioblastoma with a primitive neuronal component. A Diffuse astrocytoma component on the right and
vated Ki-67 proliferation index compared
primitive neuronal component on the left. B Homer Wright rosettes within the primitive neuronal component of a
with adjacent foci of glioma. This subtype
glioblastoma. C Strong synaptophysin positivity in the primitive cells.
Glioblastoma, IDH-wildtype 33
they may have a better prognosis than
standard glioblastoma {975,1031,1360}.
More recent studies suggest that this is
a heterogeneous tumour group, and that
some cases are IDH1- or /DH2-mutant
glioblastomas. The current WHO classi-
fication does not consider glioblastoma
with an oligodendroglioma component
to be a distinct diagnostic entity; with
genetic analysis, it should be possible to
classify such tumours as IDH-wildtype
glioblastoma (in particular the small-cell
variant, given the morphological overlap
with oligodendroglial cells), IDH-mutant
glioblastoma, or IDH-mutant and 1p/19q-
codeleted anaplastic oligodendroglioma.
Gemistocytesand gemistocytic
astrocytic neoplasms
Gemistocytes are cells with copious,
Fig. 1.27 Granular cell glioblastoma. A Eosinophilic cytoplasm reminiscent of a granular cell tumour of the pituitary, but glassy, non-fibrillary cytoplasm that dis-
with cytologically more atypical cells. B GFAP Immunoreactivity. C The strong nuclear 0LIG2 Immunoreactivity helps places the dark, angulated nucleus to
to establish its glial lineage. D In contrast to most glioblastomas, the granular cell variant often shows immunoreactivity the periphery of the cell. Processes ra-
for EMA.
diate from the cytoplasm, but are stubby
and not long-reaching. GFAP staining is
presents either de novo or during pro- patients, the typically strong and exten-
largely confined to the periphery of the
gression from a known diffuse glioma. In sive tumoural p53 immunoreactivity, and
cell, with the central hyaline organelle-
both settings, the survival time and ge- the presence of IDH1 R132H mutations in
rich zone remaining largely unstained.
netic background are similar to those of 15-20% of cases {1183,2394}.
Perivascular lymphocytes frequently
glioblastoma in general {1946}. However,
Oligodendroglioma components populate gemistocytic regions, but of-
this subtype is distinctive in its high rate
Occasional glioblastomas contain foci ten avoid other regions in the same neo-
(30-40%) of cerebrospinal fluid dissemi-
that resemble oligodendroglioma. These plasm. When present in large numbers,
nation and frequency (~40%) of MYCN
areas are variable in size and frequency, particularly in a patient known to have a
or MYC gene amplification. MYC ampli-
and individual pathologists’ thresholds pre-existing glioma (e.g. an IDH-mutant
fication is found only in the primitive-ap-
for identifying oligodendroglioma fea- gemistocytic astrocytoma), these cells
pearing nodules, and it is likely that such
tures vary. Two large studies of malignant may constitute a lower-grade precursor
alterations drive the primitive-appearing
gliomas suggest that necrosis is associ- lesion within a secondary IDH-mutant
clonal transformation at least in part,
ated with a significantly worse prognosis glioblastoma. Better-differentiated areas
given that a similar phenotype has been
in the setting of anaplastic glioma with can sometimes be identified radiologi-
observed in N-myc-driven murine fore-
both oligodendroglial and astrocytic cally as non-contrast-enhancing periph-
brain tumours {2468}. In some cases, ei-
components {1667,2617}; patients whose eral regions, and in whole-brain sections,
ther new 10q losses or expanded regions
tumours had necrosis had a substantially as WHO grade II to III astrocytomas
of 10q loss are also found in the primi-
shorter median overall survival than did clearly distinct from foci of glioblastoma
tive neuronal focus {750}. Evidence that
patients whose tumours did not. Such tu- {317,2266}. Immunohistochemical stud-
some examples of this subtype are sec-
mours were classified as glioblastomas ies have emphasized the low proliferation
ondary glioblastomas includes the his-
with an oligodendroglial component, and rate of the neoplastic gemistocyte itself,
tory of a lower-grade precursor in some
despite the reported tendency of WHO
grade II or III gemistocytic astrocytoma
lesions to progress more rapidly to glio-
blastoma than non-gemistocytic coun-
terparts of the same grade {2706}. The
proliferating component presents as a
population of cells with larger hyperchro-
matic nuclei and scant cytoplasm {2706}.
Multinucleated giant cells
Large, multinucleated tumour cells are
often considered a hallmark of glio-
Fig. 1.28 Glioblastoma, IDH-wildtype. A High degree of anaplasia with multinucleated giant cells. B Focal blastomas and occur with a spectrum
oligodendroglioma-like component. of increasing size and pleomorphism.
34 Diffuse gliomas
Fig. 1.29 Glioblastoma with epithelial metaplasia. A In addition to adenoid cytology, this glioblastoma features occasional squamous morules, indicative of true epithelial metaplasia.
B Loss of GFAP expression within foci of epithelial metaplasia. C Focal squamous cell metaplasia characterized by marked cytokeratin expression.
Although common, the presence of multi- lesion such as demyelinating disease. 2506}. The lipidized cells may be grossly
nucleated giant cells is neither an obliga- Given their lysosomal content, granular enlarged {811}. If such a lesion is super-
tory feature nor associated with a more tumour cells may be immunoreactive for ficially located in a young patient, the
aggressive clinical course {315}. Despite macrophage markers such CD68, but diagnosis of pleomorphic xanthoastrocy-
their appearance, these cells are con- not for specific markers such as CD163. toma should be considered, particularly
sidered a type of regressive change. If Occasional cells may have peripheral im- if the xanthomatous cells are surrounded
multinucleated giant cells dominate the munopositivity for GFAP, but most cells by basement membranes staining posi-
histopathological picture, the designation are negative {271,793}. Some diffuse as- tively for reticulin and accompanied by
of giant cell glioblastoma is justified (see trocytic tumours feature extensive granu- eosinophilic granular bodies {1248}.
Giant cell glioblastoma, p. 46). lar cell change and have been termed Other lipid-rich lesions have epithelioid
“granular cell astrocytoma" or “granular cytological features {2180}. Lobules of
Granular cells and granular cell
cell glioblastoma”. These lesions have a juxtaposed fully lipidized (i.e. not foamy)
astrocytoma/glioblastoma cells can simulate adipose tissue.
distinct histological appearance and are
Large cells with a granular, periodic acid-
typically characterized by aggressive
Schiff-positive cytoplasm may be scat- Metaplasia and gliosarcoma
glioblastoma-like clinical behaviour {271},
tered within glioblastoma. In rare cases, In general, ‘metaplasia’ refers to the ac-
even when the histology otherwise sug-
they dominate and create the impression quisition by a differentiated cell of mor-
gests only a WHO grade II or III desig-
of a morphologically similar but unrelated phological features typical of another dif-
nation; one review of 59 reported cases
granular cell tumour of the pituitary stalk ferentiated cell type. However, the term is
found median survival times of 11 months
{569,948}. In the cerebral hemispheres, also used to designate aberrant differen-
for WHO grade II cases and 9 months for
transitional forms between granular cells tiation in neoplasms. In glioblastoma, this
WHO grade lll-IV cases {2283}.
and neoplastic astrocytes can be identi- is exemplified by foci displaying features
fied in some cases, but in others it is dif- Lipidized cells and heavily lipidized of squamous epithelial cells (i.e. epithelial
ficult to identify any conventional astro- glioblastoma whorls with keratin pearls and cytokeratin
cytoma component. Although larger and Cells with foamy cytoplasm are another expression) {320,1734}.
more coarsely granular, the tumour cells feature occasionally observed in glio- Occasionally, glioblastomas contain foci
also resemble macrophages. Especially blastoma. The rare lesions in which they with glandular and ribbon-like epithelial
in the context of perivascular chronic predominate have been designated structures {2180}. These elements have
inflammation, the tumour cells may be malignant gliomas with heavily lipidized a large oval nucleus, prominent nucleo-
misinterpreted as a macrophage-rich (foamy) tumour cells {1247,1253,2180, lus, and round well-defined cytoplasm.
Fig. 1.30 Adenoid glioblastoma. A Adenocarcinoma-like cytology with small epithelioid cells arranged in nests and rows set within a mucin-rich stroma. B Despite the Carcinoma-Iike
appearance, the glial histogenesis of this adenoid glioblastoma is supported by strong nuclear expression of OLIG2.
Glioblastoma, IDH-wildtype 35
for the formation of bone and cartilage,
which predominates in gliosarcoma and
in a variety of childhood CNS neoplasms
{1608}.
Secondary structures
The migratory capacity of glioblastoma
cells within the CNS becomes readily
apparent when they reach a border that
constitutes a barrier: tumour cells line up
and accumulate in the subpial zone of
Fig. 1.31 IDH-wildtype glioblastoma. GFAP immunohisto- the cortex, in the subependymal region, Fig. 1.32 Subpial, perivascular, and perineuronal
chemistry typically labels only some cells in glioblastoma, accumulation of glioblastoma cells. Asterisk indicates
and around neurons (so-called satellito-
highlighting the tumour cell bodies and processes. uninvolved subarachnoid space.
sis) and blood vessels. These patterns,
called secondary structures {2267}, re-
They are also referred to as adenoid One feature of many glioblastomas, es-
sult from the interaction of glioma cells
glioblastomas. Expression of GFAP in pecially the small-cell variant, is exten-
with host brain structures, and are highly
these areas may be diminished, and re- sive involvement of the cerebral cortex.
diagnostic of an infiltrating glioma. Sec-
placed by expression of epithelial mark- Secondary structures and most of the
ondary structures may also be present
ers. Small cells with even more epithelial apparently multifocal glioblastomas arise
in other highly infiltrative gliomas, such
features and cohesiveness are less com- essentially as a result of the pathways
as oligodendroglioma {2266,2267}. This
mon {1250}. When there is an extensive of migration of glioma cells in the CNS
concept also extends to the adaptation
mesenchymal component, in particular {1440}. The subependymal region may
of tumour cells to myelinated pathways,
a spindle cell sarcoma-like component, also be diffusely infiltrated, especially in
which often acquire a fusiform, polar
a diagnosis of gliosarcoma should be the terminal stages of disease.
shape as a result. Identifying neoplas-
considered. A mucinous background
tic astrocytes in the perifocal zone of Proliferation
and a mesenchymal component (gliosar-
oedema and at more distant sites can Proliferative activity is usually prominent,
coma) are not uncommon in metaplastic
be challenging for pathologists, in par- with detectable mitoses in nearly every
glioblastomas. Adenoid and squamous
ticular when dealing with stereotaxic case. Atypical mitoses are frequently
epithelial metaplasia are more common
biopsies {535}. Small cell glioblastomas present. However, there is great intertu-
in gliosarcoma than in ordinary glioblas-
pose a particular problem in this regard. moural and intratumoural variation in mi-
toma {1250,1734}. This is similarly true
totic activity. The growth fraction as de-
termined by the Ki-67 proliferation index
can thus show great regional variation.
Typical values are 15-20%, but some
tumours have a proliferation index of
> 50% focally. Rare tumours have a low
proliferation index despite other histo-
logical features of malignancy. Tumours
with small, undifferentiated, fusiform cells
often show marked proliferative activ-
ity, in contrast to tumours composed of
neoplastic gemistocytes, which typically
have a lesser degree of proliferation
{2706}. Despite the wide range in the pro-
liferation index observed in glioblastoma,
an association between proliferation in-
dex and clinical outcome has not been
demonstrated {1715}.
Microvascular proliferation and
angiogenesis
The presence of microvascular prolif-
eration is a histopathological hallmark
Fig. 1.33 Intravascular thrombosis in glioblastoma (GBM). A A central vessel within a GBM is occluded by intravascular of glioblastoma. On light microscopy,
thrombus (arrow). The vessel is dilated proximal to the occlusion and surrounded by delicate fibrillarity and scattered microvascular proliferation typically pre-
apoptotic cells, most likely representing the initial stages of palisade formation (arrowhead). B As the palisading front
sents as so-called glomeruloid tufts of
of tumour cells (arrowhead) enlarges around a central thrombosed vessel (arrow), perivascular necrosis becomes
multilayered mitotically active endothelial
more prominent. C H&E staining of a GBM demonstrates intravascular thrombosis occluding and distending a vessel
cells together with smooth muscle cells /
(arrow) within the centre of a palisade (arrowhead). D Immunohistochemistry for HIF1A of a serial tissue section shows
increased nuclear staining in palisades, indicating an adaptive response to hypoxia (arrowhead). Reprinted from Rong Y
pericytes {920,1741,2734}. Another (less
et al. {2170}.
36 Diffuse gliomas
pericytes (which are negative for CD31 of VEGFA by monoclonal antibodies,
and CD34, positive for SMA, and positive used for the treatment of recurrent glio-
for PDGFRB) {2264}. Morphologically blastoma {1998}, seems to target pri-
inconspicuous vessels have a Ki-67 pro- marily small, immature vessels and lead
liferation index of 2-4%, whereas prolif- to vascular normalization accompanied
erating tumour vessels have an index of by improved perfusion and oxygenation
> 10% {2702}. {2398}. Other signalling pathways impor-
Glioblastomas are among the most vascu- tant for glioblastoma angiogenesis in-
larized of all human tumours. Vasculariza- clude angiopoietin/Tie2 receptor signal-
tion occurs through several mechanisms, ling, IL8/IL8R signalling, platelet-derived
including vessel cooption (adoption of growth factor (PDGF) / PDGF receptor
pre-existing vessels by migrating tumour signalling, WNT/beta-catenin signalling,
cells {708,1559}), classic angiogenesis Eph/ephrin signalling, and transforming
(sprouting of capillaries from pre-existing growth factor beta signalling. Pericytes /
vessels by endothelial cell proliferation/ smooth muscle cells and perivascular
migration), and vasculogenesis (homing bone marrow-derived cells (in addition
of bone marrow-derived cells that sup- to endothelial cells) also participate in the
port vessel growth in a paracrine man- vascular remodelling processes typically
ner {6,708,1559}). Intussusception and observed in glioblastoma.
Fig. 1.34 Potential mechanism of palisade formation.
cancer stem cell-derived vasculogen- Necrosis
A Endothelial injury and the expression of procoagulant
factors result in intravascular thrombosis and increasing
esis have also been described {944,1127, Tumour necrosis is a fundamental feature
perivascular hypoxia (light blue). Tumour cells begin
1989}. Hypoxia is a major driving force of glioblastoma, and its presence is one
to migrate away, creating a peripherally moving of glioblastoma angiogenesis {6} and of the strongest predictors of aggres-
wave of palisading cells. B The zone of hypoxia and leads to intracellular stabilization of the sive behaviour among diffuse astrocytic
central necrosis expands. Hypoxic tumour cells of master regulator HIF1A. HIF1A accumu- tumours {315,1031,2079}. Presenting on
palisades secrete proangiogenic factors (VEGF, IL8). lation leads to transcriptional activation of neuroimaging as a hypodense core within
C Microvascular proliferation in regions adjacent to > 100 hypoxia-regulated genes encod- a contrast-enhancing rim, necrosis con-
central hypoxia causes an accelerated outward migration ing proteins that control angiogenesis stitutes areas of non-viable tumour tissue
of tumour cells towards a new vasculature. Illustration ©
(e.g. VEGFA, angiopoietins, erythropoi- that can range from extremely small to
2005 Mica Duran. Adapted from Rong Y et al. {2170}.
etin, and IL8), cellular metabolism (e.g. accounting for > 80% of the total tumour
common) form is hypertrophic proliferat- carbonic anhydrase and lactate dehydro- mass. Higher proportions of necrosis on
ing endothelial cells within medium-sized genase), survival/apoptosis (e.g. BNIP), MRI have been associated with shorter
vessels. Microvascular proliferation of and migration (e.g. hepatocyte growth survival, and the extent of necrosis is also
the glomeruloid type is most commonly factor receptor, CXCR4, and ACKR3). related to the tumour’s transcriptional
located in the vicinity of necrosis and is VEGFA seems to be the most important profile {904,1969}. Grossly, necrosis pre-
directionally oriented to it, reflecting the mediator of glioma-associated vascu- sents as a yellow or white granular co-
response to vasostimulatory factors re- lar functions; it is primarily produced by agulum. Microscopically, glioma cells in
leased from the ischaemic tumour cells. perinecrotic palisading cells as a conse- various stages of degeneration are seen
Vascular thrombosis is common and quence of cellular stress such as hypoxia within necrobiotic debris, together with
may be apparent to the neurosurgeon and hypoglycaemia {1239,1988,2357}. faded contours of large, dilated necrotic
as so-called black veins. It may play a VEGFA is regulated by transcription fac- tumour vessels. Occasionally, preserved
role in the pathogenesis of ischaemic tu- tors, oncogenes, tumour suppressor tumour vessels with a corona of viable tu-
mour necrosis {2170}. The hyperplastic genes, cytokines, and certain hormones. mour cells can be seen within extensive
endothelial cells (which are positive for VEGFA induces tumour angiogenesis, in- areas of necrosis.
CD31 and CD34, negative for SMA, and creases vascular permeability (oedema), A second form of necrosis that is a his-
positive for VEGFR2) are surrounded by and regulates homing of bone marrow- tological hallmark of glioblastoma is the
basal lamina and an incomplete layer of derived cells {6}. Therapeutic blocking
Fig. 1.35 Extensive coagulative ischaemic necrosis Fig. 1.36 A Longitudinal cut of perinecrotic palisades, presenting as long, serpiginous pattern. B Reticulin stain of a
(right). Note several large thrombosed tumour vessels. perinecrotic garland of proliferated tumour vessels.
Glioblastoma, IDH-wildtype 37
palisading form (historically called the the release of mitochondrial factors glioblastomas. In poorly differentiated
pseudopalisading form), which consists or by death receptor ligation by mem- tumours, the expression of OLIG2 may
of multiple, small, irregularly shaped bers of the tumour necrosis factor fam- be of diagnostic utility, being strongly
band-like or serpiginous foci surround- ily, including TNFSF10/TNFRSF10B and positive far more commonly in astrocy-
ed by radially oriented, densely packed TNFSF6/TNFRSF6 {943,1872}. The high- tomas and oligodendrogliomas than in
glioma cells {2170}. The outdated term er levels of apoptosis seen in palisading ependymomas and non-glial tumours
“pseudopalisading" implied that the tu- cells surrounding necrosis may be due {1101,1865}. The expression of cytokerat-
mour cells did not truly aggregate around to increased expression or ligation of ins is determined by the class of these
necrosis, but only created this impres- death receptors {264,2485}. TNFSF10 intermediate filaments and antibodies
sion, because they were believed to be induces apoptosis in glioblastoma by used, some of which may indicate cross-
a rim of hypercellular tumour cells that binding to TNFRSF10B and ultimately reactivity with GFAP; keratin positivity is
remained after central degeneration of a activating caspase-8 {943}. Levels of most often detected with the keratin anti-
highly proliferative clone. However, this both TNFRSF6 and TNFSF6 are higher body cocktail AE1/AE3, in contrast to the
is likely not actually the case, given that in astrocytomas than in normal brain lack of positivity for many other keratins
the palisading cells have lower rates of and correlate with tumour grade {2485, {2535}. Nestin is frequently expressed in
proliferation than adjacent glioma cells 2563}. MostTNFRSF6 expression in glio- glioblastoma and can be diagnostically
and the central area of smaller palisading blastoma is within palisading cells; physi- useful to distinguish glioblastoma from
structures often consists of a fine fibrillary cal interactions between tumour cells other high-grade gliomas {88}.
network without viable or necrotic glioma expressing TNFRSF6 and TNFSF6 may Glioblastomas with missense TP53 mu-
cells {264,1847,2170[. Palisading cells promote apoptosis. In malignant gliomas, tations show strong and diffuse immu-
are hypoxic and strongly express HIF1A the overall levels of cell death due to apo- nohistochemical overexpression of p53
and other hypoxia-inducible transcription ptosis are low (compared with coagula- {2496}, with such overexpression evident
factors {2841,2861}. Downstream hypox- tive necrosis), and apoptotic rates do not in 21-53% of cases {276,1443,2007,
ic upregulation of VEGF, IL8, and other correlate with prognosis {1663,2272}. 2455}. This may facilitate discrimina-
proangiogenic factors is responsible for tion between neoplastic astrocytes and
Inflammation
the microvascular proliferation that oc- those in reactive gliosis in treated cases
The number of inflammatory cells in glio-
curs immediately adjacent to palisading of glioblastoma {268}. Detection of WT1
blastomas varies. Notable perivascular
cells, providing a biological link between expression, which is sometimes pres-
lymphocyte cuffing occurs in a minority
the histological hallmarks of necrosis and ent in both low-grade and high-grade
of glioblastomas, most typically in areas
microvascular hyperplasia in glioblasto- gliomas, may serve a similar purpose
with a homogeneous gemistocytic com-
ma {1989,2170}. The initiating necrogenic {2281}. EGFR expression occurs in about
ponent. Inflammatory cells are scant if
events have yet to be firmly established, 40-98% of glioblastomas and correlates
present at all in small cell glioblastomas.
but vascular cooption by neoplastic (to some extent) with the presence of
The inflammatory cells have been char-
cells has been hypothesized to induce gene amplification {198,678,1023,1443}.
acterized primarily as CD8+ T lympho-
vascular regression through endothelial EGFRvlll expression is less common (oc-
cytes, with CD4+ lymphocytes present
angiopoetin-2 expression {708,1030}. It curring in 27-33% of cases) {198,678}.
in smaller numbers {227,2184} and with
has been speculated that microscopic Tumours harbouring H3 K27M mutations
B lymphocytes detectable in < 10% of
vaso-occlusion and intravascular throm- (see Diffuse midline glioma, H3 K27M-
cases {2184}. Extensive CD8+ T-cell
bosis may initiate or propagate the devel- mutant, p. 57) can be detected using an
infiltrates may be more common in the
opment of hypoxia and necrosis, given antibody specific for K27M-mutant H3,
tumours of long-term glioblastoma sur-
that thrombi are present near regions of which can be useful in distinguishing
vivors {2813}. Microglia and histiocytes
necrosis in nearly all glioblastomas (but these neoplasms from other astrocytic
are also present in glioblastomas {1494,
not in lower-grade, non-necrotic astro- tumours {2644}. Some glioblastomas
2162}, although lipid-laden histiocytes are
cytomas) and are often observed within (i.e. IDH-mutant glioblastomas) express
uncommon in untreated glioblastomas.
or emerging from palisades {264,2529}. R132H-mutant IDH1, but the presence
In this proposed sequence, hypoxia- Immunophenotype of R132H-mutant IDH1 expression is
induced cell migration away from cen- Glioblastomas often express GFAP, but not compatible with a diagnosis of IDH-
tral hypoxia establishes the palisading the degree of reactivity differs markedly wildtype glioblastoma.
structures, which subsequently develop between cases; for example, gemisto-
Cell of origin
into increasingly larger regions of central cytic areas are frequently strongly posi-
The cellular origin of glioblastoma re-
necrosis and continue to expand radially tive, whereas primitive cellular compo-
mains unknown. The expression of mark-
outward {2170}. nents are often negative. The gliomatous
ers of differentiated astrocytes by glio-
component of gliosarcoma may show
Apoptosis blastoma cells has long been considered
expression of GFAP, as opposed to ab-
Apoptosis, the programmed death of to indicate the dedifferentiation of the
sent or meagre focal expression in the
individual cells, is a cell-intrinsic process cells after transformation. More recently,
sarcomatous component, which may
characterized by nuclear fragmentation the cellular, biochemical, and genetic
express alpha-1-antitrypsin, alpha-1-an-
and condensation, with packaging of heterogeneity that typify glioblastoma, to-
tichymotrypsin, actin, and EMA. S100
apoptotic bodies within an intact mem- gether with the distinct clinical responses
protein is also typically expressed in
brane. The process is initiated through of histologically similar tumours, has led
38 Diffuse gliomas
to the hypothesis that the tumours arise Table 1.01 Genetic profile of IDH-wildtype glioblastomas
from the malignant transformation of ei- Gene Change % of tumours References
ther a bipotential precursor cell {1794} or TERT Mutation 72-90% {622,1268,1270}
an even more primordial cell: the neural
EGFR Amplification 35-45% {350,1823,1895}
stem cell {1616}. This interpretation is
supported by the coincident anatomical CDKN2A Deletion 35-50% {350,1823,1895}
glioblastoma tumours and cell lines and PIC3CA Mutation 5-15% {350,1288A, 1895}
can be produced by the expression of a PDGFRA Amplification 13% {350}
set of developmental transcription factors
PTPRD Mutation 12% {350}
in glioblastoma cells {2461}. These cells,
called brain tumour stem cells, are only RB1 Mutation 8-12% {350}
Glioblastoma, IDH-wildtype 39
mutations in the region homologous to rare {993}, and gene promoter methyla- Genetic parameters (p. 28) for discus-
tensin/auxilin and dual-specificity phos- tion correlated with loss of RB1 expres- sion of the steps necessary to designate
phatases are associated with a malignant sion is more common in secondary glio- a glioblastoma as IDH-wildtype.
phenotype. Mutations in the NF1 gene blastomas (occurring in 43% of cases)
Chromatin-related genes
are present in approximately 20% of glio- than in primary glioblastomas (occurring
Mutations in chromatin-remodelling
blastomas {350}. in 14% of cases) {1755}.
genes are common in glioblastomas.
p53/MDM2/p14ARF pathway TERT promoter mutations Paediatric high-grade gliomas also bear
Alterations in the p53 pathway occur in The promoter region of TERT contains signature mutations directly affecting the
nearly 90% of glioblastomas {350}. TP53 two hotspots for point mutations, with histone gene H3F3A and less commonly
mutations are more often genetic hall- most glioblastomas (-80% in one study) HIST1H3B/C. These histone genes have
marks of clinicopathologically defined carrying these mutations {1270}. Within two mutation hotspots, in codons K27
secondary glioblastomas and, in almost IDH-wildtype adult diffuse gliomas, TERT and G34, with K27 mutations more often
all cases, are already present in precur- promoter mutations are inversely corre- found in midline, i.e. brain stem, thala-
sor lower-grade or anaplastic astrocyto- lated with TP53 mutations {1801}. They mus, and spinal cord tumours (see Dif-
mas {2705}. They are significantly less are frequent in IDH1-wildtype glioblasto- fuse midline glioma, H3 K27M-mutant,
common in clinicopathologically defined mas but rare in secondary (IDH1-mutant) p. 57) and G34 alterations in hemispheric
primary glioblastomas (present in -25% glioblastomas and astrocytomas. TERT lesions {1263,2444}. In paediatric high-
of cases) {1823}. G:C—>A:T transitions at mutations are also frequent in oligoden- grade gliomas, H3 mutations are asso-
CpG sites are most common {1823}. drogliomas. TERT promoter mutations ciated with mutations in its chaperone
Amplification of MDM2or overexpression lead to the recruitment of multimeric GA- ATRX and are inversely related to IDH
of MDM2 is an alternative mechanism for binding protein (GABP) transcription fac- mutations. ATRX mutations also occur
escaping p53-regulated control of cell tor specifically to the mutant promoter, in adult astrocytomas and glioblastomas
proliferation. Amplification is observed in leading to aberrant TERT expression {277}, particularly in those with IDH muta-
< 10% of glioblastomas without TP53 mu- {159A}. In IDH1-mutant glioblastomas tions {1160,2304,2792}.
tations {2084}. Overexpression of MDM2 and astrocytomas, telomere mainte-
Epigenetics, chromatin, and promoter
has been observed in > 50% of primary nance preferentially uses the alternative
methylation
but only 11% of secondary glioblastomas lengthening of telomeres pathway, which
The interplay between epigenetic regu-
{199}. is activated by mutations in the ATRX
lation and gliomagenesis has several
The CDKN2A locus gives rise to several gene (see Epigenetics, chromatin, and
modalities. Epigenetic modifiers can be
splice variants encoding distinct proteins promoter methylation).
bona fide oncogenes or tumour sup-
(CDKN2A and p14ARF) with tumour-
IDH mutations pressors that are directly affected by
suppressing function. The p14ARF pro-
Mutations of the IDH1 and IDH2 genes, gain- or loss-of-function genetic muta-
tein binds directly to MDM2 and inhibits
which encode IDH1 and IDH2 {1895}, tions, resulting in the disruption of epige-
MDM2-mediated p53 degradation. Loss
are frequent in diffuse astrocytomas, netic regulatory processes by affecting
of p14ARF expression is frequent in glio-
anaplastic astrocytomas, oligodendro- histone modifications, DNA methylation,
blastomas (occurring in 76% of cases),
gliomas, anaplastic oligodendroglio- and chromatin remodelling {2462}. In
and correlates with homozygous deletion
mas, oligoastrocytomas, and anaplastic one study, nearly half of the 291 IDH-
or promoter methylation of the CDKN2A
oligoastrocytomas (occurring in > 70% wildtype glioblastoma samples sub-
gene {1752}.
of cases) {2810}. These mutations are jected to whole-exome sequencing har-
CDKN2A / CDK4 / retinoblastoma present in nearly all glioblastomas that boured one or more non-synonymous
protein pathway have progressed from astrocytomas (i.e. mutations affecting chromatin organiza-
Alterations in the retinoblastoma pro- clinicopathologically defined secondary tion {277}. Even in the absence of direct
tein pathway occur in nearly 80% of all glioblastomas), but they are exceptional genetic alterations, epigenetic modifiers
glioblastomas {350}. In glioblastomas, in primary glioblastomas and absent in can modulate gene expression to directly
CDKN2A deletion and RB1 altera- pilocytic astrocytomas {118,277,2709, regulate glioma-relevant processes such
tions are mutually exclusive {2594}. The 2810}. A clinically primary glioblastoma as glioma stem cell programmes, senes-
CDKN2A locus encodes the CDK4 in- with an IDH1 mutation may be misclas- cence, genome stability, and invasion
hibitor CDKN2A as well as the alternate sified and may actually constitute an {2443,2461}.
reading frame protein p14ARF. Inactiva- asymptomatic lower-grade glioma that One of the key functions of chromatin
tion of genes in this pathway is common has progressed and has only become regulation is to maintain inactive portions
in both primary and secondary glioblas- symptomatic as a secondary glioblas- of the genome in repressive chromatin
tomas {200,1752}. The CDK4 gene is am- toma {1797}. Thus, IDH1 mutations con- structures with a compact organization
plified in approximately 15% of all high- stitute a reliable molecular signature of a refractory to regulatory activity. Canoni-
grade gliomas {1789,2086}, particularly separate group of glioblastomas that may cal repressive states include classic het-
in those without CDKN2A homozygous be synonymous with the secondary type erochromatin marked by H3K27me3, a
deletion {1789}. These homozygous de- {1797}. Notably, the presence of IDH1 mark deposited by PRC2 and its catalytic
letions also involve the nearby CDKN2B mutation is incompatible with the diag- subunit, EZH2. EZH2 is overexpressed in
gene on 9p {2397}. RB1 mutations are nosis of IDH-wildtype glioblastoma. See IDH-wildtype glioblastoma and various
40 Diffuse gliomas
other cancer types, presumably con-
tributing to the silencing of key tumour
Active chromatin Repressive chromatin
suppressor genes {556}. Loss of func-
tion of EZH2 can also promote cancer in
a context-dependent manner. Although
loss-of-function mutations of EZH2 in
IDH-wildtype glioblastoma are rare (oc-
curring in < 1% of cases), studies have
strongly implicated an inhibition of its en-
zymatic activity through a mutation of H3
genes in paediatric glioblastoma {277,
2304,2791}. Apparently, a fine-tuning of
PRC2 activity must be maintained, with
both gain and loss of activity linked to
gliomagenesis. Mutations in ATRX, which Fig. 1.37 Pathways of chromatin organization. DNA methylation, histone modifications, and numerous chromatin
encodes a chromatin remodeller that de- regulators determine the global structure of chromatin and are frequently altered in glioblastoma. Active chromatin (left)
posits H3.3 in pericentromeric and sub- is globally accessible for transcriptional regulation. Repressive chromatin (right) sequesters portions of the genome, is
enriched for characteristic histone modifications, and is refractory to regulatory activity. DNMTs, DNA methyltransferases;
telomeric regions, were observed in 13 of
HDMs, histone demethylases; HMTs, histone methyltransferases; MLL, mixed-lineage leukaemia protein; UTX, histone
291 IDH-wildtype glioblastomas {277}.
demethylase UTX (also called KDM6A). Adapted from Suva ML et al. {2462}.
ATRX mutations are observed in about
60-70% of IDH-mutant gliomas and in
about 30% of paediatric glioblastomas promutagenic alkyl groups from the 06 pilocytic astrocytoma {2124}, anaplastic
{1160,2304,2792}. position of guanine in DNA, thereby astrocytoma {765}, and oligodendroglio-
Within chromatin, both genes and regu- blunting the treatment effects of alkylat- ma {765}; primary glioblastoma from sec-
latory elements are associated with ing agents {653,798}. MGMT promoter ondary glioblastoma {2580}; and IDH-
characteristic chromatin modifications. methylation is common in glioblastoma mutant glioma from IDH-wildtype glioma,
Actively transcribed gene bodies are (present in 40-50% of cases) {277,654, across grades and histology {277,870,
marked by H3K36me3, a mark deposit- 982}, with the percentage varying de- 1810,2444}. Unsupervised analysis of
ed by the methyltransferase SETD2. Rare pending on the assay used {2051}. It is expression profiles can be used to clus-
mutations in SETD2 occur in about 2% of predictive of benefit from therapy with ter glioma into groups that correlate with
IDH-wildtype glioblastoma and are more alkylating agents such as temozolomide histology and grade {886,1812} and may
common in paediatric and IDH-mutant in patients with glioblastoma {982,1577, be a better predictor of patient outcome
gliomas {277,722}. Enhancers and pro- 2742}. A higher frequency of MGMT pro- {645}. A commonly used gene expres-
moters are marked by histone acetylation moter methylation (> 75%) is associated sion-based classification of glioblastoma
and H3K4 methylation. The methylation with glioblastomas that have G-CIMP, defines proneural, neural, classic, and
mark is catalysed by complexes that con- which is characteristic of IDH-mutant mesenchymal subtypes, which correlate
tain the mixed-lineage leukaemia (MLL) gliomas {105,277,1830}. Distinct DNA with genomic alterations including TP53
homologues. Missense mutations in methylation subclasses (three of which mutation, EGFR mutation/amplification,
KMT2B, KMT2C, and KMT2D have been are linked with specific mutations) have and NF1 deletion/mutation {2645}. How-
detected in some cases {2-3%) of IDH- been identified, which is suggestive of di- ever, individual cells characteristic of dif-
wildtype glioblastoma. Histone deacety- verse developmental and pathogenetic/ ferent subtypes can be found within the
lases (HDAC2 and HDAC9) and a range pathoepigenetic origins {277,2444}. Mu- same glioblastoma {1906}.
of histone demethylases (e.g. KDM4D, tations in IDH1 have been causally linked
Genotype-phenotype correlations
KDM5A/B/C, and KDM6A/B) are also in- with G-CIMP and longer survival {1810,
Most cases (> 90%) are glioblastomas
frequently mutated in IDH-wildtype glio- 2589}. Two methylation subtypes are re-
that develop rapidly and de novo (so-
blastoma, broadly affecting chromatin lated to hotspot mutations in H3 genes
called primary glioblastoma), with no
activity. Both histone and DNA demethyl- (H3 K27 and H3 G34), which are most
known less-malignant precursor lesion,
ases are inhibited by the IDH mutations, prevalent in paediatric glioblastomas
often in middle-aged or elderly patients
suggesting that different classes of glio- {2105,2444}. H3F3A G34 is associated
(as opposed to the so-called secondary
mas use different modalities to inactivate with a CpG hypomethylator phenotype
glioblastomas that have IDH1 mutations;
key epigenetic regulators {2443}. {2444}. Cancer-relevant pathways (e.g.
see Glioblastoma, IDH-mutant, p. 52).
In addition to chromatin regulation, epi- the WNT pathway) that contribute to
Glioblastomas in which multinucleated
genetic gene silencing by DNA meth- malignant behaviour and resistance to
giant cells constitute > 5% of the tumour
ylation of their promoters is a common therapy are frequently deregulated by
are associated with frequent TP53 muta-
mechanism of inactivating genes or non- aberrant promoter methylation of genes
tions but infrequent EGFR amplification
coding RNAs with tumour suppressing encoding inhibitory factors {914,1425}.
{1931}, whereas small cell glioblastomas
functions {2010}. The MGMT gene is the
often have EGFR amplification {318}. In
most commonly methylated gene across Expression profiles
younger patients, high-grade gliomas
tumour types {462} and encodes a DNA Gene expression patterns can be
(including glioblastomas) of the brain
repair protein. It specifically removes used to distinguish glioblastoma from
Glioblastoma, IDH-wildtype 41
Paediatric high-grade diffuse Clinicopathological aspects are found exclusively in diffuse midline
astrocytic tumours The annual incidence of paediatric gliomas, whereas H3.3 G34R or (rarely)
Paediatric high-grade diffuse astrocytic glioblastoma (defined by patient age G34V mutations are found exclusively
tumours (WHO grade lll/IV) should be < 20 years at diagnosis) is 0.14 cases in tumours of the cerebral hemispheres
considered, for therapeutic purposes, per 100 000 population; lower than that {2443,2792}, which are more frequently
as a single category encompassing of adult glioblastoma, which is approxi- seen in teenagers and young adults. In
both paediatric glioblastoma and pae- mately 4 per 100 000 {282,1863}. Most contrast, hemispheric glioblastomas in
diatric anaplastic astrocytoma. This ap- diffuse WHO grade II astrocytomas pre- infants harbour NTRK fusions in approx-
proach is supported by our understand- senting in adults eventually progress to imately 40% of cases, and histone mu-
ing of these childhood tumours’ similar high-grade astrocytomas (anaplastic tations have not been reported. Other
genetic profiles and clinical courses. astrocytoma or glioblastoma). In con- commonly altered genes in hemispheric
Although the histopathologies of paedi- trast, nearly all paediatric high-grade high-grade astrocytomas of childhood
atric high-grade astrocytomas overlap diffuse astrocytic tumours arise de novo, are TP53 (present in 30-50% of cas-
with those of their adult counterparts, rarely deriving from a WHO grade II es), ATRX (in -25%), SETD2 (in -15%),
the two groups have distinct genetic al- astrocytoma. CDKN2A (deletion; in -30%), and
terations {2304,2444,2792}. Unlike adult PDGFRA (amplification and/or mutation;
Genetic aspects
glioblastomas, paediatric high-grade in -30%) {2792}. In contrast, IDH muta-
Recurrent mutations in paediatric
diffuse astrocytic tumours frequently tions, TERT promoter mutations, and
high-grade diffuse astrocytic tumours
arise in the midline of the neuraxis, EGFR mutations/amplifications are rare.
involve genes coding for proteins in-
commonly in the pons (as diffuse pon- Several hereditary tumour syndromes
volved in chromatin and transcription
tine glioma) or the thalamus and rarely predispose paediatric patients to diffuse
regulation, or the receptor tyrosine ki-
in the spinal cord or cerebellum. These astrocytic tumours, including Li-Frau-
nase / RAS / MAPK and/or retinoblas-
diffuse midline gliomas share genetic al- meni syndrome (associated with TP53),
toma protein / p53 pathways. Many of
terations and are discussed separately neurofibromatosis type 1, and constitu-
these genes are also mutated in the
(see Diffuse midline glioma, H3 K27M- tional mismatch repair deficiency.
equivalent adult tumours, but some al-
mutant, p. 57). Distinct from these tu-
terations are particularly associated
mours and from their adult counterparts
with paediatric or adult disease. H3
are the cerebral hemispheric high-grade
variant (H3.1/H3.3) K27M mutations
diffuse astrocytic tumours of childhood.
42 Diffuse gliomas
Table 1.03 IDH-wildtype glioblastoma: genetic susceptibility because of partial blood-brain barrier
Syndrome Gene Chromosome OMIM preservation and high interstitial pressure
Li-Fraumeni* TP53 17p13.1 151623 in the tumour tissue; (2) invasive proper-
ties of glioblastoma cells that enable
L-2-hydroxyglutaric aciduria L2HGDH 14q21.3 236792
them to spread distantly within the CNS
Turcot MLH1, PMS2, MSH2, MSH6 3p21.3, 7p22, 2p22-p21,2p16 276300
and remain behind an intact blood-brain
Neurofibromatosis type 1 NF1 7q12 162200 barrier; (3) retention of DNA repair ma-
Ollier/Maffucci PTHR1 3p21-22 166000 chinery that abrogates the effectiveness
of chemotherapy and radiotherapy; (4)
•Glioblastomas associated with Li-Fraumeni syndrome are IDH-mutant.
intratumoural heterogeneity and genomic
instability resulting in clonal populations
Age that these uncertainties will be clarified of resistant cells, making it necessary to
A prospective series {2728} and numer- by molecular-based classifications of identify the driving events on an ongoing
ous clinical trials {439,837,838,2442} such tumours. basis; (5) the presence of a population
have shown that younger patients with of tumour-initiating or stem cell-like cells
Genetic alterations and biomarkers
glioblastoma (those aged < 50 years that may harbour resistance mechanisms
MGMT promoter methylation is a strong
at diagnosis) have a substantially bet- distinct from those of the majority of bulk
predictive marker for the efficacy of and
ter prognosis. In one large population- tumour cells and that may contribute to
response to alkylating and methylating
based study, patient age was a signifi- cellular heterogeneity; and (6) secondary
chemotherapy agents in glioblastoma
cant prognostic factor; the correlation oncogenic changes induced by tumour
{982,2729,2741,2742,2480}. More than
persisted through all of the age groups in progression.
90% of long-term surviving patients with
a linear manner {1823}. Because elderly Besides MGMT promoter methylation,
glioblastoma have a methylated MGMT
patients have an inferior prognosis over- there are no predictive biomarkers {2743}
promoter {2442}, versus only 35% of the
all, distinct and de-escalated treatment that facilitate the tailoring of primary {982,
general population of patients with glio-
strategies favouring a short therapeutic 2741,2742} or secondary {2480,2729}
blastoma {2441}. IDH1 and IDH2 muta-
course and the best quality of life pos- therapies, and MGMT promoter methyla-
tions are positive prognostic factors and
sible are commonly proposed to patients tion is only identified in less than half of
are closely associated with secondary
aged > 65-70 years. However, there is all patients using current assays {2441,
glioblastoma {2810} (see Glioblastoma,
no prospectively validated age cut-off 2743}. Cellular responses to DNA dam-
IDH-mutant, p. 52). There is no consist-
for clinical decisions. Although the fre- age involve distinct DNA repair path-
ent correlation between EGFR amplifica-
quency of MGMT promoter methylation ways, such as mismatch repair and base
tion and survival, regardless of patient
(see Genetic alterations and biomarkers) excision repair. Mismatch repair is criti-
age at clinical manifestation {1823}. Allel-
is stable across the various age groups, cal for mediating the cytotoxic effect of
ic loss of 10q was associated with shorter
recent research has identified molecular 6-O-methylguanine. The mismatch repair
survival in one study {1823}; however, the
profiles associated with paediatric glio- pathway consists of several proteins (i.e.
presence of PTEN mutations is not clear-
blastoma, younger patient age, and sec- MLH1, PMS2, MSH2, MSH3, and MSH6)
ly associated with prognosis {1823,2289,
ondary glioblastoma, and these profiles and corrects errors in DNA base pairing
2374,2728}.
may suggest novel therapeutic targets that occur during DNA replication. De-
{2444,2728}. Mechanisms of treatment response and fects in this system arise in the setting
resistance of alkylating chemotherapy and may re-
Histopathology sult in resistance to such therapy {342,
Glioblastoma is highly resistant to thera-
In general, histopathological features do 2826}, potentially by causing tolerance of
py, with only modest survival increases
not confer significant prognostic informa- the mispairing of 6-O-methylguanine with
achieved in a minority of patients, even
tion, but in some studies, giant cell glio- thymine {2244}, but also through chemo-
after aggressive surgical resection, ex-
blastoma (see Giant cell glioblastoma, therapy-induced mutagenesis {1167}. Te-
ternal beam radiation therapy, and maxi-
p. 46) has been noted to have a some- mozolomide treatment of WHO grade II
mum tolerated doses of chemotherapy
what better prognosis than ordinary glio- gliomas induces a hypermutational state
with agents such as temozolomide or ni-
blastoma {1356,1853}. and causes driver mutations in the ret-
trosoureas, including in conjunction with
Greater extent of necrosis is associated inoblastoma protein and AKT/mTOR
blood stem cell transplantation or use
with shorter survival {126,315,1031}. The pathways {2627}. In one small series,
of transgenic haematopoietic stem cells
presence of necrosis in a high-grade 5 of 6 hypermutated tumours showed
{8}. Over the past several decades, hun-
oligoastrocytic neoplasm confers a pro- de novo mutations in mismatch repair
dreds of clinical trials have achieved only
gnosis consistent with a WHO grade IV genes {2627}.
limited therapeutic success; responders
designation {1667}, but whether the Molecular abnormalities in glioblastoma
have been very rare and trial designs
presence of oligodendroglial features also provide specific mechanisms of
have limited the lessons learned from
in a glioblastoma has prognostic value resistance and susceptibility to therapy.
the failed approaches, including those
relative to other glioblastomas remains Some of the signature genetic alterations
of targeted therapies. The therapeutic
uncertain, with some studies showing a in glioblastoma (e.g. mutations in PTEN,
resistance is due to a variety of factors,
positive association {85,1667} and others TP53, EGFR, NF1, RB1, PIK3CA,
including: (1) uncertain drug delivery
having negative results {983}. It is likely PIK3R1, and IDH1) may be related to
resistance
Glioblastoma, IDH-wildtype 43
may be seen (in particular, decreases
in enhancement and oedema). These
changes reflect the effect of the agents
on the tumour vasculature and may ben-
efit patients symptomatically, but antian-
giogenic agents have not clearly been
shown to improve survival {141,1543}. By
normalizing the tumour vasculature to
some extent, antiangiogenic agents may
also facilitate perfusion and oxidation of
tumours.
Cellular immunotherapy / tumour vaccine
approaches were initiated decades ago,
but to date have had little effect on the
survival of patients with glioblastoma.
However, recent vaccine/immunotherapy
treatment of glioblastoma may be more
promising; for example, against targets
such as cytomegalovirus, the poliovirus
receptor, and EGFRvlll. It is also possible
Fig. 1.38 MGMT promoter methylation (meth) and progression-free survival in glioblastoma patients randomized to that combining vaccine approaches with
treatment with radiotherapy (RT) alone or radiotherapy plus temozolomide (TMZ). Reprinted from Hegi ME et al. {982}. the checkpoint inhibitors discussed be-
low could increase efficacy. The glioblas-
{350,1895}. Inactivation of the p53 path- analyses encompassing the full genome, toma microenvironment shows profound
way leads to defects in apoptosis and epigenome, and transcriptome, or even alterations compared with the normal
cell cycle arrest. Mutations of the retino- the proteome and metabolome, possibly brain microenvironment. Blood-brain
blastoma protein pathway in glioblasto- at the single-cell level {1906}, will be nec- barrier leakage, hypoxia, acidosis, accu-
mas result in failure of appropriate cell essary to identify driving changes that mulation of soluble mediators, and attrac-
cycle arrest. Point mutations of the RAS are accessible to targeted therapeutic tion of stromal cells from the peripheral
genes in glioblastoma are rare, but the approaches. circulation markedly alter the immuno-
RAS pathway is secondarily activated Recently, a population of glioma-initi- biology of gliomas {415}. One compel-
through insulin-like growth factor recep- ating, potentially neural stem cell-like ling explanation is that a pool of particu-
tor, EGFR, and PDGF receptor signalling. glioma cells has been identified in glio- larly resistant and slow-proliferating cells
Downstream events such as silencing blastoma {122,780,2365}. These cells called glioma-initiating cells, perhaps lo-
of the NF1 tumour suppressor gene can are highly tumorigenic in immunosup- cated in a perivascular or hypoxic niche,
also activate the RAS pathway, causing pressed mice, inducing intracranial tu- may act as a source for repopulation of
uncontrolled cellular proliferation. Simi- mours with a much smaller cellular inocu- the bulk tumour, thus complicating im-
larly, the PI3K pathway can be activated lum than do non-stem cell-like glioma munotherapeutic approaches. Glioma-
by abnormal IGF1, epidermal growth fac- cells from glioblastomas. The intracranial initiating cells have been investigated
tor, or PDGF signalling, or downstream tumours induced by these stem cell-like with respect to their immunosuppressive
by abnormalities in the PTEN gene {891, glioma cells have the morphological hall- potential and as a potential target for im-
2432}. These redundant signalling path- marks of glioblastoma. They respond to munotherapy, given that they have anti-
way abnormalities suggest that a sin- treatment with bevacizumab (a neutral- genic properties that are different from
gle, specific, small-molecule signalling- izing antibody to VEGF), and the same those of bulk tumour cells {423}. Mo-
pathway inhibitor could only be effective humanized VEGF-neutralizing antibody lecular mechanisms of immunosuppres-
in treating glioblastoma if it targeted a has achieved a 60-65% response rate in sion involve transforming growth factor
downstream and driving factor. Deter- a phase II trial in recurrent glioblastomas beta, STAT3, PDL1 (which is expressed
mining such an effect may be difficult, {2671}. One of the mechanisms of ra- by many cancer cells and binds to its
without orthotopic patient-derived mod- diation resistance, activation of the DNA receptor PD1 to suppress T-cell prolif-
els or clinical data available to develop checkpoint response, may exist preferen- eration and IL2 production {385}), and
tightly constructed controls. For example, tially in the stem cell-like glioma cell pop- CD276 {1469}. In addition, CTLA4, an
the assumption that testing individual ulation {122}. BMP4 causes a significant immunoglobulin similar to the costimula-
glioblastoma biopsies for EGFRvlll and reduction of stem-like precursor cells of tory protein CD28 that is expressed pref-
PTEN {1634} could potentially enable the human glioblastoma and abolishes their erentially on helper T cells, transduces
identification of patients responsive to the tumour-initiating capacities in vivo. inhibitor signals upon engagement of
EGFR kinase inhibitors is complicated Given the marked vascularity of glio- the costimulatory receptors CD80 and
by the fact that this signature character- blastomas, antiangiogenic agents such CD86, which are expressed on antigen-
izes a poor prognostic subgroup that as bevacizumab and cediranib are now presenting cells {2681}. The kynurenine
currently lacks therapeutic implication widely used for the treatment of these pathway may also be involved in altering
{2614}. This suggests that more intensive tumours. On scans, notable responses the immunobiology within gliomas; for
44 Diffuse gliomas
1. Cross-Resistance 2. Tumor Heterogeneity
Fig. 1.39 Malignant glioma and therapeutic resistance. Glioblastomas are adept at evading inhibition of EGFR receptor function through several possible mechanisms. (1) Brain
tumour cells that are intractable to DNA damage-induced apoptosis may also tolerate apoptotic cues driven by TKI-mediated inhibition of EGFR. Combinatorial therapy using
inhibitors of anti-apoptotic activity may overcome this cross-resistance. (2) Intratumoural diversity within glioblastomas may drive resistance to single agent-based anti-EGFR
therapy due to: RTK co-activation, PTEN deletion/mutations, and tumour cell-tumour cell interactions via secreted molecules. PTEN* denotes mutation. (3) Efflux of EGFR TKIs
and increased genetic stability may lead to the maintenance of cancer stem cell populations and tumour relapse. (4) Enhanced immunosuppression mediated by circulating growth
factors, cytokines, and suppressor T cells can antagonize the systemic immune responses generated by anti-EGFR immunotherapies. Additionally, circulating IL6 in the tumour
microenvironment can facilitate resistance intracellularly via activation of the JAK/STAT3/Bcl-xL pathway. Reprinted from Taylor TE et al. {2526A}.
Glioblastoma, IDH-wildtype 45
Giant cell glioblastoma Ohgaki H. Macroscopy
Kleihues P. Due to its high connective tissue content,
Plate K.H. giant cell glioblastoma may have the
Nakazato Y. gross appearance of a firm, well-
Bigner D.D. circumscribed mass, which can be
mistaken for a metastasis or (when
attached to the dura) ameningioma.
Lesions less rich in connective tissue may
Definition have features more typical of
A rare histological variant of IDH-wildtype glioblastoma {1533}.
glioblastoma, histologically characterized
Microscopy
by bizarre, multinucleated giant cells and
Giant cell glioblastoma is histologically
an occasionally abundant reticulin network.
characterized by numerous
Despite the high degree of anaplasia, gi-
multinucleated giant cells, small fusiform
ant cell glioblastoma is often more circum-
syncytial cells, and a reticulin network
scribed and has a somewhat better pro-
{1584}. The giant cells are often
gnosis than ordinary glioblastoma {1356,
extremely bizarre, can be as large as 0.5
1853}. The genetic profile differs from that
mm in diameter, and can contain
of IDH-wildtype glioblastoma in the high Fig. 1.41 Giant cell glioblastoma. The multinucleated
anywhere from a few nuclei to >20.Giant
frequency of TP53 mutations {1932} and in giant cells are easily recognizable in the smear
cells are often angulated, may contain
AURKB expression {2533}, whereas EGFR preparation {1956}.
prominent nucleoli, and on occasion
amplification is rare.
contain cytoplasmic inclusions. Both
cell glioblastoma (n = 592) was 54.5 years
palisading and large ischaemic necroses
ICD-0 code 9441/3 {1853}. The male-to-female ratio is 1.1-
are observed. Atypical mitoses are
15:1 {1356,1533,1853} .
frequent, but the overall proliferation rate
Grading Localization
is similarto that of ordinary glioblastomas.
The localization of giant cell glioblastoma
Giant cell glioblastoma corresponds histo- A typical,(although vari-able) feature is
issimilar to that of IDH-wildtype
logically to WHO grade IV. the perivascular accumulation of tumour
glioblastoma {1356,1853} .
cells with the formation of a
Epidemiology Clinical features
pseudorosette-like pattern {1533}. Occa-
Giant cell glioblastomas account for < 1% Giant cell glioblastomas develop de novo
sionally, perivascular lymph-ocyte cuffing
of all glioblastomas {1853}, but may be after a short preoperative history and
is observed. Microvascular proliferation is
more common in paediatric populations without clinical or radiological evidence of
not common.
{1356}. Giant cell glioblastoma develops in a less-malignant precursor lesion. The
younger patients than does ordinary glio- symptoms are similar to those of IDH- Immunophenotype
blastoma, with an age distribution covering wildtype glioblastoma. GFAP expression is consistently present,
a wider range, including children {1226, but the level of expression is highly vari-
Imaging
1356,1658,1931}. In a study of 16 430 glio- able. TP53 mutation is present in > 80%
Giant cell glioblastomas are distinctive be-
blastomas in the SEER database of the of all cases, and these tumours typically
cause of their circumscription. They are
United States National Cancer Institute, show marked nuclear accumulation of
often located subcortically in the temporal
the mean age of patients with giant cell p53
and parietal lobes. On CT and MRI, they
glioblastoma (n = 171) was 51 years, sig- can mimic a metastasis.
nificantly younger than that of patients with
glioblastoma (62 years) {1356}. Similarly, in
a SEER-based study of 69 935 glioblasto-
mas, the mean age of patients with giant
46 Diffuse gliomas
protein {1233,1931}. Neuronal markers
are virtually all negative, unlike in
pleomorphic xanthoastrocytoma {1597}.
Genetic profile
Giant cell glioblastomas do not carry IDH
mutations and are therefore considered
variants of IDH-wildtype glioblastoma.
They are further characterized by
frequent mutations in TP53 (occurring in
75-90% of cases) and PTEN (in 33%),
but typically lack EGFR
amplification/overexpression and
homozygous CDKN2A deletion
{1596,1658,1931,1932}.
These attributes indicate that giant cell
glioblastoma has a hybrid profile, shar-
ing with IDH-wildtype glioblastoma a
short clinical history, the absence of a
less-malignant precursor lesion, and fre-
quent PTEN mutations. Like IDH-mutant
glioblastoma, which typically develops Fig. 1.43 Giant cell glioblastoma. A Most of the tumour cells show strong reactivity for nestin. B The expression of
through progression from a lower-grade GFAP is highly variable. In this case, smaller GFAP-expressing tumour cells form a corona around GFAP-negative
astrocytoma, giant cell glioblastoma has multinucleated giant cells. C High Ki-67/MIB1 proliferation index. The proliferation rate of smaller tumour cells is
a high frequency of TP53 mutations particularly high, whereas multinucleated giant cells are often quiescent. D Prominent reticulin fibre deposition.
{1932}. The level of AURKB expression
at the mRNA and protein levels is
is somewhat better than that of ordinary with ordinary glioblastoma {3.4%) {1356}.
significantly higher in giant cell
glioblastoma {323,1060,1356,1820,1853, Similarly, a study of 67 509 glioblastomas
glioblastomas than in ordinary
2347}. A study of 16430 glioblastomas in in the USA National Cancer Data Base
glioblastomas, and ectopic over-
the SEER database found that the medi- found that patients with giant cell glio-
expression of aurora kinase B induces a
an survival time of patients with giant cell blastoma (n = 592) had a median overall
significant increase in the proportion of
glioblastoma was 11 months, significantly survival of 13.5 months, versus 9.8 and
multinucleated giant cells in TP53-mu-
longer than that of patients with ordinary 8.8 months for patients with ordinary glio-
tant U373-MG (but not TP53-wildtype
glioblastoma {8 months) {1356}. The over- blastoma and gliosarcoma, respectively
U87-MG) malignant glioma cells {2533}.
all 5-year survival rate among patients {1853}.
Prognosis and predictive factors with giant cell glioblastoma was > 10%,
Most giant cell glioblastomas have a significantly higher than that of patients
poor prognosis, but the clinical outcome
Table 1.04 Genetic profiles of histologically defined glioblastoma (GBM) variants; adapted from Oh JE et al. {1819}
Length of clinical history 3.9 months 3.0 months 1.6 months 15.2 months
Light blue, typical for IDH-wildtype GBMs; yellow, typical for IDH-mutant GBMs. Giant cell GBM shares characteristics with both GBM types.
Fig. 1.44 Gliosarcoma. Spindle cells, often mitotically Fig. 1.45 Gliosarcoma. Biphasic pattern. Serial sections showing an alternating pattern of (A) GFAP-expressing glioma
active, are a typical feature in smear preparations. tissue and (B) sarcomatous areas that contain reticulin fibres but lack GFAP.
Reprinted from Burger PC {312}.
48 Diffuse gliomas
Fig. 1.46 Gliosarcoma. The gliomatous component shows strong GFAP expression and may be (A) geographically separated from or (B) intermingled with the sarcomatous tumour
cells. C Biphasic tissue pattern denoting reticuiin-rich sarcomatous and reticulin-free gliomatous elements.
neuronal components occur rarely a sarcomatous phenotype {1179,1633}. mutations, but infrequent EGFR ampli-
{2349}. Distinction of the two components In a study using FISH, 2 of 3 gliosarco- fication {7,2095}, suggesting that they
is facilitated by combined histochemical mas showed identical numerical aberra- have a distinct profile, similar to that of
and immunohistochemical staining. Col- tions of chromosomes 10 and 17 in the IDH-wildtype glioblastoma (except for
lagen deposition in the mesenchymal glial and mesenchymal components, the infrequent EGFR amplification). Com-
part is well demonstrated by a trichrome whereas in the third case, trisomy X was parative genomic hybridization in 20
stain. Similarly, reticulin staining shows restricted to the chondrosarcomatous gliosarcomas found that several chromo-
abundant connective tissue fibres in the element {1913}. Similar cytogenetic pat- somal imbalances were common: gains
mesenchymal (but not glial) component. terns were observed in both glial and on chromosomes 7 (present in 75% of
The demonstration of a clearly malignant mesenchymal components in another cases), X {20%), 9q {15%), and 20q {15%)
mesenchymal component negative for study, using FISH, comparative genomic and losses on chromosomes 10 {35%),
GFAP is important to distinguish true glio- hybridization, microsatellite allelic imbal- 9p {35%), and 13q {15%) {7} [http://www.
sarcomas from glioblastomas with florid ance analysis, and cytogenetic analysis progenetix.net/progenetix/l94423]. Simi-
fibroblastic proliferation (desmoplasia) {232}. These results suggested that both lar genetic alterations have been found in
elicited by meningeal invasion. components were derived from neoplas- the gliomatous and mesenchymal com-
tic glial cells. This explanation has been ponents, indicating a monoclonal origin.
Immunophenotype further supported by the observation of Expression of SNAI2, TWIST, MMP2, and
The reticulin-free glial component is posi- p53 immunoreactivity in both tumour MMP9 is characteristic of mesenchymal
tive for GFAP. The mesenchymal com- components {39}. Proof of a monoclonal tumour areas, suggesting that the mech-
ponent is largely negative for GFAP, but origin has been demonstrated in 2 cases anisms involved in epithelial-mesenchy-
isolated positive spindle cells are com- of gliosarcoma in which the gliomatous mal transition in epithelial neoplasms
mon. Staining for R132H-mutant IDH1 and sarcomatous components each may also play roles in mesenchymal
is negative in almost all cases {1183}. contained an identical TP53 mutation differentiation in gliosarcomas {1737}.
Immunopositivity for p53, if present, is {197}. In addition, identical PTEN, TP53, Microarray-based comparative genomic
identified in both glial and mesenchymal and TERT mutations were detected in hybridization analysis in glial and mes-
components {197,1038}. the gliomatous and sarcomatous tumour enchymal tumour areas also suggests
Cell of origin components of other gliosarcoma cases that the mesenchymal components may
Originally, gliosarcoma was thought to {2095,2679}. The monoclonality of the be derived from glial cells with additional
be a collision tumour, with a separate two components of the gliosarcomas genetic alterations in a small proportion
astrocytic component and independent was also confirmed by identification of of gliosarcomas {1736}. See Table 1.04
development of the sarcomatous portion CDKN2A deletion and MDM2 and CDK4 on p. 47.
from the proliferating vessels. Several im- coamplification in both tumour areas
Prognosis and predictive factors
munohistochemical studies seemed to {2095}. These studies strongly support
Large clinical trials have failed to reveal
support this assumption, by demonstrat- the hypothesis that the sarcomatous ar-
any significant differences in outcome
ing immunoreactivity for von Willebrand eas are a result of a phenotypic change
between gliosarcoma and classic glio-
factor {2276}, UEA-I {2370}, and mono- in the glioblastoma cells, rather than an
blastoma {779}. However, there have
histiocytic markers {885,1312}. Another indication of the coincidental develop-
been multiple reports of gliosarcomas
hypothesis was that the sarcomatous ment of two separate neoplasms.
with systemic metastases and even inva-
portion resulted from advanced glioma Genetic profile sion of the skull {148,1902,2302}.
dedifferentiation with subsequent loss Gliosarcoma contains PTEN muta-
of GFAP expression and acquisition of tions, CDKN2A deletions, and TP53
Gliosarcoma 49
Epithelioid glioblastoma Ellison D.W. astrocytoma has been identified by bi-
Kleinschmidt-DeMasters B.K. opsy as pre-existent or coexistent with
Park S.-H. the epithelioid tumour {285,1297,1735,
1795,1977}. The fact that anaplastic pro-
gression of a pleomorphic xanthoastro-
cytoma can manifest as an epithelioid
glioblastoma raises the possibility that
the two entities may be related, an asso-
Definition ciation reinforced by their sharing a high
A high-grade diffuse astrocytic tumour frequency of BRAF V600E mutation {48,
variant with a dominant population of 2508}.
closely packed epithelioid cells, some Approximately 50% of epithelioid glio-
rhabdoid cells, mitotic activity, microvas- blastomas harbour a BRAF V600E mu-
cular proliferation, and necrosis. tation, but it is unknown what genetic
Epithelioid glioblastomas occur predomi- mechanism(s) might be responsible for
nantly in young adults and children, are the emergence of epithelioid morphology
preferentially located in the cerebrum or di- in the remainder. One microarray-based
encephalon, and are aggressive tumours comparative genomic hybridization study
with short survival, particularly in children. of a coexistent diffuse astrocytoma and
Compared with other glioblastomas, more epithelioid glioblastoma identified three
epithelioid glioblastomas (-50%) contain a copy number alterations observed only
BRAF V600E mutation. in epithelioid tumour cells: a homozygous
Epithelioid glioblastoma is distinct from gli- deletion in LSAMP and heterozygous de-
Fig. 1.47 Epithelioid glioblastoma. Complex abnormali- letions in TENM3 and LRP1B. This result
omas or glioneuronal tumours with a poor-
ties (including solid and cystic areas and focal
ly differentiated SMARCB1-deficient com- awaits independent validation, but sug-
enhancement) usually characterize the MRI.
ponent (which may contain rhabdoid cells gests that BRAF V600E mutation alone
and exhibit a polyimmunophenotype). It is may be permissive but not sufficient for
also distinct from glioblastoma with epi- development of epithelioid phenotype.
thelial metaplasia, which exhibits glandu- ICD-0 code 9440/3
Localization
lar formations and squamous metaplasia.
Grading Epithelioid glioblastomas have been
The term “rhabdoid glioblastoma” should
described mainly in the cerebral cortex
be avoided. Tumours previously reported Epithelioid glioblastoma corresponds
and diencephalon. Temporal and frontal
as such are either epithelioid glioblasto- histologically to WHO grade IV.
lobes are common sites, but any lobe
mas without evidence of SMARCB1 or
Epidemiology can be affected {285,331,1297,1699}.
SMARCA4 alteration or rare glioblastomas
Incidence data are not yet available for Rare examples occur in the cerebellum,
with a population of SMARCB1-deficient
this uncommon variant, which has been but none have been reported in the spi-
cells, from which the epithelioid glioblasto-
inconsistently defined in various studies. nal cord {1302}.
ma, with its different genetic profile, should
be distinguished. Epithelioid glioblastoma Etiology Clinical features
may coexist with pleomorphic xanthoas- The etiology and cell of origin of epithe- The clinical manifestation of epithelioid
trocytoma, but the relationship between lioid glioblastoma are unknown, but most glioblastoma parallels that of other glio-
epithelioid glioblastoma and malignant cases arise de novo. In several cases of blastomas; most patients present with
progression in pleomorphic xanthoastro- epithelioid glioblastomas with confirmed symptoms and signs of raised intracranial
cytoma requires further clarification. SMARCB1 expression, a low-grade
Fig. 1.48 Epithelioid glioblastoma. A Foci of necrosis are found in most cases. B Tumours may contain cells with an epithelioid, rhabdoid, or gemistocytic morphology.
50 Diffuse gliomas
Fig. 1.49 Epithelioid glioblastoma. A Most tumours contain plentiful GFAP-immunopositive cells, though these may be sparse in others. B Focal cytokeratin expression. EMA may
also be seen. C BRAF V600E mutations are present in about half of cases, and expression of the mutant gene product can be detected by immunohistochemistry.
pressure, although a minority of patients membrane, eosinophilic cytoplasm, a express melan-A, desmin, myoglobin, or
manifest neurological deficit or epilepsy paucity of cytoplasmic processes, and a smooth muscle antigen. SMARCB1 is re-
{331,1297,1699}. Studies rarely suggest laterally positioned nucleus. There is vari- tained throughout the tumour cell popula-
a precursor lesion, but there have been ation in how often cytoplasmic filamen- tion. In cases where it has been sought,
several reports of transformation from tous-like balls are described or sought expression of SMARCA4 has been dem-
pleomorphic xanthoastrocytoma or WHO by electron microscopy, but some rhab- onstrated {285}. Immunohistochemistry
grade II astrocytoma {1297,2508}. doid cells are found in epithelioid glio- using the VE1 antibody that recognizes
blastoma. Less xanthomatous change V600E-mutant BRAF shows reactivity in
Imaging about 50% of epithelioid glioblastomas, a
is seen in epithelioid glioblastoma than
On MRI, epithelioid glioblastoma char- result concordant with sequencing results
in pleomorphic xanthoastrocytoma, al-
acteristically presents as a gadolinium- {1298}.
though exceptional cases have been
enhancing solid mass, occasionally with
noted to contain giant cells {1298}, lipidi-
cysts {285,1297,2508}. Epithelioid glio- Genetic profile
zation {2151}, a desmoplastic response
blastomas are prone to haemorrhage and A BRAF V600E mutation is detected in
{2151}, or cytoplasmic vacuoles {1795}.
often spread through the leptomeninges. about half of all epithelioid glioblastomas
Rosenthal fibres and eosinophilic granu-
{285,1297}. An H3F3A K27M mutation
Spread lar bodies are not features of epithelioid
has been reported in a single epithe-
Epithelioid glioblastomas demonstrate glioblastoma. By definition, squamous
lioid glioblastoma, but other H3F3A and
a tendency to spread throughout the nests, glandular formation, and adenoid
HIST1H3B mutations have not been re-
neuraxis, showing leptomeningeal dis- features are absent {2151}. Necrosis is
ported {285}. Epithelioid glioblastomas
semination in as many as one third of all present, but is usually of the zonal rather
also lack IDH1 and IDH2 mutations.
patients {976,1299,1699,2755}. One re- than palisading type. Some reports have
Copy number alterations in genes in-
ported paediatric tumour spread to the noted a relative paucity of microvascular
volved in high-grade gliomas are oc-
scalp via a shunt device {285}. proliferation, but others have found no
casionally present; EGFR amplification,
substantial difference in the vasculature
Macroscopy homozygous deletion of CDKN2A, and
patterns of epithelioid glioblastoma and
Epithelioid glioblastomas are typically loss of PTEN have been reported, but
classic glioblastoma {285}.
unifocal lesions, although at least one copy number alterations at the PDGFRA,
case with multifocal distribution has Immunophenotype PTEN, and MET loci are rare {285,1297}.
been reported, and metastatic disease Epithelioid glioblastomas show Immunore-
Genetic susceptibility
may occur {788}. Although no feature activity for vimentin and S100. They also
Epithelioid glioblastomas have not been
is pathognomonic on gross examina- show Immunoreactivity for GFAP, although
reported in association with dysgenetic
tion, haemorrhage and necrosis may be it is often patchy and in a few cases entire-
or hereditary tumour syndromes.
prominent. A superficial location, even ly absent from most areas of the tumour.
with dural attachment, has occasionally Some epithelioid glioblastomas express Prognosis and predictive factors
been noted. Leptomeningeal spread is epithelial markers, cytokeratins, and EMA In both adult and paediatric patients, epi-
relatively common. Cyst formation oc- {285,2151}. Because classic glioblasto- thelioid glioblastoma has a particularly poor
curs, but is not a common feature. mas sometimes express cytokeratin AE1/ prognosis, even for a glioblastoma {285,
AE3 or EMA {965,1818}, an epithelial Im- 426,1299}. It demonstrates early progres-
Microscopy munophenotype should not be consid- sion and a median survival of 6.3 months
Epithelioid glioblastomas are dominated ered diagnostic of the epithelioid variant (range: 0.6-82 months) in adults and
by a relatively uniform population of epi- in isolation, without additional morphologi- 5.6 months (range: 1.5-9.7 months) in chil-
thelioid cells showing focal discohesion, cal evidence. Most authors have noted fo- dren, despite various adjuvant therapies.
scant intervening neuropil, a distinct cell cal immunoreactivity for synaptophysin
or NFP. Epithelioid glioblastomas do not
Epithelioid glioblastoma 51
Ohgaki H.
Glioblastoma, IDH-mutant Kleihues P.
Reifenberger G.
Yan H.
von Deimling A. Weller M.
Louis D.N.
Definition
A high-grade glioma with predominantly
astrocytic differentiation; featuring nucle-
ar atypia, cellular pleomorphism (in most
cases), mitotic activity, and typically a dif-
fuse growth pattern, as well as microvas-
cular proliferation and/or necrosis; with a
mutation in either the IDH1 or IDH2 gene.
IDH-mutant glioblastomas account for
approximately 10% of all glioblastomas.
Glioblastomas that develop through
malignant progression from diffuse as-
trocytoma (WHO grade II) or anaplastic
astrocytoma (WHO grade III) are almost
always associated with IDH mutation and
therefore carry the synonym “secondary
glioblastoma, IDH-mutant”. IDH-mutant
glioblastoma is morphologically indistin-
guishable from IDH-wildtype glioblas-
toma, except for a lesser extent of necro-
sis. IDH-mutant glioblastomas manifest
in younger patients (with a mean patient
age at diagnosis of 45 years), are pref-
Fig. 1.50 Genetic pathways to IDH-wildtype and IDH-mutant glioblastoma. This chart is based on the hypothesis
erentially located in the frontal lobe, and
that IDH-mutant glioblastomas share common glial progenitor cells not only with diffuse and anaplastic astrocytomas,
carry a significantly better prognosis than but also with oligodendrogliomas and anaplastic oligodendrogliomas. Adapted from Ohgaki H and Kleihues P {1830}.
IDH-wildtype glioblastomas {1797,2810}.
Genetic hallmarks grading reflects the natural course of the glioblastoma had a histologically proven
The defining genetic hallmark is the disease rather than response to therapy. prior low-grade glioma {605}. When IDH1
presence of IDH mutations {1895}, Therefore, because most patients even- mutations were used as a genetic mark-
which are associated with a hyper- tually succumb to high-grade disease, er, secondary glioblastomas accounted
methylation phenotype {1810}. These IDH-mutant glioblastomas are designat- for 9% of all glioblastomas at the popula-
mutations are the earliest detectable ed as WHO grade IV. tion level {1797} and for 6-13% of cases
genetic alteration in precursor low- Synonym in hospital-based studies {118,1078,1417,
grade diffuse astrocytoma, indicating 2810}.
that these tumours are derived from Secondary glioblastoma, IDH-mutant Age distribution
common neural precursor cells that At the population level, secondary glio-
differ from those of IDH-wildtype glio- Epidemiology blastomas develop in patients signifi-
blastoma. Additional typical genetic cantly younger (mean: 45 years) than do
Incidence
alterations are TP53 and ATRX muta- primary glioblastomas (mean: 62 years)
Until the discovery of IDH1 mutation as
tions and loss of chromosome arm {1823,1826}. Correspondingly, the mean
a molecular marker, the diagnosis of
10q {1822,1830}. age of patients with /DHI-mutant glio-
secondary glioblastomas was based on
clinical observations (i.e. neuroimaging blastoma is 48 years, significantly youn-
ICD-0 code 9445/3 and/or histological evidence of a preced- ger than that of patients with glioblasto-
ing low-grade or anaplastic astrocytoma) mas that lack IDH1 mutations {61 years)
Grading {1823,1827}. In a population-based study {1797}. Several hospital-based studies
IDH-mutant glioblastoma corresponds in Switzerland, using clinical criteria and have also shown that patients with IDH-
histologically to WHO grade IV. histopathological evidence, only 5% of all mutant glioblastoma were significantly
The prognosis of IDH-mutant glioblasto- glioblastomas diagnosed were second- younger than those with IDH-wildtype
ma is considerably better than that of IDH- ary {1823,1826}. Similarly, another study glioblastoma {214,1078,2810}.
wildtype glioblastoma; however, WHO showed that 19 of 392 cases {5%) of
52 Diffuse gliomas
Table 1.05 Key characteristics of IDH-wildtype and IDH-mutant glioblastoma in adults
Sex distribution
One population-based study of IDH-mu- IDH-wildtype glioblastoma IDH-mutant glioblastoma References
Clinical features glioblastoma, IDH-mutant glioblastoma which are hallmarks of IDH-wildtype glio-
presents more frequently with non-en- blastoma, are usually absent.
Clinical history
hancing tumour components on MRI,
The mean length of the clinical history of
with larger size at diagnosis, with lesser Microscopy
patients with clinically diagnosed second-
extent of oedema, and with increased The histological features of IDH-mutant
ary glioblastoma was 16.8 months, sig-
prevalence of cystic and diffuse compo- glioblastomas are similar to those of
nificantly longer than that of patients with IDH-wildtype glioblastomas. However,
nents {644,1417}.
primary glioblastoma {6.3 months) {1823, morphological studies have revealed
1826,1827}. Correspondingly, patients
Macroscopy two significant differences. Areas of is-
with secondary glioblastoma harbour-
Like all glioblastomas, IDH-mutant glio- chaemic and/or palisading necrosis
ing an IDH1 mutation had a much longer
blastomas diffusely infiltrate the brain have been observed in 50% of IDH-
mean clinical history (15.2 months) than
parenchyma, without clear macroscopic mutant glioblastomas, significantly less
did patients with primary IDH-wildtype frequently than in IDH-wildtype glio-
delineation. However, large yellowish ar-
glioblastomas (3.9 months) {1797}. blastomas (90%) {1797}, whereas focal
eas of central necrosis or haemorrhage,
Symptoms
Because IDH-mutant glioblastomas are
preferentially located in the frontal lobe,
behavioural and neurocognitive changes
are likely to predominate, although focal
neurological deficits (e.g. hemiparesis
and aphasia) also frequently occur. Due
to the slow evolution from diffuse astrocy-
toma or anaplastic astrocytoma, tumour-
associated oedema is less extensive and
symptoms of intracranial pressure may
develop less rapidly than in patients with
primary IDH-wildtype glioblastoma.
Imaging
Unlike in IDH-wildtype glioblastoma, Age at diagnosis
large areas of central necrosis are usu-
Fig. 1.51 Cumulative age distribution of glioblastomas with and without IDH1 mutations. Combined data from
ally absent. Compared with IDH-wildtype
Nobusawa S et al. {1797} and Cancer Genome Atlas Research Network {350}.
Glioblastoma, IDH-mutant 53
diagnosis in 385 of 407 cases {95%)
{1797}. In this regard, IDH mutations are
considered to be a defining diagnostic
molecular marker of glioblastomas de-
rived from IDH-mutant diffuse astrocy-
toma or IDH-mutant anaplastic astrocy-
toma that is more objective than clinical
and/or histopathological criteria.
Timing of IDH mutation
IDH mutations are an early event in glio-
magenesis and persist during progres-
sion to IDH-mutant glioblastoma. Analy-
sis of multiple biopsies from the same
patients revealed no cases in which the
IDH1 mutation occurred after the ac-
Fig. 1.52 These MRIs show the typical progression of a frontotemporal IDH1-mutant diffuse astrocytoma (left) to an
quisition of a TP53 mutation {2709}. An
IDH1-mutant secondary glioblastoma (right) over a period of 5 years {1533}. Note the absence of central necrosis.
exception is IDH1 mutations in patients
with Li-Fraumeni syndrome, caused by a
oligodendroglioma-like components are Cell of origin germline TP53 mutation. In this inherited
more common in IDH-mutant glioblasto- Despite their similar histological fea- tumour syndrome, the TP53 mutation is
mas than in IDH-wildtype glioblastomas tures, IDH-mutant glioblastomas and by definition the initial genetic alteration
{54% vs 20%) {1797}. A larger propor- IDH-wildtype glioblastomas seem to be and significantly affects the subsequent
tion of tumour cells with oligodendroglial derived from different precursor cells. acquisition of the IDH1 mutation. The
morphology has also been reported in Secondary glioblastomas, astrocytomas, R132C (CGT->TGT) mutation, which is
IDH1-mutant glioblastomas, in a large and oligodendrogliomas contain IDH uncommon in sporadic cases, was the
study of 618 cases {1417}. mutations, share a preferential frontal lo- only IDH1 mutation found in diffuse as-
cation, and have been hypothesized to trocytomas, anaplastic astrocytomas,
Immunophenotype originate from precursor cells located in and secondary glioblastomas carrying a
The presence of IDH1 R132H (the most (or migrating to) the frontal lobe. In con- TP53 germline mutation {2710}.
frequent IDH1 mutation in oligodendro- trast, IDH-wildtype glioblastomas have
gliomas, astrocytomas, and IDH-mutant more widespread locations. Additional Types of IDH mutation
glioblastomas) can be detected immuno- All reported IDH1 mutations are located
evidence supporting this hypothesis in-
histochemically using an antibody to the at the first or second base of codon 132
cludes the observation that glioblasto-
gene product, R132H-mutant IDH1 {357}. {118,1895,2709}. The most frequent is
mas that are IDH-mutant and those that
Positivity in a glioblastoma is indicative of the R132H (CGT—>CAT) mutation, found
are IDH-wildtype develop in patients of
an IDH-mutant glioblastoma, but negativ- in 83-91% of astrocytic and oligoden-
different ages, have a different sex distri-
ity could be due to the presence of one bution, and have a significantly different droglial gliomas {118,2709,2810}. Other
of the less common types of IDH1 mu- mutations are rare, including R132C
clinical outcome {1830}. Their stem cells
tation or an IDH2 mutation {953}. Lack (CGT—>TGT; found in 3.6-4.6% of cases),
may also be different; in one study, the
of immunoreactivity could also indicate R132G (in 0.6-3.8%), R132S (in 0.8-
relative content of CD133-positive cells
the presence of a primary IDH-wildtype 2.5%), and R132L (in 0.5-4.4%) {118,
was significantly higher in primary glio-
glioblastoma. 2709,2810}.
blastomas than in secondary glioblasto-
Mutations in the ATRX gene are typically mas, and CD133 expression was associ- The IDH2 gene encodes the only human
present with IDH1/2 mutations and TP53 protein homologous to IDH1 that uses
ated with neurosphere formation only in
mutations in WHO grade II or III diffuse primary glioblastomas {158}.
astrocytomas and IDH-mutant glioblas-
tomas {1160}. Mutations in ATRX result Genetic profile
in lack of expression, which can be dem-
onstrated immunohistochemically {2750}. IDH mutations
Immunohistochemical overexpression of IDH mutations were first reported in 2008
p53 is frequent, reflecting the high fre- {1895}, and the authors noted that “mu-
quency of TP53 mutations (present in the tations in IDH1 occurred in a large pro-
vast majority of cases). Overexpression portion of young patients and in most pa-
of EGFR is unusual; EGFR amplification tients with secondary glioblastomas and
is a hallmark of IDH-wildtype glioblas- were associated with an increase in over-
toma. GFAP expression is consistently all survival”. In one study, the presence
present, although the level of expression of IDH1 mutations as a genetic marker of Fig. 1.53 Immunohistochemistry of a glioblastoma using
is variable. secondary but not primary glioblastoma an antibody to R132H-mutant IDH1. Note the strong
corresponded to the respective clinical cytoplasmic expression by tumour cells and the lack of
expression in the vasculature.
54 Diffuse gliomas
NADP+ as an electron acceptor. IDH2 studies found that 3-6% of patients with Genetic alterations typical of IDH-
mutations are all located at residue R172, IDH1-mutant glioblastomas clinically di- wildtype glioblastoma include EGFR
which is the analogue of the R132 resi- agnosed as primary were 13-27 years amplification, PTEN mutation, TERT
due in IDH1 {2805}. It is located in the ac- younger than those with glioblasto- promoter mutation, and complete loss
tive site of the enzyme and forms hydro- mas without IDH1 mutations {118,1829, of chromosome 10 {89,752,1801,1823,
gen bonds with the isocitrate substrate. 2561,2810}. The possibility exists that 1827}. Alterations more common in
IDH2 mutations are rare in IDH-mutant these glioblastomas have rapidly pro- secondary IDH-mutant glioblastomas
glioblastoma and located at codon 172 gressed from precursor astrocytomas include TP53 mutations and 19q loss
{2810}, with the R172K mutation being that escaped clinical diagnosis and {1754,1823,1827}. However, until the iden-
the most frequent. were therefore misclassified as primary tification of IDH mutation as a molecular
glioblastomas. marker of secondary glioblastoma {118,
Secondary glioblastomas without IDH 1797,2709,2810}, the patterns of genetic
mutation ATRX mutations alterations, although different, did not en-
The few clinically diagnosed second- Mutations in the ATRX gene cause loss
able unequivocal diagnosis of these two
ary glioblastomas that lack an IDH mu- of expression. They are typically present
glioblastoma subtypes.
tation have infrequent TP53 mutations, with IDH and TP53 mutations in WHO
and patients have a shorter clinical his- grade II IDH-mutant diffuse astrocytoma, Expression profile
tory and a poor prognosis {1797}. Most WHO grade III IDH-mutant anaplastic More than 90% of IDH-mutant glioblas-
secondary glioblastomas lacking IDH1 astrocytoma, and IDH-mutant glioblasto- tomas have a proneural expression sig-
mutations develop through progression mas {1160,1519}. nature, and approximately 30% of glio-
from a WHO grade III anaplastic astro- blastomas with a proneural signature are
Other genetic alterations
cytoma, whereas the majority of second- IDH-mutant {2645}. These findings sug-
Genetic profiling of primary and second-
ary IDH1-mutant glioblastomas progress gest that IDH-mutant glioblastomas are a
ary glioblastomas has shown that the fre-
from a WHO grade II diffuse astrocytoma relatively homogeneous group of gliomas,
quency of TP53 mutations is significantly
{1797}. Therefore, some tumours diag- characterized by a proneural expression
higher in secondary glioblastomas {67%) pattern. IDH-mutant diffuse astrocytoma
nosed as anaplastic astrocytoma may
than in primary glioblastomas {11%)
actually have been primary glioblasto- and IDH-mutant and 1p/19q-codeleted
{2705}. EGFR overexpression prevails
mas misdiagnosed due to a sampling oligodendroglioma also have the typical
in glioblastomas that are IDH-wildtype
error. proneural signature {496}, further sup-
but is rare in secondary glioblastomas
porting the assumption that these neo-
Primary glioblastomas with IDH mutation {2705}. In one study, only 1 of 49 glio-
plasms share common neural progenitor
In a population-based study, only 14 of blastomas showed both TP53 mutation cells. In contrast, IDH-wildtype glioblas-
4D7 glioblastomas {3.4%) clinically diag- and EGFR overexpression, suggesting
tomas are heterogeneous, with several
nosed as primary carried an IDH1 mu- that these alterations are mutually exclu-
distinct expression profiles.
tation. The patients were approximately sive events that could define two differ-
10 years younger than patients with sec- ent genetic pathways in the evolution of Hypermethylation phenotype
ondary glioblastomas, but the genetic glioblastoma {2705}. Subsequent studies IDH-mutant glioblastomas show con-
profiles of the two tumour groups were provided evidence that primary and sec- certed CpG island methylation at many
similar, including frequent TP53 muta- ondary glioblastomas develop through loci {1810}. A similar hypermethyla-
tions and absence of EGFR amplification distinct genetic pathways. tion phenotype has been observed in
{1797}. Similarly, several hospital-based IDH-mutant diffuse astrocytomas {454}
Fig. 1.54 A Cumulative survival rate of patients with glioblastoma treated with surgery plus radiotherapy. Note that patients carrying an IDH1 mutation had significantly longer overall
survival survival. Reprinted from NobusawaSetal.{1797}. B In a more recent study, the median survival was 31 months for 14 patients with mutated IDH1 or IDH2, versus 15 months for
115 patients with wildtype IDH1 or IDH2. For patients with IDH-mutant glioblastomas, survival was calculated from the date of the secondary diagnosis. Reprinted from Yan H et al. {2810}.
Glioblastoma, IDH-mutant 55
and oligodendrogliomas {454}, as well as neural precursor cells that already carry
in IDH-mutant acute myeloid leukaemia a germline TP53 mutation.
{706}. The introduction of mutant IDH1 Glioblastoma, NOS
Prognosis and predictive factors
into primary human astrocytes alters spe-
In his pioneering work on glioblastomas, Definition
cific histone markers and induces exten-
H-J Scherer {2265} wrote, in 1940: ‘‘From A high-grade glioma with predominantly
sive DNA hypermethylation, suggesting
a biological and clinical point of view, the astrocytic differentiation; featuring nucle-
that the presence of an IDH1 mutation is
secondary glioblastomas developing in ar atypia, cellular pleomorphism (in most
sufficient to establish a hypermethylation
astrocytomas must be distinguished from cases), mitotic activity, and typically a
phenotype {2589}. Moreover, IDH muta-
‘primary’ glioblastomas. They are prob- diffuse growth pattern, as well as micro-
tions disrupt chromosomal topology and
ably responsible for most of the ‘glioblas- vascular proliferation and/or necrosis; in
thus allow aberrant chromosomal regula-
tomas of long clinical duration' mentioned which IDH mutation status has not been
tory interactions that induce oncogene
in the literature." This early observation fully assessed.
expression, including glioma oncogenes
has been repeatedly confirmed. In a Determination of IDH mutation status
such as PDGFRA {713A}.
1980-1994 population-based study, the is important for all glioblastomas; how-
Genetic susceptibility median overall survival of patients with ever, if full testing is not possible (see
Astrocytic gliomas, including diffuse as- clinically diagnosed secondary glioblas- Genetic parameters in Glioblastoma,
trocytomas, anaplastic astrocytomas, toma was 7.8 months, significantly longer IDH-wildtype, p. 28), the diagnosis of
and secondary glioblastomas, are the than that of patients with primary glio- glioblastoma, NOS, can be made, pro-
most frequent brain tumours associated blastoma {4.7 months) {1823}. Similarly, vided that the histological variants giant
with TP53 germline mutations in fami- the analysis of patients who were treated cell glioblastoma, gliosarcoma, and epi-
lies with Li-Fraumeni syndrome {1294, with surgery and radiotherapy showed thelioid glioblastoma can be ruled out.
1841}. In patients from three families that the mean overall survival of patients
with Li-Fraumeni syndrome, IDH1 mu- with IDH-mutant glioblastomas was ICD-O code 9440/3
tations were observed in 5 astrocytic 27.1 months, 2.4 times as long as that of
Grading
gliomas that developed in carriers of a patients with IDH-wildtype glioblastoma
Glioblastoma, NOS, and its variants (e.g.
TP53 germline mutation. All 5 contained {11.3 months) {1797}. In another study,
giant cell glioblastoma that cannot be
the R132C (CGT—TGT) mutation {2710}, patients with IDH-mutant glioblastomas
tested for IDH mutation status) corre-
which in sporadic astrocytic tumours ac- treated with radiotherapy/chemotherapy
spond histologically to WHO grade IV.
counts for < 5% of all IDH1 mutations had an overall survival time of 31 months,
overall {118,2709,2810}. This remark- twice as long as that of patients with IDH-
ably selective occurrence suggests wildtype glioblastoma {2810}.
a preference for R132C mutations in
56 Diffuse gliomas
Hawkins C.
Diffuse midline glioma, Ellison D.W.
Sturm D.
H3 K27M-mutant
amples were previously known as brain mutant. Pontine gliomas manifest primarily in children,
stem glioma and diffuse intrinsic pontine whereas spinal cord lesions predominantly affect adults.
Reprinted from Solomon DA et al. {2392A}.
Grading
H3 K27M-mutant diffuse midline glioma
corresponds to WHO grade IV.
Epidemiology
Incidence data on diffuse gliomas specif-
ically arising in midline structures are not
available, because large brain tumour
registries have not yet included these as
a distinct category. The median patient
age at diagnosis of diffuse midline glioma
is 5-11 years, with pontine tumours aris-
ing earlier on average (at ~7 years) than
their thalamic counterparts (at ~11 years).
There is no clear sex predilection {1229,
1358,1863,2700,2776}.
Localization
Diffuse midline gliomas typically arise
in the pons, thalamus, or spinal cord,
with occasional examples involving the
cerebellum.
Clinical features
Most patients with DIPG present with
brain stem dysfunction or cerebrospinal
fluid obstruction, typically developing
over a short period of time {1-2 months).
Classic clinical symptoms include the tri-
ad of multiple cranial neuropathies, long
tract signs, and ataxia {2700}. With tha-
lamic gliomas, common initial symptoms
include signs of increased intracranial
Fig. 1.55 H3 K27M-mutant diffuse midline glioma. A Sagittal T2-weighted MRI showing a diffusely infiltrating
pressure, motor weakness/hemiparesis,
pontine glioma expanding the pons with crowding of the neural structures at the craniocervical junction and tonsillar and gait disturbance {1358}.
herniation to the level of the C1 posterior arch. B Axial FLAIR MRI demonstrates a diffusely infiltrating pontine glioma
Imaging
expanding the pons and encasing the basilar artery. C Axial FLAIR MRI shows an expansile left thalamic glioma and
associated obstructive hydrocephalus, with mild to moderate dilatation of the lateral ventricles, periventricular oedema,
On MRI, diffuse midline gliomas are
and distortion of the third ventricle. D Expansile thalamic glioma showing heterogeneous enhancement on the post-
gadolinium coronal T1 sequence.
Fig. 1.58 H3 K27M-mutant diffuse midline glioma. A Tumour cells infiltrate and entrap normal brain elements. B High-grade morphological features with focal necrosis.
58 Diffuse gliomas
in TP53, PPM1D, CHEK2, or ATM; occur- Table 1.06 Additional mutations in H3 K27M-mutant
Imaging structures, brain stem, cerebellum, and cellular tumours. Areas of increased cel-
On CT, IDH-mutant and 1p/19q-codelet- spinal cord {2489}. lularity, often in the form of circumscribed
ed oligodendrogliomas usually present nodules, can occur in some otherwise
Macroscopy
as hypodense or isodense well-demar- well-differentiated tumours, so wide sam-
Oligodendroglioma usually presents as a
cated mass lesions, typically located in pling of resection specimens is required.
relatively well-defined, soft, greyish-pink
the cortex and subcortical white matter. However, small biopsies sometimes show
mass. The tumour is typically located in only scattered oligodendroglioma cells
Calcification is common but not diagnos-
the cortex and white matter, leading to
tic. MRI shows a lesion that is T1-hypoin- infiltrating the brain parenchyma, which
blurring of the grey matter-white mat-
tense and T2-hyperintense. The lesion is are identifiable by their characteristic nu-
ter boundary. Local invasion into the
usually well demarcated and shows little clei and (if the most common IDH muta-
overlying leptomeninges may be seen.
perifocal oedema {2678}. Some tumours tion is present) by immunostaining for
Calcification is frequent and may impart
show heterogeneous features due to In- R132H-mutant IDH1 (see Immunophe-
a gritty texture to the tumour. Occasion- notype). Classic oligodendroglioma cells
tratumoural haemorrhages and/or areas
ally, densely calcified areas may present
of cystic degeneration. Gadolinium en- have uniformly round nuclei that are slight-
as intratumoural stones. Zones of cystic
hancement has been detected in < 20% ly larger than those of normal oligodendro-
degeneration, as well as intratumoural
of WHO grade II oligodendrogliomas but cytes and show an increase in chromatin
haemorrhages, are common. Rare cases
in > 70% of WHO grade III anaplastic density or a delicate salt-and-pepper
with extensive mucoid degeneration look
oligodendrogliomas {1260}. Contrast pattern similar to that of neuroendocrine
gelatinous. tumours. A distinct nuclear membrane is
enhancement in low-grade oligodendro-
gliomas has been associated with less Microscopy often apparent. In routinely formalin-fixed
favourable prognosis {2621}. Demonstra- and paraffin-embedded material, there is
tion of elevated 2-hydroxyglutarate lev- Histopathology a tendency for the tumour cells to undergo
els by MR spectroscopy is a promising Oligodendrogliomas are diffusely infil- degeneration by acute swelling, which re-
new means of non-invasive detection of trating gliomas of moderate cellularity sults in an enlarged rounded cell with a
IDH-mutant gliomas (including oligoden- that in classic cases are composed of well-defined cell membrane and clear
drogliomas) {449}. Differences in certain monomorphic cells with uniform round cytoplasm around a central spherical nu-
features between 1p/19q-codeleted and nuclei and variable perinuclear haloes on cleus. This creates the typical honeycomb
1p/19q-intact low-grade gliomas have paraffin sections (a honeycomb or fried- or fried-egg appearance, which although
been reported on MR spectroscopy {292, egg appearance). Additional features in- artefactual is a helpful diagnostic feature
685,2678}, but reliable discrimination by clude microcalcifications, mucoid/cystic when present. However, this artefact is not
neuroimaging is not yet possible. degeneration, and a dense network of seen in smear preparations or frozen sec-
delicate branching capillaries. Mitotic tions, and may also be absent in rapidly
Spread activity is either absent or low. Nuclear fixed tissue and in paraffin sections made
IDH-mutant and 1p/19q-codeleted oligo- atypia and an occasional mitosis are from frozen material.
dendrogliomas characteristically extend compatible with the diagnosis of a WHO Some oligodendrogliomas contain tu-
into adjacent brain in a diffuse manner. grade II tumour, but brisk mitotic activity, mour cells with the appearance of small
Like other diffuse gliomas, oligodendro- prominent microvascular proliferation, gemistocytes with a rounded belly of
glioma can also (although rarely) mani- and spontaneous necrosis are indica- eccentric cytoplasm that is positive for
fest at initial clinical presentation with a tors of anaplasia, corresponding to WHO GFAP. These cells have been referred
gliomatosis cerebri pattern of extensive grade III (see Anaplastic oligodendrogli- to as minigemistocytes or microgemisto-
involvement of the CNS, with the affected oma, IDH-mutant and 1p/19q-codeleted, cytes. Gliofibrillary oligodendrocytes are
area ranging from most of one cerebral p. 70). typical-looking oligodendroglioma cells
hemisphere (three lobes or more) to both on routine stains but show a thin peri-
cerebral hemispheres with additional Cellular composition
Oligodendrogliomas are moderately nuclear rim of positivity for GFAP {994}.
involvement of the deep grey matter
GFAP-negative mucocytes or even sig-
net ring cells are occasionally seen. Rare
62 Diffuse gliomas
Fig. 1.63 IDH-mutant and 1p/19q-codeleted oligodendroglioma. A Typical honeycomb or fried-egg pattern of oligodendrogliomas: the tumour cells show a clear perinuclear halo
and a sharply delineated plasma membrane; although this feature is an artefact that occurs during tissue processing, it is a hallmark of oligodendroglioma. B Perinuclear clearing.
C Delicate “chicken-wire” network of branching capillaries. Note the moderate nuclear atypia and occasional microcalcification. D Conspicuous network of branching capillaries.
cases of oligodendroglioma consisting astrocytic morphology is also compatible Mineralization and other degenerative
largely of signet ring cells (called sig- with this diagnosis when molecular test- features
net ring cell oligodendroglioma) have ing confirms IDH mutation and 1p/19q A frequent histological feature is the pres-
been described {1373}, and eosinophilic codeletion; in other words, diffuse glio- ence of microcalcifications (sometimes
granular cells are present in some oligo- mas with oligoastrocytoma histology or associated with blood vessels) within the
dendrogliomas {2498}. Rare cases with with ambiguous histological features tumour tissue proper or in the invaded
neurocytic or ganglioglioma-like differ- should be diagnosed as IDH-mutant and brain. Mineralization along blood vessels
entiation have also been reported {1939, 1p/19q-codeleted oligodendroglioma typically takes the form of small, punctate
1948}. The presence of these various when molecular testing reveals this en- calcifications, whereas microcalcifica-
cellular phenotypes does not preclude tity-defining genotype {349,2464,2731}. tions in the brain (called calcospher-
an oligodendroglioma diagnosis if the Reactive astrocytes are typically scat- ites) tend to be larger, with an irregular
tumour is positive for IDH mutation and tered throughout oligodendrogliomas and sometimes laminated appearance.
1p/19q codeletion. The presence of tu- and may be particularly prominent at the However, this feature is not specific for
mour cells with fibrillar or gemistocytic tumour borders. oligodendroglial tumours, and due to
Fig. 1.64 Immunohistochemical features of IDH-mutant and 1p/19q-codeleted oligodendroglioma. A MAP2. B 0LIG2. C GFAP.
generally incomplete tumour sampling, an antibody specific for R132H-mutant oligodendrogliomas {1336}. GFAP and
is sometimes not found in the available IDH1 {360}. Positive R132H-mutant IDH1 vimentin immunostaining is often posi-
tissue sections even when clearly dem- staining greatly facilitates the immuno- tive in the astrocytic-appearing tumour
onstrated on CT. Areas characterized histochemical differential diagnosis of components of IDH-mutant and 1p/19q-
by extracellular mucin deposition and/ oligodendroglioma versus other clear codeleted oligodendrogliomas that his-
or microcyst formation are frequent. Rare cell tumours of the CNS and non-neo- tologically resemble oligoastrocytoma.
tumours are characterized by marked plastic and reactive lesions {356,357}. Cytokeratins are absent, although cer-
desmoplasia {1156}. However, a lack of R132H-mutant IDH1 tain antibody cocktails, such as AE1/
immunopositivity does not exclude oli- AE3, may give false-positive staining due
Vasculature
godendroglioma, given the possibility of to cross-reactivity {1773}.
Oligodendrogliomas typically show a
less common IDH1 and IDH2 mutations Several antigens are specifically ex-
dense network of branching capillaries
that cannot be detected with the R132H- pressed by normal oligodendrocytes in
resembling the pattern of chicken wire. In
mutant IDH1 antibody and instead re- vivo or in vitro, including myelin basic
some cases, the capillary stroma tends
quire DNA sequence analysis. Unlike protein; proteolipid protein; myelin-asso-
to subdivide the tumour into lobules.
most IDH-mutant diffuse astrocytomas, ciated glycoprotein; galactolipids, such
There is a tendency for intratumoural
IDH-mutant and 1p/19q-codeleted oli- as galactocerebroside and galactosul-
haemorrhages.
godendrogliomas typically retain nuclear fatide; certain gangliosides; and several
Growthpattern expression of ATRX {1519,2105}. In addi- enzymes, such as carbonic anhydrase C,
Oligodendrogliomas grow diffusely in tion, IDH-mutant and 1p/19q-codeleted CNP, glycerol-3-phosphate dehydroge-
the cortex and white matter. Within the oligodendrogliomas usually lack wide- nase, and lactate dehydrogenase. How-
cortex, tumour cells tend to form sec- spread nuclear p53 staining, a finding ever, none of these antigens has demon-
ondary structures such as perineuronal consistent with the mutual exclusivity of strated significance as a diagnostically
satellitosis, perivascular aggregates, and TP53 mutation and 1p/19q deletion in useful marker for oligodendrogliomas.
subpial accumulations. Circumscribed IDH-mutant gliomas {349,2464}. Some are not expressed in oligodendro-
leptomeningeal infiltration may induce a Oligodendrogliomas are consistently im- glioma cells (e.g. myelin basic protein
desmoplastic reaction. A rare spongio- munopositive for MAP2, S100 protein, {1746}), some are expressed only in a
blastic growth pattern consists of paral- and LEU7 {221,1746,2087}. MAP2 often minority of cases (e.g. myelin-associated
lel rows of tumour cells with somewhat reveals perinuclear cytoplasmic immu- glycoprotein {1746}, galactocerebroside,
elongated nuclei forming rhythmic pali- nostaining without significant process proteolipid protein, and CNP {2457}), and
sades. Occasionally, perivascular pseu- labelling. However, all three markers some have expression that is not restrict-
dorosettes are seen, although some of are also commonly positive in astrocytic ed to oligodendroglial tumour cells (e.g.
these are a result of perivascular neuropil gliomas. Similarly, the oligodendrocyte carbonic anhydrase C {1747}).
formation within foci of neurocytic differ- lineage-associated transcription fac- Synaptophysin immunoreactivity of re-
entiation {1948}. These patterns are gen- tors OLIG1, OLIG2, and SOX10 are ex- sidual neuropil between the tumour cells
erally present only focally. pressed in oligodendrogliomas but also is frequently seen in oligodendroglial tu-
in other gliomas {121,1500}. GFAP is mours and should not be mistaken for
Immunophenotype detectable in intermingled reactive as- evidence of neuronal or neurocytic dif-
To date, no single immunohistochemical trocytes but can also be found in neo- ferentiation. However, IDH-mutant and
marker has been found that is specific for plastic cells such as minigemistocytes 1p/19q-codeleted oligodendroglioma
oligodendroglial tumour cells. The major- and gliofibrillary oligodendrocytes {994, may contain neoplastic cells that express
ity of oligodendrogliomas demonstrate 2087}. Vimentin is infrequently expressed synaptophysin and/or other neuronal
strong and uniform immunoreactivity with in well-differentiated oligodendroglio- markers, such as NeuN and neurofila-
mas but more often found in anaplastic ments {1939,1948}. Immunostaining for
64 Diffuse gliomas
the proneural alpha-internexin protein is are common in IDH-mutant and 1p/19q- diastase-sensitive periodic acid-Schiff
frequent {607} but cannot substitute as codeleted oligodendrogliomas but positivity, Immunoreactivity for EMA and
a reliable surrogate marker for 1p/19q exceptional in IDH-mutant diffuse as- desmoplakin, and lack of IDH mutation.
codeletion {625}. Similarly, NOGO-A trocytomas. The considerable overlap Metastatic clear cell carcinomas dif-
positivity is typical of, but not exclusive between TERT promoter mutation and fer from oligodendrogliomas in that they
to, 1p/19q-codeleted oligodendroglio- 1p/19q codeletion in IDH-mutant gliomas have sharp tumour borders, are immuno-
mas {1600}. suggests that TERT promoter mutation reactive for cytokeratins and EMA, and
may be useful as a surrogate marker for lack R132H-mutant IDH1 immunostain-
Proliferation
1p/19q codeletion. However, minor sub- ing or other IDH mutations.
Mitotic activity is low or absent in WHO
sets of IDH-mutant and 1p/19q-codelet- In adult patients, the differential diagnosis
grade II oligodendrogliomas. Accord-
ed oligodendrogliomas have been re- with pilocytic astrocytoma rarely poses a
ingly, the Ki-67 proliferation index is usu-
ported to lack TERT promoter mutation, major problem, because foci of classic
ally < 5% (see Prognosis and predictive pilocytic features are usually present in
and some IDH-mutant but 1p/19q-intact
factors). On average, the Ki-67 prolifera-
astrocytomas may carry TERT promoter pilocytic astrocytomas, and IDH muta-
tion index is significantly lower in WHO
mutations {89,1314,1408,2464}. There- tion and 1p/19q deletion are absent.
grade II oligodendrogliomas than in ana-
fore, the general use of TERT promoter Neuroradiological features, such as mid-
plastic oligodendrogliomas. However, a
sequencing instead of 1p/19q codeletion line tumour location and mural nodule/
definitive diagnostic cut-off point cannot
testing is not recommended. Immuno- cyst formation, may also provide helpful
be established, due to marked variability ancillary information. Molecular demon-
histochemical features that may further
in staining results between institutions.
support the differential diagnosis include stration of BRAF fusion genes supports
Nevertheless, interobserver agreement
frequent nuclear p53 immunostaining the diagnosis of pilocytic astrocytoma,
on Ki-67 proliferation index scoring as
and loss of nuclear ATRX expression in although BRAF gain and KIAA1549-
determined by MIB1 monoclonal anti-
diffuse astrocytomas. BRAFfusions have also been reported in
body staining was good when six pathol-
Other neoplastic lesions that can histo- some IDH-mutant and 1p/19q-codeleted
ogists independently reviewed the same oligodendroglial tumours {104,1282}. In
logically mimic oligodendroglioma are
set of MIB1-stained slides from 30 oligo-
clear cell ependymoma, neurocytoma, children, the molecular distinction of oli-
dendrogliomas {2024}. Minigemistocytes
and dysembryoplastic neuroepithelial godendroglioma from pilocytic astrocy-
are reported to be mostly MIB1-negative
tumour. These entities and oligodendro- toma is challenging because paediatric
and thus non-proliferative, whereas gliofi-
gliomas share the feature of neoplastic oligodendrogliomas typically lack com-
brillary oligodendrocytes are more com-
cells with uniform, round nuclei and clear bined IDH mutation and 1p/19q codele-
monly positive {1371}. Other proliferation tion but occasionally demonstrate BRAF
cytoplasm, collectively referred to as
markers, such as PCNA {2096}, TOP2A
oligodendroglial-like cells. In the routine fusion genes (see Oligodendroglioma
{1344}, and MCM2 {2736} have been re-
diagnostic setting, evidence of an IDH lacking IDH mutation and 1p/19q codele-
ported to correlate with WHO grade and
mutation, typically demonstrated by posi- tion, p. 68). This differential diagnosis
survival in patients with oligodendroglial
tive R132H-mutant IDH1 immunostaining, must therefore rely primarily on histologi-
tumours, but do not provide clear advan-
rules out all these differential diagnoses. cal and ancillary radiological features,
tages over MIB1 immunostaining in the unless advanced molecular testing
In the absence of IDH mutation, immu-
routine setting.
nostaining for neuronal markers, in par- methods based on large-scale methyla-
Differential diagnosis ticular diffuse synaptophysin and at least tion and/or mutation profiling that provide
The morphological spectrum of IDH-mu- focal NeuN, provides further evidence entity-specific methylation or mutation
tant and 1p/19q-codeleted oligodendro- for neurocytoma. Similarly, rare cases of profiles can be applied. The differential
gliomas is broad, with some similarities liponeurocytoma are distinguished from diagnosis of diffuse leptomeningeal glio-
to a variety of reactive and neoplastic le- oligodendroglioma by extensive positive neuronal tumour (p. 152) is facilitated by
sions. Macrophage-rich processes such staining for neuronal markers, the ab- the clinical presentation and the charac-
as demyelinating diseases or cerebral in- sence of IDH mutation, and the presence teristic molecular profile, with combined
farcts should be readily distinguished by of lipidized cells resembling adipocytes. KIAA1549-BRAFgene fusion and solitary
immunostaining for macrophage mark- Clear cell ependymomas often show at 1p deletion (or 1p/19q codeletion) but ab-
ers and lack of IDH mutation. Reactive least focal perivascular pseudorosettes sence of IDH mutation {2156}.
changes such as the increased numbers and dot-like or ring-shaped EMA im-
Cell of origin
of oligodendrocytes sometimes seen in munoreactivity. Formation of specific
Although the designation of CNS neo-
partial lobectomy specimens performed glioneuronal elements, absence of IDH
plasms as oligodendroglial tumours
for intractable seizures can also be dis- mutation and 1p/19q codeletion, and (in
could imply histogenesis from cells of the
tinguished by lack of IDH mutation. a subset) eosinophilic granular bodies,
oligodendroglial lineage, the evidence
The differential diagnosis with diffuse a CD34-positive cell population, and/or
supporting this assumption is circum-
astrocytoma relies on histological, immu- BRAF V600E mutation, distinguish dys-
stantial, based solely on morphological
nohistochemical, and molecular features. embryoplastic neuroepithelial tumour
similarities of the neoplastic cells in these
Most importantly, IDH-mutant diffuse from IDH-mutant and 1p/19q-codeleted
tumours to normal oligodendrocytes. It
astrocytomas lack 1p/19q codeletion. oligodendroglioma {414}. A rare differen-
is also unknown whether human oligo-
In addition, TERT promoter mutations tial diagnosis is clear cell meningioma,
dendrogliomas arise from neoplastic
which can be distinguished by abundant
transformation of mature oligodendro- codon 172 mutations are present, with IDH-mutant and 1p/19q-codeleted oligo-
cytes, immature glial precursors, or the proportion of IDH2 mutations being dendrogliomas lack ATRX mutation but
neural stem cells. Experimental data in higher in oligodendroglial gliomas than virtually always carry activating muta-
transgenic mice indicate that gliomas in astrocytic gliomas {953}. Combined tions in the TERT promoter region, lead-
with oligodendroglial histology may origi- whole-arm loss of 1p and 19q is invaria- ing to increased expression of TERT {89,
nate from different cell types in the CNS, bly associated with IDH mutation, indicat- 1270,1314}. In fact, TERT promoter muta-
including neural stem cells, astrocytes, ing that detection of 1p/19q codeletion in tion is strongly associated with 1p/19q
and oligodendrocyte precursor cells the absence of IDH mutation should raise codeletion in IDH-mutant gliomas and
{2872}. An oligodendroglioma-like phe- suspicion of incomplete/partial deletions, is an early event in oligodendroglioma
notype is commonly found in transgenic which have been detected in subsets of development {2464}. However, TERT
brain tumours, despite a variety of target- IDH-wildtype anaplastic astrocytomas promoter mutations are also frequent in
ed cell types and oncogenic events {589, and glioblastomas, with associated poor IDH-wildtype glioblastomas {1270}. Con-
2725}. Some studies have suggested a outcome {2658}. sequently, large-scale sequencing stud-
likely origin of oligodendrogliomas from ies have identified three major groups
NG2-positive and asymmetrical cell divi- Aberrantgenes on 1p or 19q
of cerebral gliomas, with distinct biolo-
sion-defective oligodendroglial progeni- Oligodendroglial tumours have frequent gies and clinical outcomes. These three
tor cells {1954,2449}. However, oligo- mutations in the human homologue of groups are defined, respectively, by IDH
dendroglial precursor cells may give rise the Drosophila capicua gene (CIC) on mutation associated with 1p/19q codele-
to either oligodendroglial or astrocytic 19q13.2 {183,2825}, with the majority of tion and TERT promoter mutation, IDH
gliomas, depending on the genes driv- IDH-mutant and 1p/19q-codeleted oli- mutation associated with TP53 and fre-
ing transformation {1508}, suggesting a godendrogliomas harbouring CIC muta- quent ATRX mutation, and IDH-wildtype
dominance of oncogenic signalling over tions {2219,2464,2825}. A smaller subset status associated with TERT promoter
cell of origin in determining the glioma of these tumours also carries mutations mutation and glioblastoma-associated
phenotype. in the FUBP1 gene on 1 p31.1. One study genomic aberrations {349,2464}.
identified IDH mutation, 1p/19q codele-
Genetic profile Other genetic alterations
tion, and TERT promoter mutation as ear-
Cytogenetics ly genetic changes in oligodendroglioma Mutations in NOTCH1, and less com-
Cytogenetic studies of oligodendro- pathogenesis, whereas CIC mutations monly in other NOTCH pathway genes,
glioma have revealed an unbalanced may appear later in tumour progression have been detected in approximately
translocation between chromosomes 1 {2464}. Other genes on 1p (e.g. CAMTA1, 15% of oligodendrogliomas {349,2464}.
and 19 that results in loss of the der(1;19) CHD5, CITED4, DFFB, DIRAS3, PRDX1, Other less commonly mutated genes in-
(p10;q10) chromosome, causing whole- ATRX, AJAP1, and TP73) and 19q (e.g. clude epigenetic regulator genes such
arm deletions of 1p and 19q, and reten- EMP3, ARHGAP35, PEG3, and ZNF296) as SETD2 and other histone methyltrans-
tion of the del [t({1;19)(q10;p10)] chromo- have been reported to show aberrant ferase genes, as well as genes encoding
some {887,1151}. promoter methylation and/or reduced components of the SWI/SNF chromatin-
expression in IDH-mutant and 1p/19q- remodelling complex {349,2464}. Unlike
IDH mutation and 1p/19q codeletion codeleted oligodendrogliomas {2126}. in IDH-mutant astrocytic tumours, TP53
The entity-defining alteration in oligo- Epigenetic silencing of the pH regulator mutation is usually absent and mutu-
dendrogliomas is concurrent mutation gene SLC9A1 on 1p has been linked to ally exclusive with 1p/19q deletion {349,
of IDH1 or IDH2 and whole-arm deletion lower intracellular pH and attenuation of 2464}.
of 1p and 19q. The vast majority (> 90% acid load recovery in oligodendroglioma
{953}) of IDH mutations in WHO grade II Epigenetic and transcriptional changes
cells, which may contribute to the distinc-
oligodendrogliomas are the IDH1 R132H IDH-mutant and 1p/19q-codeleted oli-
tive biology of IDH-mutant and 1p/19q-
mutation, which is readily detectable by godendrogliomas are characterized by
codeleted oligodendrogliomas {217}.
immunohistochemistry {360}. In < 10% widespread changes in DNA methylation,
of cases, other IDH1 codon 132 or IDH2 TERT promoter mutations leading to concurrent hypermethylation
Unlike IDH-mutant diffuse astrocytomas, of multiple CpG islands, a phenomenon
66 Diffuse gliomas
that is referred to as G-CIMP {1810}. and/or maturation of oligodendroglial child with hereditary non-polyposis colo-
Mechanistically, this phenomenon has cells {2085}. PDGFA and PDGFB, as well rectal cancer and oligodendroglioma
been linked with mutant IDH proteins as the corresponding receptors (PDG- {1642}; and an adolescent with Lynch
producing 2-hydroxyglutarate, which FRA and PDGFRB) are commonly co- syndrome and anaplastic oligodendro-
functions as a competitive inhibitor of expressed in oligodendrogliomas {582}. glioma {978}. One child with retinoblas-
alpha-ketoglutarate-dependent dioxy- However, PDGFRA mutations are rare, toma syndrome and anaplastic oligoden-
genases including histone demethylases and elevated expression seems to be droglioma {16} and identical twins with
and the TET family of 5-rmethylcytosine independent of 1p/19q codeletion {955}. Ollier-type multiple enchondromatosis
hydroxylases {1540,2804}. This in turn The functional role of PDGFB has been and oligodendroglioma have also been
leads to increased histone methylation demonstrated by the induction of oligo- documented {411}.
and G-CIMP {1810,2589}. One study dendrogliomas in transgenic mice with
suggested that CIC mutations cooper- targeted overexpression of this growth Prognosis and predictive factors
ate with IDH mutations to further increase factor in neural stem or progenitor cells
Prognosis
2-hydroxyglutarate levels {443}. In fact, {521,1508}. VEGF and its receptors serve
WHO grade II IDH-mutant and 1p/19q-
DNA methylation profiles in IDH-mutant as angiogenic factors in oligodendroglial
codeleted oligodendrogliomas are typi-
and 1p/19q-codeleted oligodendroglio- tumours, particularly in anaplastic oligo-
cally slow-growing tumours and are asso-
mas differ from those in IDH-mutant but dendrogliomas {402,456}.
ciated with relatively long overall survival.
1p/19q-intact astrocytomas {1723,2464,
Genetic susceptibility A population-based study from Switzer-
2751}, a distinction that has been referred
Most oligodendrogliomas develop spo- land demonstrated a median survival
to as G-CIMP type A versus G-CIMP type
radically, in the absence of an obvi- time of 11.6 years for oligodendroglioma
B {2464}, and can be exploited for clas-
ous familial clustering or a hereditary and 6.6 years for oligoastrocytoma (both
sification purposes (e.g. by 450k meth-
predisposition syndrome. Large-scale defined according to histological criteria
ylation bead array analysis {2751}). As a
genotyping data indicate a strong asso- only), as well as 10-year survival rates of
consequence of G-CIMP, many different
ciation between a low-frequency SNP at 51% and 49%, respectively {1826}. The
genes may be epigenetically inactivated
8q24.21 and increased risk of IDH-mu- CBTRUS has documented 5-year sur-
in oligodendrogliomas, including genes
tant oligodendroglioma and astrocytoma vival rates of 79.5% and 61.1%, as well
on 1p and 19q as well as genes on other
{1152}. Other genetic polymorphisms that as 10-year survival rates of 62.8% and
chromosomes, such as the tumour sup-
have been associated with increased oli- 46.9%, for oligodendroglioma and oli-
pressors CDKN2A, CDKN2B, RB1, and
godendroglioma risk include the GSTT1 goastrocytic glioma, respectively {1863}.
many others {2126}. MGMT promoter hy-
null genotype {1245} and SNPs in the However, survival estimates have varied
permethylation and reduced expression
GLTSCR1 and ERCC2 genes {2814}. markedly. Some single-institution studies
is also common {1733}. At the mRNA lev-
Germline mutations in shelterin com- have documented even longer median
el,' IDH-mutant and 1p/19q-codeleted oli-
plex genes, including the POT1 gene, overall survival times (e.g. > 15 years
godendrogliomas often show a proneural
have been linked to familial oligoden- {1845}) for patients with low-grade oli-
glioblastoma-like gene expression signa-
droglioma {110}. The largest series of godendroglioma, and others have docu-
ture {608,2731}.
non-syndromic familial glioma cases mented shorter median survivals (e.g.
Growthfactorsand receptors published to date comprised 841 pa- 3.5 years {567}). Most of the variability
About half of all WHO grade II oligoden- tients from 376 families with > 2 affected in these studies is likely due to differing
drogliomas and anaplastic oligodendro- family members each {2212}. Within this diagnostic criteria, the absence of mo-
gliomas show strong expression of EGFR cohort, 59 patients {8%) were diagnosed lecular information on IDH mutation and
mRNA and protein in the absence of with WHO grade II oligodendroglioma, 1p/19q codeletion, and differing treat-
EGFR gene amplification {2090}. The si- 29 patients {3.9%) with WHO grade II ment approaches.
multaneous expression of the mRNAs for oligoastrocytoma, 31 patients {4.2%) with Oligodendrogliomas generally recur lo-
the pre-pro forms of EGFR and/or trans- WHO grade III anaplastic oligodendro- cally. Malignant progression of recur-
forming growth factor alpha indicates the glioma, and 12 patients {1.6%) with WHO rence is common, although it takes
possibility of auto-, juxta-, or paracrine grade III anaplastic oligoastrocytoma. longer on average than in diffuse astro-
growth stimulation via the EGFR system Isolated cases of familial oligodendro- cytomas {1121}. Rare cases of gliosar-
{626}. One study reported that high EGFR glioma with 1p/19q codeletion have also coma (so-called oligosarcoma) arising
expression was linked to shorter survival been reported {713,1858}. from IDH-mutant and 1p/19q-codeleted
in patients with 1p/19q-codeleted oligo- Only a few patients with oligodendroglial oligodendroglioma have been reported
dendrogliomas of WHO grade II but long- tumours have been reported in families {1004,2152}. Unusual cases of oligoden-
er survival in patients with WHO grade III with hereditary cancer predisposition droglioma, including 1p/19q-codeleted
anaplastic oligodendrogliomas {1036}. syndromes. These include one patient tumours, have been noted in which the
Several other growth factors (including manifesting ESRCA1 mutation with oligo- patients developed systemic metasta-
basic fibroblast growth factor, platelet- dendroglioma {1165}; one patient with ses, usually at late stages of the disease
derived growth factors, transforming Turcot syndrome, germline PMS2 muta- {1148,1651}. It has been suggested that
growth factor beta, IGF1, and nerve tion, and two metachronous glioblas- oligodendroglial tumours with 1p/19q
growth factor) have been reported to be tomas showing histological features of codeletion may be more prone to extra-
involved in the regulation of proliferation oligodendroglial differentiation {2525}; a neural metastasis despite their generally
68 Diffuse gliomas
that a prognostically favourable role of patients treated with radiotherapy Oligodendroglioma, NOS
IDH mutation, 1p/19q losses, and MGMT plus PCV chemotherapy versus radio-
promoter methylation in WHO grade II therapy alone {2338}. However, recent Definition
glioma is linked to higher sensitivity to cy- long-term follow-up data also showed a A diffusely infiltrating glioma with classic
totoxic treatment rather than to generally major increase in overall survival after oligodendroglial histology, in which mo-
more indolent behaviour independent radiotherapy plus PCV chemotherapy, lecular testing for combined IDH muta-
of therapy. It remains to be investigated in particular for patients with 1p/19q- tion and 1p/19q codeletion could not be
whether genetic or epigenetic alterations codeleted low-grade oligodendroglio- completed or was inconclusive.
in other genes can improve prognostic mas {2481,2612}. Adjuvant chemother- The diagnosis of oligodendroglioma,
assessment within the group of patients apy with temozolomide may also be a NOS, is reserved for diffusely infiltrat-
with IDH-mutant and 1p/19q-codeleted feasible therapeutic strategy for pa- ing WHO grade II gliomas with clas-
WHO grade II oligodendrogliomas. tients with progressive low-grade oligo- sic oligodendroglial histology but with-
dendroglioma, with 1p/19q codeletion out confirmation of IDH mutation and
Predictive factors 1p/19q codeletion, due to limited tissue
suggested as a predictive marker for
The optimal postoperative treatment of availability, low tumour-cell content, in-
better response to temozolomide {1022,
patients with IDH-mutant and 1p/19q- conclusive test results, or other circum-
1256,1476}. Another study reported that
codeleted WHO grade II oligodendro- stances impeding molecular testing. In
IDH mutation predicts better response
gliomas is a matter of ongoing discus- general, molecular testing for IDH muta-
to radiochemotherapy in patients with
sion. After tumour resection, radiotherapy tion and 1p/19q codeletion is important
WHO grade II glioma {1835}. Collec-
and chemotherapy are often deferred for WHO classification of oligodendro-
tively, these findings agree with data
until tumour progression because ther- glial tumours, implying that the diagnosis
from phase III trials in patients with ana-
apy-associated neurotoxicity is a major of oligodendroglioma, NOS, should be
plastic gliomas (WHO grade III) that in-
concern in patients with expected long- limited to a small minority of cases. Im-
dicated IDH mutation {346} and 1p/19q
term survival. Patients with symptomatic munohistochemical demonstration of
codeletion as predictive markers for
residual and progressive tumours after IDH mutation (in particular IDH1 R132H)
long-term survival after combined treat-
surgery usually receive upfront treatment and nuclear positivity for ATRX support
ment with radiotherapy and PCV chem-
with radiotherapy and/or chemotherapy. the diagnosis. However, unless success-
otherapy {344,2615}. The presence of
The European Organisation for Research fully tested for 1p/19q codeletion, glio-
MSH6 mismatch repair gene mutations
and Treatment of Cancer (EORTC) 22845 mas with oligodendroglial histology, IDH
has been linked to temozolomide resist-
trial showed that adjuvant radiotherapy mutation, and nuclear ATRX positivity still
ance independent of MGMT promoter
prolonged progression-free but not over- correspond to the diagnosis of oligoden-
methylation status {1779}. One study re-
all survival in patients with progressive droglioma, NOS. Immunohistochemical
ported that 1p/19q codeletion predict-
WHO grade II gliomas {2613}. The Ra- positivity for oligodendroglioma-associ-
ed a lower risk of pseudoprogression in
diation Therapy Oncology Group (RTOG) ated markers such as alpha-internexin
patients with oligodendroglial tumours
9802 trial initially also showed only in- {607,625} and NOGO-A {1600}, as well
despite being associated with longer
creased progression-free survival for as immunohistochemical demonstration
survival {1504}.
of loss of nuclear CIC or FUBP1 expres-
sion {146,401}, are not sufficient to substi-
tute for 1p/19q codeletion testing.
Unlike with IDH-mutant and 1p/19q-
codeleted oligodendroglioma, the pres-
ence of a conspicuous astrocytic compo-
nent is not compatible with the diagnosis
of oligodendroglioma, NOS (see Oligoas-
trocytoma, NOS, p. 75).
Grading
Oligodendroglioma, NOS, corresponds
histologically to WHO grade II.
70 Diffuse gliomas
patients with anaplastic oligodendro- {2616}. Seizures are also common but
glioma among the 12 103 children aged are less frequent than in patients with
0-14 years registered with neuroepithe- low-grade oligodendroglioma {933}.
lial tumours, and only 32 patients with Anaplastic oligodendroglioma develops
anaplastic oligodendroglioma were doc- either de novo (typically with a short pre-
umented among the 3051 children regis- operative history) or by progression from
tered with neuroepithelial tumours in the a pre-existing WHO grade II oligoden-
15-19 years age group {1863}. In an in- droglioma. The mean time to progression
stitutional cohort of 50 paediatric patients from WHO grade II oligodendroglioma to
with oligodendroglioma, 12 patients were WHO grade III anaplastic oligodendro-
diagnosed with anaplastic oligodendro- Fig. 1.68 Large, macroscopically well-delineated glioma has been estimated at approxi-
gliomas, including 4 patients with 1p/19q anaplastic oligodendroglioma of the left basal ganglia, mately 6-7 years {1446,1826}.
codeletion {2157}. compressing the adjacent lateral ventricle, with shift of
Imaging
Overall, anaplastic oligodendroglioma midline structures towards the right hemisphere. The
Anaplastic oligodendrogliomas can
shows a slight male predominance, with arrowhead points to a ventricular shunt.
show heterogeneous patterns, due to the
a male-to-female ratio of 1.2:1 reported
variable presence of necrosis, cystic de-
among 1650 patients {1863}. In the USA, a preference for the frontal lobe, followed
generation, intratumoural haemorrhages,
anaplastic oligodendroglioma is more by the temporal lobe. However, the tu-
and calcification. On CT and MRI, con-
common in Whites than in Blacks, with an mours can also originate at other sites
trast enhancement is seen in most pa-
incidence ratio of 2.4:1 {1863}. within the CNS, and there have been rare
tients and can be either patchy or ho-
cases of spinal intramedullary anaplastic
Etiology mogeneous {2616}. However, lack of
oligodendroglioma.
See Etiology (p. 61) in Oligodendroglio- contrast enhancement does not exclude
ma, IDH-mutant and 1p/19q-codeleted. Clinical features anaplastic oligodendroglioma. Ring en-
Patients with anaplastic oligodendro- hancement is less common in IDH-mu-
Localization
glioma commonly present with focal tant and 1p/19q-codeleted anaplastic
Anaplastic oligodendrogliomas and
neurological deficits, signs of increased oligodendrogliomas than in malignant
WHO grade II oligodendrogliomas share
intracranial pressure, or cognitive deficits
Fig. 1.69 Anaplastic oligodendroglioma. A Typical image of a cellular glioma with honeycomb cells and mitotic activity (arrows). B Marked nuclear atypia and brisk mitotic activity.
C Focal necrosis with palisading tumour cells. D Marked microvascular proliferation.
mour shows the IDH-mutant and 1p/19q- lignant small cell astrocytic tumours CIC Mutation -60% {349,2464}
codeleted genotype, classification as (including small cell glioblastoma) is of
CDKN2A/
major importance, because malignant p14ARF
LOH -40% {45A}
Homozygous
{1069,1993,
CDKN2C deletion or <5%
2464}
Fig. 1.70 Anaplastic oligodendroglioma. MIB1 mutation
immunohistochemistry shows high proliferative activity.
72 Diffuse gliomas
Fig. 1.71 Anaplastic oligodendroglioma. A R132H-mutant IDH1 stains tumour cells but is negative in blood vessels. B Cortical infiltration zone with tumour cells expressing R132H-
mutant IDH1, including perineuronal satellitosis.
the low frequency of gene amplification anaplastic oligodendrogliomas due to ho- anaplastic oligodendroglioma {1863}.
detected in molecular profiling studies mozygous deletion, mutation, or aberrant However, none of these data considered
{2464,2731}. promoter methylation {666,1084,2779}. In IDH mutation or 1p/19q codeletion sta-
isolated cases, homozygous deletion or tus, which have been strongly associated
Molecular genetics
mutation of the CDKN2C gene at 1p32 with improved response to adjuvant radi-
As the entity name suggests, IDH muta-
has been observed in tumours without otherapy/chemotherapy and longer sur-
tion and 1p/19q codeletion are the defin-
CDKN2A deletions {1069,1993}. Losses vival {344,2615}. A retrospective analysis
ing genetic aberrations of IDH-mutant
of 10q, mutations of the PTEN tumour of 1013 adult patients with anaplastic
and 1p/19q-codeleted anaplastic oligo-
suppressor gene, and amplifications of oligodendroglial tumours found a median
dendroglioma. Promoter mutations in
proto-oncogenes are infrequent in IDH- overall survival of 8.5 years in patients
TERT are also present in the vast ma-
mutant and 1p/19q-codeleted anaplastic with 1p/19q-codeleted tumours, versus
jority of these tumours, as is the case
oligodendrogliomas {666,1083,2246}. 3.7 years in patients with 1p/19q-intact
for IDH-mutant and 1p/19q-codeleted
Epigenetically, these tumours are char- tumours {1436}. Long-term follow-up
low-grade oligodendroglioma {89,1314,
acterized by G-CIMP type A {2464} and data from the Radiation Therapy Oncol-
1408,2464}. Investigation of regionally
often demonstrate a proneural glioblas- ogy Group (RTOG) 9402 and European
or spatially distinct tissue samples from
toma-like expression profile. The MGMT Organisation for Research and Treatment
individual patients has indicated that IDH
promoter is typically hypermethylated of Cancer (EORTC) 26951 trials indicate
mutation, 1p/19q codeletion, and TERT
{1733}. even higher median overall survival times
promoter mutation are early events in
(> 10 years) for patients with IDH-mutant
oligodendroglioma development that are Genetic susceptibility
and 1p/19q-codeleted anaplastic oligo-
shared by neoplastic cells from different See Genetic susceptibility (p. 67) in
dendrogliomas who were treated with
tumour areas as well as between primary Oligodendroglioma, IDH1-mutant and
combined radiotherapy and PCV chemo-
and recurrent tumours {2464}. As in low- 1p/19q-codeleted.
therapy {344,2615}. Patients rarely devel-
grade oligodendroglioma, CIC mutation
Prognosis and predictive factors op cerebrospinal fluid spread or systemic
is frequent in anaplastic oligodendro-
metastases. Local tumour progression is
glioma, whereas FUBP1 mutation occurs Prognosis the most common cause of death.
in fewer cases. Other (less commonly) Recent therapeutic advances have mark-
mutated genes include NOTCH pathway edly improved survival times of patients Predictive factors
genes (in particular, NOTCH1), various with anaplastic oligodendrogliomas. Be- Clinical factors that have been associ-
epigenetic regulator genes (e.g. SETD2)}, fore the introduction of adjuvant treat- ated with longer survival are younger
and PI3K pathway genes (e.g. PIK3CA) ment with combined radiochemotherapy, age at diagnosis, higher Karnofsky per-
{2464}. Mutations in the oligodendroglial reported median survival times ranged formance score, and greater extent of
lineage-associated transcription factor from < 1 year {567} to 3.9 years {2337}. resection {1095,2617,2740}. Previous re-
gene TCF12 have been detected in a A population-based analysis from Swit- section for lower-grade tumour has also
small subset {7.5%) of anaplastic oligo- zerland reported a median survival time been linked to more favourable prognosis
dendrogliomas and are associated with of 3.5 years for patients with anaplastic {2621}. Recursive partitioning analysis of
an aggressive tumour type {1407}. Over- oligodendroglioma, which was markedly various clinical and histological param-
all, the average number of chromosomes shorter than the median of 11.6 years for eters together with the 1p/19q codele-
involved in copy number abnormalities is patients with WHO grade II oligodendro- tion status identified five distinct prog-
higher in anaplastic oligodendrogliomas glioma {1826}. The CBTRUS calculated nostic classes, defined mainly by patient
than in low-grade oligodendrogliomas 5- and 10-year survival rates of 52.2% age, tumour location, and 1p/19q status
{1353,2160}. The CDKN2A and CDKN2B and 39.3%, respectively, for patients with {1884}. A study based on the EORTC
loci on 9p21 are altered in a subset of 26951 trial found a strong prognostic
Grading
Anaplastic oligodendroglioma, NOS,
corresponds histologically to WHO
grade III.
74 Diffuse gliomas
Reifenberger G. Cairncross J.G
Oligoastrocytoma, NOS Collins V.P. Yokoo H.
Hartmann C. Yip S.
Hawkins C. Louis D.N.
Kros J.M.
Definition subjected to molecular testing for IDH with immunohistochemistry for ATRX and
A diffusely infiltrating, slow-growing gli- mutation and 1p/19q codeletion. Tumours R132H-mutant IDH1, followed by testing
oma composed of a conspicuous mix- with combined IDH mutation and 1p/19q for 1p/19q codeletion, and then followed
ture of two distinct neoplastic cell types codeletion are classified as IDH-mutant by IDH sequencing of the tumours that
morphologically resembling tumour cells and 1p/19q-codeleted oligodendroglio- were negative for R132H-mutant IDH1
with either oligodendroglial or astro- ma, irrespective of a mixed or ambiguous {2105}. With this approach, the vast ma-
cytic features, and in which molecular histology. Tumours with IDH mutation but jority of diffuse and anaplastic gliomas
testing could not be completed or was without 1p/19q codeletion are classified can be assigned to one of three major
inconclusive. as IDH-mutant diffuse astrocytoma, also glioma classes: IDH-mutant diffuse as-
In oligoastrocytoma, NOS, tumour cells irrespective of mixed or ambiguous his- trocytomas, IDH-mutant and 1p/19q-
with oligodendroglial or astroglial fea- tology. Immunohistochemical testing for codeleted oligodendrogliomas, or IDH-
tures can be either diffusely intermingled loss of nuclear ATRX expression may also wildtype gliomas (including IDH-wildtype
or separated into distinct, biphasic areas. provide diagnostically helpful informa- glioblastomas). Overall, the diagnosis of
The mixed or ambiguous cellular dif- tion. Loss of ATRX positivity in the tumour oligoastrocytoma, NOS, should therefore
ferentiation precludes histological clas- cell nuclei but retained nuclear expres- remain exceptional (i.e. restricted to dif-
sification as either diffuse astrocytoma, sion in non-neoplastic cells (e.g. vascular fuse gliomas in which histology does not
NOS, or oligodendroglioma, NOS. Oli- endothelia, reactive astrocytes, and acti- allow for unequivocal stratification into ei-
goastrocytoma, NOS, is an exceptional vated microglial cells) supports the diag- ther astrocytic or oligodendroglial lineage
diagnosis, because most diffuse glio- nosis of IDH-mutant diffuse astrocytoma tumours and that cannot be subjected to
mas with mixed or ambiguous histology {2105,2220}. Similarly, strong nuclear appropriate molecular testing or in which
can be classified as either IDH-mutant immunopositivity for p53, typically as a molecular findings are inconclusive).
diffuse astrocytoma or IDH-mutant and consequence of TP53 mutation leading
1p/19q-codeleted oligodendroglioma, to nuclear accumulation of mutant p53 ICD-0 code 9382/3
based on molecular testing. Oligoastro- protein, is often associated with loss of
Grading
cytomas, NOS, usually manifest in adult nuclear ATRX expression and is virtually
Oligoastrocytoma, NOS, corresponds
patients, with preferential localization in mutually exclusive with 1p/19q codeletion
histologically to WHO grade II.
the cerebral hemispheres. {2220}. Recent data support a diagnostic
algorithm for diffuse and anaplastic glio-
Genetic classification of
mas based on stepwise analyses starting
oligoastrocytomas
The WHO classification discourages the
diagnosis of tumours as oligoastrocy-
toma or mixed glioma. Molecular genetic
analyses have clearly shown that the vast
majority of tumours previously classified
as oligoastrocytomas have a genetic pro-
file typical of either diffuse astrocytoma
(i.e. IDH mutation combined with TP53
mutation and ATRX mutation / loss of nu-
clear ATRX expression) or oligodendro-
glioma (i.e. IDH mutation combined with
1p/19q codeletion and TERT promoter
mutation) {349,2220,2464}. The histo-
logical criteria provided in previous WHO
classifications for oligoastrocytic gliomas
left room for considerable interobserver
variability {494,2611}. Thus, diffuse glio-
mas, including those with mixed or am-
biguous histological features, should be
Fig. 1.72 Oligoastrocytoma. Clearly separated tumour areas displaying oligodendroglial (left) and astrocytic (right)
differentiation.
Oligoastrocytoma, NOS 75
initial diagnosis Anaplastic oligoastrocytoma,
NOS
Definition
An oligoastrocytoma, NOS, with focal or
diffuse histological features of anaplasia,
including increased cellularity, nuclear
atypia, pleomorphism, and brisk mitotic
activity.
Anaplastic oligoastrocytoma, NOS, is
an exceptional diagnosis, because most
high-grade gliomas with mixed or am-
biguous histology can be classified as
either IDH-mutant anaplastic astrocyto-
ma or IDH-mutant and 1p/19q-codeleted
anaplastic oligodendroglioma, based on
molecular testing. Moreover, if molecu-
lar testing of an anaplastic glioma with
mixed or ambiguous histology shows an
IDH-wildtype status, IDH-wildtype glio-
blastoma must be considered as a likely
differential diagnosis, because most
IDH-wildtype anaplastic gliomas have
genetic profiles of glioblastoma and are
associated with correspondingly poor
integrated diagnosis
prognosis. Anaplastic oligoastrocyto-
Fig. 1.73 Changes from initial (purely histology-based) to integrated diagnosis in 405 adult patients with supratentorial mas, NOS, usually manifest in adult pa-
glioma. Width of bars indicates relative proportions of the initial tumour groups. A, astrocytoma; OA, oligoastrocytoma; tients, with preferential localization in the
0, oligodendroglioma; GBM, glioblastoma; GBMo, glioblastoma with oligodendroglial component; GBMs, secondary
cerebral hemispheres.
glioblastoma; gcGBM, giant cell glioblastoma; GS, gliosarcoma. Note that all oligoastrocytomas were redistributed
to other diagnoses (IDH-mutant and 1p/19q-codeleted oligodendroglioma, IDH-mutant astrocytoma, IDH-wildtype ICD-0 code 9382/3
astrocytoma, or IDH-wildtype glioblastoma) after molecular marker analysis, including IDH mutation / G-CIMP, ATRX
loss of nuclear expression, 1p/19q codeletion, and 7p gain /10q loss. Reprinted from Reuss DE et al. {2105}. Grading
Anaplastic oligoastrocytoma, NOS,
corresponds histologically to WHO
grade III.
Oligoastrocytoma, genetic alterations, including 1p/19q requires detailed molecular and immuno-
dual-genotype codeletion, in the oligodendroglial and histochemical analyses to unequivocally
Dual-genotype oligoastrocytoma is not astrocytic tumour components of the demonstrate the two genetically distinct
considered to be a distinct entity or vast majority of oligoastrocytomas {1359, tumour cell subpopulations. Care must
variant in the WHO classification. The 2050j. However, a few instances of oli- be taken to avoid misinterpretations (e.g.
designation refers to an IDH-mutant oli- goastrocytoma showing evidence of ge- due to artefactually negative nuclear im-
goastrocytoma of WHO grade II that is netically distinct oligodendroglial and munostaining for ATRX) and false-posi-
composed of a conspicuous mixture of astrocytic cell populations have been tive detection of 1p/19q-codeleted nuclei
astrocytic and oligodendroglial tumour reported {1067,2050,2754}. It can be as- by FISH (e.g. due to incomplete chro-
cell populations demonstrating molecu- sumed that dual-genotype oligoastrocy- mosomal representation in transected
lar evidence of an astrocytic genotype tomas are monoclonal tumours that arise nuclei, aneuploidy/polyploidy, or partial
(i.e. IDH mutation combined with TP53 from an IDH-mutant cell of origin but later hybridization failure) {763}. Overall, dual-
mutation / nuclear p53 accumulation, during tumorigenesis develop cytologi- genotype oligoastrocytoma seems to be
loss of nuclear ATRX expression, and cally distinct subpopulations of tumour very rare, but its true incidence is difficult
lack of 1p/19q codeletion) and an oligo- cells with an astrocytic genotype (i.e. to ascertain because tissue sampling is
dendroglial genotype (i.e. IDH mutation TP53 and ATRX alteration but no 1p/19q rarely comprehensive in diffuse gliomas
combined with 1p/19q codeletion, lack codeletion) or an oligodendroglial geno- and molecular analysis of DNA extracted
of TP53 mutation / nuclear p53 accu- type (i.e. 1p/19q codeletion but no TP53 from a bulk sample may not detect such
mulation, and retained nuclear ATRX ex- or ATRX alteration). Classification of du- molecular heterogeneity.
pression). Studies have revealed shared al-genotype oligoastrocytoma therefore
76 Diffuse gliomas
Genetic classification of anaplastic Anaplastic oligoastrocytoma, (i.e. IDH mutation combined with 1p/19q
oligoastrocytomas dual-genotype codeletion, lack of TP53 mutation / nu-
The WHO classification discourages Dual-genotype anaplastic oligoastrocy- clear p53 accumulation, and retained
the diagnosis of tumours as anaplastic toma is not considered to be a distinct nuclear ATRX expression). To date, only
oligoastrocytoma or anaplastic mixed entity or variant in the WHO classifica- isolated cases of tumours considered to
glioma. Molecular genetic analyses have tion. The designation refers to an IDH- be dual-genotype anaplastic oligoas-
not demonstrated entity-specific genetic mutant anaplastic oligoastrocytoma of trocytoma have been reported {1067,
or epigenetic profiles for these tumours. WHO grade III that demonstrates mo- 2754}. These tumours occurred in the
Instead, large-scale molecular profiling lecular evidence of genetically distinct cerebral hemispheres of adult patients.
studies have shown that the vast major- astrocytic and oligodendroglial tumour Utmost care must be taken to exclude
ity of anaplastic oligoastrocytomas have cell populations characterized by an technical shortcomings that may lead to
genetic alterations and DNA methylation astrocytic genotype (i.e. IDH mutation artefactual regional variation in immu-
profiles typical of either IDH-mutant ana- combined with TP53 mutation / nuclear nohistochemical staining for ATRX or in
plastic astrocytoma (with commonly as- p53 accumulation, loss of nuclear ATRX FISH analysis for 1p/19q codeletion.
sociated TP53 mutation and ATRX muta- expression, and lack of 1p/19q codele-
tion / loss of nuclear ATRX expression) or tion) and an oligodendroglial genotype
IDH-mutant and 1p/19q-codeleted ana-
plastic oligodendrogliomas (with com-
monly associated TERT promoter muta- including those with a mixed or ambigu- astrocytomas, IDH-mutant and 1p/19q-
tions). A third, smaller subset of cases ous histological phenotype, should be codeleted anaplastic oligodendroglio-
correspond to IDH-wildtype anaplastic subjected to thorough molecular test- mas, or IDH-wildtype anaplastic glio-
gliomas, which commonly demonstrate ing, most notably for IDH mutation and mas (most of which are characterized by
hallmark genetic aberrations of glioblas- 1p/19q codeletion. As with oligoastrocy- glioblastoma-associated genetic profiles
toma - in particular, gain of chromosome toma, NOS, immunohistochemical test- and the associated poor prognosis).
7 and loss of chromosome 10 combined ing for loss of nuclear ATRX expression Overall, the diagnosis of anaplastic oli-
with TERT promoter mutation and gene and nuclear accumulation of p53 may goastrocytoma, NOS, should therefore
amplifications (such as EGFR amplifica- provide additional, diagnostically helpful remain exceptional, i.e. restricted to
tion) {349,2464,2731,2751}. The criteria information {2105,2220}. This integrated anaplastic gliomas with astrocytic and
provided in previous WHO classifications approach enables a clear diagnostic oligodendroglial components that cannot
for anaplastic oligoastrocytoma left room stratification of the vast majority of ana- be subjected to appropriate molecular
for considerable interobserver variability plastic gliomas into one of the three testing or in which molecular findings are
{1370,2611}. Thus, anaplastic gliomas, major classes: IDH-mutant anaplastic inconclusive.
Oligoastrocytoma, NOS 77
Collins V.P. Jones D.
Pilocytic astrocytoma Tihan T. Giannini C.
VandenBerg S.R. Rodriguez F.
Burger P.C. Figarella-Branger D.
Hawkins C.
Definition 100 000 population, which declines sub- intraventricular and their site of origin dif-
An astrocytoma classically character- stantially from < 14 years to 15-19 years ficult to define.
ized by a biphasic pattern with variable {1863}. Pilocytic astrocytoma is the most
Clinical features
proportions of compacted bipolar cells common glioma in children, without a
Pilocytic astrocytomas produce focal
with Rosenthal fibres and loose, textured significant sex predilection. It accounts
neurological deficits or non-localizing
multipolar cells with microcysts and oc- for 33.2% of all gliomas in the 0-14 years
signs, such as macrocephaly, head-
casional granular bodies. age group {1862} and 17.6% of all child-
ache, endocrinopathy, and increased
Genetically, pilocytic astrocytomas are hood primary brain tumours {1863}.
intracranial pressure due to mass effect
characterized by the presence of mu- Similarly, in a study of 1195 paediatric tu-
or ventricular obstruction. Seizures are
tations in genes coding for proteins in- mours from a single institution, pilocytic
uncommon because the lesions involve
volved in the MAPK pathway {1176,2855}. astrocytoma was the single most com-
the cerebral cortex infrequently {466,
The most frequent genetic change is tan- mon tumour (accounting for 18% of cas-
725}. Given their slow rate of growth,
dem duplication of 7q34 involving the es overall) in the cerebral compartment
pilocytic tumours’ clinical presentation
BRAF gene resulting in oncogenic BRAF {2174}. In adults, pilocytic astrocytoma
is generally that of a slowly evolving le-
fusion proteins. Pilocytic astrocytomas tends to appear about a decade earlier
sion. Pilocytic astrocytomas of the op-
are the most common glioma in children (mean patient age: 22 years) than does
tic pathways often produce visual loss.
and adolescents, and affect males slight- WHO grade II diffuse astrocytoma {784},
Proptosis may be seen with intraorbital
ly more often than females. They are but relatively few arise in patients aged
examples. Early, radiologically detected
preferentially located in the cerebellum > 50 years.
lesions may not be associated with visual
and cerebral midline structures (i.e. the Localization
symptoms or ophthalmological deficits
optic pathways, hypothalamus, and brain Pilocytic astrocytomas arise throughout
{1054,1515}. Hypothalamic/pituitary dys-
stem) but can be encountered anywhere the neuraxis; however, in the paediat-
function, including obesity and diabetes
along the neuraxis {1533}. They are gen- ric population, more tumours arise in
insipidus, is often apparent in patients
erally circumscribed and slow-growing, the infratentorial region. Preferred sites
with large hypothalamic tumours {2159}.
and may be cystic. Pilocytic astrocytoma include the optic nerve (optic nerve
Some hypothalamic/chiasmatic lesions
largely behaves as is typical of a WHO glioma) {1054}, optic chiasm/hypothala-
in young children have been associated
grade I tumour {1533}, and patients can mus {2159}, thalamus and basal ganglia
with leptomeningeal seeding and a poor
be cured by surgical resection. However, {1622}, cerebral hemispheres {725,1994},
outcome {1934}; see Pilomyxoid astro-
complete resection may not be possible cerebellum (cerebellar astrocytoma)
cytoma (p. 88), a variant of pilocytic as-
in some locations, such as the optic path- {974}, and brain stem (dorsal exophytic
trocytoma. Pilocytic astrocytomas of the
ways and the hypothalamus. Pilocytic brain stem glioma) {311,709,1995}. Pilo-
thalamus generally present with signs of
astrocytomas, particularly those involv- cytic astrocytomas of the spinal cord are
cerebrospinal fluid obstruction or neu-
ing the optic pathways, are a hallmark of less frequent but not uncommon {1677,
rological deficits (such as hemiparesis)
neurofibromatosis type 1 (NF1). 2186}. Large hypothalamic, thalamic, and
due to internal capsule compression.
Pilomyxoid astrocytoma is considered to brain stem lesions may be predominantly
Cerebellar pilocytic astrocytomas usu-
be a variant of pilocytic astrocytoma.
ally present during the first two decades
ICD-0 code 9421/1 of life, with clumsiness, worsening head-
ache, nausea, and vomiting. Brain stem
Grading
examples most often cause hydroceph-
Pilocytic astrocytoma corresponds histo-
alus or signs of brain stem dysfunction.
logically to WHO grade I.
Unlike diffuse astrocytoma of the pons,
Epidemiology which produces symmetrical so-called
Pilocytic astrocytoma accounts for 5.4% pontine hypertrophy, pilocytic tumours of
of all gliomas {1826}. According to a the brain stem are usually dorsal and ex-
2007-2011 statistical report from the Cen- ophytic into the cerebellopontine angle.
tral Brain Tumor Registry of the United Spinal cord examples produce non-spe-
0 10 20 30 40 50 60
States (CBTRUS), pilocytic astrocytoma Age at diagnosis
cific signs of an expanding mass {1678,
is most common during the first two dec- Fig. 2.01 Cumulative age distribution (both sexes) of 2074,2186}.
ades of life, with an average annual age- pilocytic astrocytomas, based on biopsies from 205
Imaging
adjusted incidence rate of 0.84 cases per patients treated at the University Hospital Zurich {1533}.
Most cerebellar and cerebral pilocytic
dergoes craniospinal spread {2555}. slightly hyperintense mural nodule along its lateral margin. B Axial T2-weighted MRI shows hyperintensity of the cyst-
like portion of the mass with lower signal intensity of the mural nodule. C Postcontrast axial T1 -weighted MRI shows
heterogeneous intense enhancement of the mural nodule.
Pilocytic astrocytoma 81
Fig. 2.04 Pilocytic astrocytoma. A Diffuse infiltration of the hippocampus and neighbouring structures. Note the focal formation of cysts. B Large, partially cystic pilocytic astrocytoma
of the cerebellum with a typical mural nodule {882}. C Large pilocytic astrocytoma extending into the basal cisterns.
the elongated cells are less compact but cytological variation, and basic cytologi- peripheral, more infiltrative areas. Cells
separated by mucin. In such cases, indi- cal patterns are often present in combi- closely resembling oligodendrocytes
vidual cell processes can be seen, and nation. Compact portions of the tumour are typically less frequent {480}, but
cell shape varies to include more full- yield bipolar piloid cells; long, hair-like can constitute a dominant component in
bodied and pleomorphic, less obviously processes that often extend across a some cases, particularly in the cerebel-
piloid cells. A distinctive lobular pattern full microscopic field; and Rosenthal fi- lum. These cells strongly express OLIG2
results when leptomeningeal involvement bres. Nuclei are typically elongated and {481}, although other tissue patterns may
induces a desmoplastic reaction. At this cytologically bland. Due to their high express OLIG2 as well. With the cells ar-
site, tissue texture varies but Rosenthal content of refractile eosinophilic fibrils, ranged in sheets or dispersed within pa-
fibres are usually abundant. Rare mi- these cells are strongly immunopositive renchyma, the overall appearance may
toses, hyperchromatic and pleomorphic for GFAP Cells derived from microcystic resemble that of an oligodendroglioma,
nuclei, glomeruloid vascular prolifera- areas have round to oval, cytologically particularly in a limited sample. The find-
tion, infarct-like necrosis, and infiltration bland nuclei; a small cell body; and rela- ing of foci of classic pilocytic astrocytoma
of leptomeninges are compatible with the tively short, cobweb-like processes that usually enables the correct classificatiort
diagnosis of pilocytic astrocytoma and are fibril-poor and only weakly positive of such lesions. Regimented palisades
are not signs of malignancy. for GFAP. This growth pattern may be as- (a so-called spongioblastoma pattern)
Due to the heterogeneity of histological sociated with eosinophilic granular bod- are a striking feature in some pilocytic
features, smear preparations of pilo- ies. Cells indistinguishable from those astrocytomas.
cytic astrocytomas show considerable of diffuse astrocytoma may populate
Fig. 2.05 Typical histological features of pilocytic astrocytoma. A Densely fibrillary areas composed of bipolar cells with long thin processes and rich in Rosenthal fibres as seen on
intraoperative cytological smears and (B) on histological sections. C Eosinophilic granular bodies. Neoplastic cell nuclei are hyperchromatic. A rare mitotic figure is present (arrow).
D Loosely arranged microcystic areas. E Pilocytic astrocytoma is typically a highly vascular tumour and shows both glomeruloid vessels and (F) thick-walled hyalinized vessels. The
vascular changes correlate with the frequent presence of contrast enhancement on imaging.
Although many pilocytic astrocytomas extent, pre-existing neurons are some- a property best seen in smear prepara-
are benign, some show considerable hy- times trapped, and some lesions even tions. Rosenthal fibres are most common
perchromasia and pleomorphism. Rare demonstrate limited cytological atypia. in compact, piloid tissue. They appear
mitoses are present, but brisk mitotic ac- Such lesions should be distinguished bright blue on Luxol fast blue staining.
tivity, in particular diffuse brisk mitotic ac- from ganglion cell tumours. The pilo- Although helpful in diagnosis, their pres-
tivity, characterizes anaplastic change, myxoid variant (see Pilomyxoid astrocy- ence is not obligatory, and they are nei-
which has prognostic implications {2150} toma, p. 88) is characterized by uniform ther specific to pilocytic astrocytoma nor
(see p. 88). In occasional (often cerebel- bipolar cells in a myxoid background indicative of neoplasia. They are often
lar) tumours, a diffuse growth pattern and frequent perivascular arrangements. seen in ganglioglioma and are a com-
overshadows more typical compact Sometimes this pattern is associated mon finding in chronic reactive gliosis.
and microcystic features. In such cases, with more conventional pilocytic regions Densely fibrillar, paucicellular lesions
the presence of hyperchromatic nuclei or so-called intermediate tumours {1168}. containing Rosenthal fibres are as likely
or mitotic figures can cause confusion Although astrocytomas in children are to be reactive gliosis as pilocytic astrocy-
with high-grade diffuse astrocytoma. usually classified as either the pilocytic toma. Ultrastructurally, Rosenthal fibres
Less worrisome are obvious degenera- or the diffuse type, many cases do not lie within astrocytic processes and con-
tive atypia with pleomorphism and nu- in fact fit clearly into either category on sist of amorphous, electron-dense ele-
clear-cytoplasmic pseudoinclusions, the basis of histology alone. Increasingly, ments surrounded by intermediate (glial)
frequently seen in long-standing lesions. molecular profiling plays an ancillary role filaments {588}. Being composed of
Multiple nuclei within large or giant cells in this distinction. In some cases, small alpha-B-crystallin {862}, they lack GFAP
are localized circumferentially (called a biopsy size contributes to difficulties in immunoreactivity except in their fibril-rich
pennies-on-a-plate arrangement) {974}. classification, especially in cases with a periphery.
Hyalinized and glomeruloid vessels are brain stem or spinal location.
Eosinophilic granular bodies
prominent features of some cases. Any
Rosenthal fibres Eosinophilic granular bodies form globu-
necrosis is often infarct-like and non-
These tapered, rounded, or corkscrew- lar aggregates within astrocytic process-
palisading. Perivascular lymphocytes
shaped, brightly eosinophilic, hyaline es. They are brightly eosinophilic in H&E
may also occur. Because pilocytic astro-
masses are intracytoplasmic in location, sections, periodic acid-Schiff-positive,
cytomas overrun normal tissue to some
Fig. 2.07 Biphasic pilocytic astrocytoma. A Cells in fibrillary areas strongly express GFAP. B OLIG2 expression is restricted to pseudo-oiigodendroglial cells.
Pilocytic astrocytoma 83
and immunoreactive for alpha-1-antichy- astrocytomas, it is not surprising that re- Growthpattern
motrypsin and alpha-1-antitrypsin {1236}. gressive features are common. Markedly Typically, pilocytic astrocytomas are
Although eosinophilic granular bodies hyalinized, sometimes ectatic vessels macroscopically somewhat discrete.
may be present in pilocytic astrocytoma, are one such feature. When neoplastic Thus, when the anatomical site permits
they are more frequent in other glial or cells are scant, it can be difficult to distin- (e.g. in the cerebellum or cerebral hemi-
glioneuronal neoplasms, in particular guish these tumours from cavernous an- spheres), many can be removed in toto
ganglion cell tumours and pleomorphic giomas with accompanying piloid gliosis. {725,974,1994}. Microscopically, howev-
xanthoastrocytomas. Evidence of previous haemorrhage (hae- er, many lesions are not well defined with
mosiderin) increases the resemblance. respect to surrounding brain. Lesions
Vasculature
Presentation with acute haemorrhage is typically permeate parenchyma for dis-
Pilocytic astrocytomas are highly vascu-
infrequent. Calcification, infarct-like ne- tances of millimetres to several centime-
lar, as evidenced by their contrast en-
crosis, and lymphocytic infiltrates are tres, often entrapping normal neurons in
hancement {761}. Although generally ob- the process. However, pilocytic tumours
additional regressive changes. Over-
vious in H&E sections, this vascularity is
all, calcification is an infrequent finding, are relatively solid compared with dif-
accentuated on immunostains for mark-
and is only rarely present in optic nerve fuse gliomas, and do not aggressively
ers of basement membrane (e.g. colla-
or hypothalamic/thalamic tumours or in overrun surrounding tissue. This prop-
gen IV and laminin) and endothelial cells
superficially situated cerebral examples. erty, evidenced by at least partial lack of
(e.g. CD31 and CD34). This glomeruloid
Cysts are a common feature of pilocytic axons on Bodian or Bielschowsky silver
vasculature may also line tumoural cyst impregnations, and NFP immunostains,
astrocytoma, especially in the locations
walls and is occasionally seen at some
specified above. Neovascularity often is of diagnostic value. Pilocytic astrocy-
distance from the lesion, but this should
lines cyst walls, resulting in a narrow tomas of the optic nerve and chiasm dif-
not prompt tumour misclassification or
band of intense contrast enhancement fer somewhat in their macroscopic and
overgrading. There may be structural
at the circumference of some cysts. microscopic patterns of growth; they are
and biological differences from similar
Dense piloid tissue with accompanying often less circumscribed and therefore
vessels occurring in glioblastomas, with difficult to delineate either macroscopi-
Rosenthal fibres external to this vascular
the microvasculature of glioblastomas
layer is sometimes seen. When this layer cally or microscopically. They share the
exhibiting a looser, more disorganized ar-
is narrow and well demarcated from the same propensity for leptomeningeal in-
chitecture and differences in expression
surrounding normal tissue, it can be as- volvement as seen in pilocytic tumours
of angiogenesis-related genes {1727}.
sumed to be reactive in nature. In other at other sites, but are somewhat more
Regressive changes instances, the glial zone is more promi- diffuse, especially within the optic nerve.
Given the indolent nature and of- nent, less demarcated, and neoplastic. This is particularly evident when patholo-
ten slow clinical evolution of pilocytic gists attempt to determine the extent of
a lesion by analysis of sequential nerve
Table 2.01 Genetic alterations affecting the MAPK pathway in pilocytic astrocytomas and their diagnostic utility; adapted from Collins VP et al. {482}
% of
Gene Change Diagnostic utility References
tumours
Tandem duplications resulting in KIAA1549-BRAF fusion proteins,
BRAF and Common in pilocytic astrocytomas, particularly cerebellar;
all having the BRAF kinase domain and with the BRAF N-terminal > 70% {1176,1178,2855}
KIAA1549 rare in other tumour forms
regulatory domain replaced by the N-terminal end of KIAA1549
Pilocytic astrocytoma 85
gene {123,575,1961}. This is a tandem
duplication resulting in a transforming fu-
sion gene between KIAA1549 and BRAF
{1178}. The N-terminus of the KIAA1549
protein replaces the N-terminal regula-
tory region of BRAF, retaining the BRAF
kinase domain, which is consequently
uncontrolled and constitutively activates
the MAPK pathway {724,1178,2360}. This
abnormality is found at all anatomical lo-
cations, but is most frequent in cerebel-
lar tumours and somewhat less common
at other sites. The gene fusions involve
nine different combinations of KIAA1549
and BRAF exons, making identification
by RT-PCR or immunochemistry diffi-
cult, resulting in many centres accept-
ing the demonstration of a duplication at
7q34 (usually using FISH probes) as evi-
dence of the KIAA1549-BRAF fusion. In
small numbers of cases, eight additional
gene partners for BRAF fusions have
also been identified (FAM131B, RNF130,
CLCN6, MKRN1, GNA11, QKI, FXR1, and
Fig. 2.09 Pilocytic astrocytoma: the development of the KM 1549-BRAFfusion gene. The upper black box represents
MACF1), with fusions occurring by vari-
7q34. Both KM 1549 and BRAF read towards the centromere (cent.). A fragment of approximately 2 Mb is duplicated
(involving parts of both genes) and inserted at the break point, producing tandem duplication and fusion between the 5'
ous genetic rearrangements (including
end of KIAA1549 and the 3' end of the BRAF gene (which codes for the kinase domain). The fusion gene thus codes deletions and translocations) and all re-
for the BRAF kinase domain together with the N-terminal part of KIAA1549, replacing the BRAF regulatory domain. sulting in loss of the N-terminal regulatory
The red and green dots show the location of FISH probes that can be used to identify the occurrence of the tandem region of the BRAF protein, with retention
duplication, as demonstrated in the lower part of the figure, showing interphase normal and tumour nuclei with the of the kinase domain {1176,2855}.
tandem duplication hybridized with such probes. The two interphase copies of chromosome 7 in the normal nucleus In addition to harbouring BRAF fusion
each show a single red and a single green signal adjacent to each other. In contrast, the tumour cell nuclei show one genes, essentially all pilocytic astrocyto-
pair of normal chromosomal signals, but the other copy of chromosome 7 shows an additional (yellow) signal, due to the
mas studied in sufficient detail have been
fusion of the extra, now adjacent, red and green signals. Reprinted from Collins VP et al. {482}.
shown to have an alteration affecting some
a glioneuronal tumour. NFP typically out- not exclude other substitutions at posi- component of the MAPK pathway {1176,
lines a mainly solid tumour, highlighting tion 132 or mutations of the IDH2 protein. 2855}. These alterations include the well-
normal surrounding axons in compressed Because essentially all pilocytic astrocy- documented NF1 mutations, the hotspot
adjacent CNS parenchyma. Optic nerve tomas have activating genetic alterations BRAF mutation commonly known as the
tumours generally produce a fusiform in components of the MAPK pathway V600E mutation, KRAS mutations, recur-
expansion of the nerve and have axons {1176}, phosphorylated MAPK immu- rent aberrations affecting the FGFR1 and
present among tumour cells, as do oc- nostaining is a consistent feature. Label- the NTRK-family receptor kinase genes,
casional cerebellar examples. Rosenthal ling with immunohistochemical markers and very occasional RAF1 gene fusions
fibres are positive for alpha-B-crystallin, of mTOR pathway activation (e.g. phos- with SRGAP3, which occur in a similar
with GFAP staining limited to their periph- phorylated S6) is more variable {1076}. manner to the BRAF fusions: a tandem
ery. Unlike in diffuse astrocytomas, p53 Immunohistochemistry for V600E-mutant duplication at 3p25, with the fusion pro-
protein staining is weak to absent, which BRAF is positive in a small subset lacking tein lacking the RAF regulatory domain
is consistent with the rarity of TP53 mu- KIAA1549-BRAF fusion and other MAPK but retaining the kinase domain with loss
tations in pilocytic astrocytoma. Immu- pathway alterations. The Ki-67 prolifera- of kinase control. In cases with altera-
nohistochemistry for the R132Fi-mutant tion index is low in most cases of pilocytic tions of the NTRK genes, the alterations
IDH1 protein has been suggested to be astrocytoma, consistent with low prolifer- are also in the form of gene fusions, with
useful for the distinction of pilocytic as- ation rates {826}. Increases in the Ki-67 several different 5' partners that contain
trocytomas from diffuse gliomas, given proliferation index have been associated a dimerization domain. This is presumed
that reactivity is absent in essentially all with more aggressive behaviour in some to lead to constitutive dimerization of the
pilocytic astrocytomas {359}. Flowever, studies but not others {258,2552}. NTRK fusion proteins and activation of
paediatric diffuse astrocytic tumours the kinase {1176,2855}. The changes are
Genetic profile more varied in the case of FGFR1. They
may also lack IDH1 or IDH2 mutations.
The most frequent abnormality in pilocyt- include hotspot point mutations (N546K
In addition, reliable antibodies are cur-
ic astrocytomas overall (found in > 70% of and K656E), FGFR1-TACC1 fusions simi-
rently available for only the most com-
all cases) is an approximately 2 Mb dupli- lar to those seen in adult glioblastoma
mon IDH1 amino acid substitutions at
cation of 7q34, encompassing the BRAF
position 132, so a negative result does {2364}, a novel internal duplication of the
Pilocytic astrocytoma 87
mutated (together with FGFR1) in spo- either recur or progress, eventually lead- a wide spectrum of morphologies and
radic pilocytic astrocytomas {1176}. How- ing to death. However, this is usually after behaved in a more aggressive manner,
ever, the number of pilocytic astrocyto- a prolonged clinical course with multiple with decreased survival, than typical pi-
mas reported in patients with Noonan recurrences {725,974,1678,1996,2159}. locytic astrocytomas. However, despite
syndrome is small {744,1743,2233,2300}. Pilocytic astrocytomas of the optic nerve exhibiting morphological features of
in patients with NF1 {2148} seem to have anaplasia similar to those of diffuse as-
Prognosis and predictive factors
a more indolent behaviour than that of trocytic tumours, they did not behave as
Pilocytic astrocytoma is typically a slow-
their sporadic counterparts {1516}. aggressively. Even so-called high-grade
growing, low-grade tumour with a favour-
Histological malignancy in pilocytic as- pilocytic astrocytoma with anaplastic fea-
able prognosis. Overall survival rates at 5
trocytoma is rare; in one study of clas- tures and necrosis did not behave like a
and 10 years are > 95% after surgical in-
sic pilocytic astrocytoma, the incidence glioblastoma. Pilocytic astrocytomas with
tervention alone {291,325,688,725,1606,
of malignancy occurring spontaneously anaplastic features such as increased mi-
1826}. Stability of WHO grade is typically
was 0.9%, and the incidence of occur- totic count (i.e. > 4 mitoses per 10 high-
maintained for decades {149,325,1878}.
rence after radiation was 1.8% {2565}. power fields) and necrosis behaved, in
The tumours may even spontaneously
Descriptions of anaplastic features in pi- respective studies, more similarly to dif-
regress, although this is rare {897,1894,
locytic astrocytomas come mainly from fuse low-grade or anaplastic astrocyto-
2421}. Very occasional cases progress
isolated case reports and small series mas than to anaplastic astrocytomas or
with more anaplastic features after a vari-
{374,591,1251,2417,2682}, in which ma- glioblastomas {2150}.
able interval, most often after irradiation
lignant histological features correlate less Pilomyxoid astrocytoma (see below), a
or chemotherapy treatment {1957,2145}.
reliably with prognosis than those seen recognized pilocytic astrocytoma vari-
There are few long-term studies docu-
in patients with diffusely infiltrative astro- ant typically occurring in young children,
menting the ultimate outcome of patients
cytomas. Malignant transformation is fre- almost exclusively in the hypothalam-
with pilocytic astrocytoma.
quently reported in association with prior ic / third ventricular region, reportedly
Patient age and extent of resection are
treatment {61,176,307,1296,1364,2303, has a higher frequency of local recur-
key prognostic factors {2431}. Depend-
2312,2420,2565,2603}. A retrospective rence and may undergo cerebrospinal
ing on the location and size of the tumour,
study of 34 pilocytic astrocytomas with fluid seeding {1534,2555}.
pilocytic astrocytoma may not be ame-
spontaneous anaplastic histological fea-
nable to gross total resection and may
tures found that these tumours exhibited
Fig. 2.13 Pilomyxoid astrocytoma. A Monomorphous population of small, often bipolar, cells sitting in a myxoid background. B Diffuse, strong immunoreactivity for GFAP.
Pilomyxoid astrocytoma 89
Lopes M.B.S.
Subependymal giant cell astrocytoma Wiestler O.D.
Stemmer-Rachamimov A.O.
Sharma M.C.
Vinters H.V.
Santosh V.
Definition occur in infants, and several congenital dilated vessels are occasionally seen
A benign, slow-growing tumour com- cases diagnosed either at birth or by an- within the tumours. Like other brain neo-
posed of large ganglionic astrocytes, tenatal MRI have been reported {1070, plasms, SEGAs may show a high ratio
typically arising in the wall of the lateral 1630,1964,2067}. of choline to creatinine and a low ratio
ventricles. of N-acetylaspartate to creatinine on
Localization
Subependymal giant cell astrocytoma proton MR spectroscopy, which seems
SEGAs arise from the lateral walls of the to be a valuable tool for the early detec-
(SEGA) has a strong association with the
lateral ventricles adjacent to the foramen
tuberous sclerosis syndrome (p. 306). tion of neoplastic transformation of sub-
of Monro.
ependymal nodules {1979}. Leptomen-
ICD-0 code 9384/1 ingeal dissemination with drop metasta-
Clinical features
Grading Most patients present either with epilepsy ses has been described {2532}.
SEGA corresponds histologically to WHO or with symptoms of increased intracrani-
Macroscopy
grade I. al pressure. Massive spontaneous haem- SEGAs are typically located in the walls
orrhage has been reported as an acute
Epidemiology of the lateral ventricles over the basal
manifestation {2188}. With the current
ganglia. The tumours are sharply demar-
Incidence practice of early screening of patients
cated multinodular lesions. Cysts of vari-
SEGA is the most common CNS neo- with tuberous sclerosis, many SEGAs are
ous sizes are commonly seen. Areas of
plasm in patients with tuberous scle- diagnosed at an initial stage while still
remote haemorrhage may be seen due
rosis, but it is uncertain whether the tu- clinically asymptomatic {1378,2188}. to the high vascularity of the tumour. Ne-
mour also occurs outside this setting {26, crosis is rare, but focal calcifications are
Imaging
1809,2188}. The incidence rate of SEGA common.
On CT, SEGAs present as solid, partially
among patients with confirmed tuberous
calcified masses located in the walls of
sclerosis is 5-15% {26,1809,2188}, and Microscopy
the lateral ventricles, mostly near the fora-
the tumour is one of the major diagnostic SEGAs are circumscribed, often calci-
men of Monro. Ipsilateral or bilateral ven-
criteria of tuberous sclerosis {1809}. fied tumours. They are composed mainly
tricular enlargement may be apparent. of large, plump cells that resemble gemi-
Age and sex distribution On MRI, the tumours are usually hetero-
stocytic astrocytes and are arranged in
This tumour typically occurs during the geneous, isointense, or slightly hypoin-
sweeping fascicles, sheets, and nests.
first two decades of life and only infre- tense on T1-weighted images, and hy-
Clustering of tumour cells and perivascu-
quently arises de novo after the age of perintense on T2-weighted images, with
lar palisading are common features. The
20-25 years {1809}. However, cases can marked contrast enhancement {1094}.
tumour cells show a wide spectrum of
Prominent signal voids that represent phenotypes. Typical appearances range
Fig. 2.14 Subependymal giant cell astrocytom extending Fig. 2.15 Subependymal giant cell astrocytoma (postcontrast axial T1-weighted MRI). A A right subependymal giant
into the left ventricle and causing hydrocephalus. cell astrocytoma near the foramen of Monro, with avid enhancement. B After 3 months of mTOR inhibitor treatment,
the tumour shows decreased size and enhancement.
Fig. 2.17 Subependymal giant cell astrocytoma. A Cellular heterogeneity is typical for these tumours; elongated cells arranged within sweeping fascicles are admixed with large
cells. B Infiltration of inflammatory cells, including mature lymphocytes and mast cells, is a consistent feature. C Multifocal calcification within the tumour and/or blood vessels is
commonly seen.
progenitor cell of origin with the capacity within the cell and form a complex {486, these two genes is 1:1 {2231}. TSC1 or
to undergo differentiation along glial, neu- 1212,1987}. A mutation of either gene re- TSC2 mutations are identified in about
ronal, and neuroendocrine lines {1526, sults in disrupted function of the tuberin- 85% of patients with tuberous sclerosis.
2334|. This hypothesis is supported by hamartin complex, with similar resulting The remaining 15% of cases may be
data from mouse models in which loss of disease phenotypes. mosaics or have a mutation in an unana-
Tsc1 or activation of the mTOR pathway Approximately 60% of patients with tu- lysed non-coding gene area. Mosaicism
in subventricular zone neural progenitor berous sclerosis have sporadic disease has been reported for TSC1 and TSC2
cells resulted in the formation of SEGA (i.e. with no family history), indicating a mutations in some parents of patients
and subependymal nodule-like lesions high rate of de novo mutations {2229A). with sporadic cases and in patients with
in the lateral ventricles {1566,2862A). In affected kindreds, the disease follows tuberous sclerosis {2229,2646}. Alter-
an autosomal dominant pattern of inherit- natively, there may be a third, unknown
Genetic profile
ance, with high penetrance but consider- locus, although to date there is no evi-
SEGA has a strong association with tu-
able phenotypic variability {2354}. dence to support this possibility {2231}.
berous sclerosis, a genetic disease
In sporadic tuberous sclerosis cases, Patients with tuberous sclerosis with no
caused by inactivating mutations in the
mutations in TSC2are 5 times more com- identified mutations have a milder pheno-
TSC1 gene at 9q or the TSC2 gene at
mon than mutations in TSC1 {51,516, type than do patients with TSC1 or TSC2
16p. The proteins encoded by the TSC
1174}, whereas in families with multiple mutations {2231}.
genes, tuberin and hamartin, interact
members affected, the mutation ratio of Like in other circumscribed astrocytomas,
Fig. 2.19 Subependymal giant cell astrocytoma. A Tumours may express primitive neural markers, including nestin. B Diffuse nuclear expression of the primitive neural marker
SOX2. C The majority of tumour cells are immunoreactive for GFAP. D Class III beta-tubulin (also called TUJ1) is the most ubiquitous neuronal-associated marker in these tumours.
E Focal expression of NFP. F MIB1/Ki-67 immunohistochemistry showing a low proliferation rate.
Definition
An astrocytic glioma with large pleomor-
phic and frequently multinucleated cells,
spindle and lipidized cells, a dense peri-
cellular reticulin network, and numerous
eosinophilic granular bodies.
Pleomorphic xanthoastrocytoma tumour
cells are neoplastic astrocytes, but there
is often neuronal differentiation {828,
1007,1254}. Mitotic activity is low (< 5 mi-
toses per 10 high-power fields). BRAF
V600E mutation is common in pleomor-
phic xanthoastrocytoma, and its pres-
ence in the absence of an IDH mutation
strongly supports the diagnosis. Pleo-
morphic xanthoastrocytoma is rare (con- Fig. 2.21 Pleomorphic xanthoastrocytoma. T1-weighted MRI with contrast enhancement. A,B The neoplasms in the
stituting < 1% of all astrocytic neoplasms) temporal lobe present as superficial nodular enhancing cystic tumours. Note the scalloping of overlying bone (A).
and most commonly affects children and
young adults, with a median patient age
at diagnosis of 22 years {825}. The tu- Epidemiology function is also possible. The rare TP53
mour has a typical superficial location in Pleomorphic xanthoastrocytoma is a rare mutations encountered do not suggest
the cerebral hemispheres, most frequent- brain tumour, accounting for < 1% of all particular carcinogenic insults {824,1238,
ly in the temporal lobe, with involvement primary brain tumours. The 2014 statisti- 1917}.
of the adjacent leptomeninges and with cal report published by the Central Brain
Localization
cyst formation. Despite its alarming his- Tumor Registry of the United States (CB-
A superficial location, involving the lep-
tological appearance, pleomorphic xan- TRUS) lists pleomorphic xanthoastrocy-
tomeninges and cerebrum (meningoce-
thoastrocytoma has a relatively favour- toma among the “unique astrocytoma
rebral) is characteristic of this neoplasm.
able prognosis compared with diffusely variants” and reports an annual inci-
Approximately 98% of cases occur su-
infiltrative astrocytoma, with 70.9% re- dence of 0.3 cases per 100 000 popula-
pratentorially, most commonly in the tem-
currence-free and 90.4% overall survival tion {1863}.
poral lobe {825,1254}. Cases involving
rates at 5 years {1081}. Pleomorphic xanthoastrocytoma typical-
the cerebellum and spinal cord have also
ly develops in children and young adults
ICD-0 code 9424/3 be reported {836,1749}, and two cases of
{825}, with mean and median patient
primary pleomorphic xanthoastrocytoma
ages of 25.9 and 22 years, respectively
Grading of the retina in children have been report-
{1935}, but occurrence in older patients,
Pleomorphic xanthoastrocytoma corre- ed {2847}.
including patients in their seventh and
sponds histologically to WHO grade II.
eighth decades of life, has also been re- Clinical features
ported {1935}. There is no sex bias. One Due to the superficial cerebral location of
study in the USA found these tumours to the lesion, many patients present with a
be more common in the Black population fairly long history of seizures. Cerebellar
{1935}. and spinal cord cases have symptoms
that reflect these sites of involvement.
Etiology
No specific etiologies have been im- Imaging
plicated in the genesis of pleomorphic Pleomorphic xanthoastrocytoma is usu-
xanthoastrocytoma. The occasional ally a supratentorial mass, peripherally lo-
association with cortical dysplasia or cated and frequently cystic, involving cor-
with ganglion cell lesions suggests that tex and overlying leptomeninges. CT and
their formation may be facilitated in MRI scans outline the tumour mass and/
malformative states {1409}. Given re- or its cyst. On CT, tumour appearance
Number of cases Number of cases ports in patients with neurofibromatosis is variable (hypodense, hyperdense, or
Fig. 2.20 Age and sex distribution of patients with
type 1 {2023}, a relation to defective NF1
pleomorphic xanthoastrocytoma.
mixed), with strong, sometimes heteroge- Microscopy also frequent {825}. The third histologi-
neous contrast enhancement {1857}. Tu- The adjective “pleomorphic” refers to the cal hallmark of pleomorphic xanthoas-
mour cysts are hypodense. On MRI, the variable histological appearance of the trocytoma is the presence of reticulin
solid portion of the tumour is either hy- tumour, in which spindled cells are in- fibres, which are best seen using silver
pointense or isointense to grey matter on termingled with mononucleated or multi- impregnation. Reactive changes in the
T1 -weighted images and shows a hyper- nucleated giant astrocytes, the nuclei of meninges are not the only source of re-
intense or mixed signal on T2-weighted which show great variation in size and ticulin fibres; individual tumour cells may
and FLAIR images, whereas the cystic staining. Intranuclear inclusions are fre- be surrounded by basement membranes
component is isointense to cerebrospinal quent {825}, as are prominent nucleoli. that also stain positively for reticulin, and
fluid. Postcontrast enhancement is mod- In some cases, the neoplastic astrocytes these can be recognized ultrastructurally
erate or strong {1857}. Perifocal oedema are closely packed, creating a so-called as pericellular basal laminae. By defini-
is usually not pronounced, due to the epithelioid pattern {1106}. In other cases, tion, the mitotic count is < 5 mitoses per
slow growth of the tumour. sheets of fusiform cells are encountered. 10 high-power fields. Necrosis is rarely
The term “xanthoastrocytoma” refers to present in WHO grade II pleomorphic
Macroscopy
the presence of large, often multinucleat- xanthoastrocytoma in the absence of
Pleomorphic xanthoastrocytomas are
ed xanthomatous cells that have intracel- brisk mitotic activity, but necrosis in itself
usually superficial tumours extending to
lular accumulation of lipids. This is usually is insufficient for a WHO grade III desig-
the leptomeninges. They are frequently
in the form of droplets, which often oc- nation (see Anaplastic pleomorphic xan-
accompanied by a cyst, sometimes thoastrocytoma, p. 98).
cupy much of the cell body, pushing cy-
forming a mural nodule within the cyst
toplasmic organelles and glial filaments
wall. Features such as invasion of the Differential diagnosis
to the periphery. This feature generally
dura {543}, predominantly exophytic Because pleomorphic xanthoastrocyto-
makes the astrocytic character easy to
growth {1688}, multifocality {1629}, and ma often includes a diffusely infiltrating,
recognize by H&E or GFAP stains. Gran-
leptomeningeal dissemination {1905} are non-pleomorphic component, diffuse
ular bodies (either intensely eosinophilic
exceptional. astrocytoma is a common differential
or pale) are a nearly invariable finding
diagnosis. In addition to the presence of
{825}. Focal collections of small lympho-
histologically more typical pleomorphic
cytes, occasionally with plasma cells, are
Pleomorphic xanthoastrocytoma 95
xanthoastrocytoma. The tumours are
predominantly diploid {1047,2701}, occa-
sionally with polyploid populations {1047},
possibly due to subgroups of particularly
bizarre, multinucleated tumour cells.
Comparative genomic hybridization of 50
cases identified loss of chromosome 9 as
the hallmark alteration (present in 50% of
cases) {2713}. Homozygous 9p21.3 de-
letions involving the CDKN2AICDKN2B
Fig. 2.23 Pleomorphic xanthoastrocytoma. A GFAP expression in large pleomorphic and xanthomatous cells. loci were identified in 6 of 10 cases {60%)
B Synaptophysin immunostaining in tumour cells {828}. {2713}. Accordingly, loss of CDKN2A
protein expression was documented by
immunohistochemistry in 61% of pleo-
xanthoastrocytoma components, the expressed in pleomorphic xanthoastro- morphic xanthoastrocytomas {1316}.
combination of BRAF V600E mutation cytoma cells {2083}. BRAF V600E muta- BRAF point mutations occur in approxi-
and absence of an IDH mutation sup- tion, a common alteration in pleomorphic mately 50-78% of cases {584,601,1082,
ports the diagnosis of pleomorphic xanthoastrocytoma, can be detected by 1316,2277,2280}. Most are of the V600E
xanthoastrocytoma. Uncommonly, gan- immunohistochemistry using a specific type, with only a single documented ex-
glioglioma can present with a glial com- antibody {1082,2280}. The immunophe- ception {2280}. However, BRAF V600E
ponent resembling pleomorphic xan- notype with V600E-mutant BRAF expres- mutations are not specific to pleomor-
thoastrocytoma; rare cases of composite sion and loss of CDKN2A expression phic xanthoastrocytoma, and are also
tumours with features of pleomorphic (secondary to homozygous deletion of observed in other primary CNS tumours,
xanthoastrocytoma and ganglioglioma CDKN2A) is frequently observed in pleo- in particular ganglioglioma and pilocytic
in which the two neoplastic compo- morphic xanthoastrocytoma {1316}. astrocytoma {414,599,1297,2277,2280}.
nents coexist side by side with minimal The occurrence of BRAF mutations
intermingling have been reported {1339, Proliferation
seems to be unrelated to the presence of
In most pleomorphic xanthoastrocyto-
1943}. Pleomorphic xanthoastrocytoma histological features of anaplasia.
mas, mitotic figures are rare or absent,
areas showing eosinophilic granular Two studies investigating a total of 7 non-
and the Ki-67 proliferation index is gener-
bodies and spindle-shaped cells may BRAF-mutant pleomorphic xanthoastro-
ally < 1% {825}.
be reminiscent of pilocytic astrocytoma, cytomas identified 1 tumour harbouring
but areas with more typical histology, Cell of origin a TSC2mutation, 1 with an NF1 mutation,
in the absence of BRAF translocations As originally proposed by Kepes, Rubin- and 1 with an ETV6-NTRK3 fusion {184,
or other genetic aberrations leading to stein, and Eng in 1979 {1254}, it has been 2855}. In four series (one published only
MAPK activation, support the diagnosis postulated that pleomorphic xanthoas- in abstract form) with a total of 123 tu-
of pleomorphic xanthoastrocytoma. Mes- trocytoma originates from subpial astro- mours, mutations in the TP53 gene were
enchymal tumours may also enter the dif- cytes. This hypothesis would explain the found in only 7 cases {6%) {824,1238,
ferential diagnosis, but this consideration superficial location of most cases, and 1917}, and were unrelated to the pres-
is usually refuted by positivity for GFAP in is supported by ultrastructural features ence of histological features of anaplasia.
unequivocal tumour (non-reactive) cells, shared between subpial astrocytes and Amplifications of the EGFR, CDK4, and
although GFAP positivity may be focal or the neoplastic cells in pleomorphic xan- MDM2 genes were absent in a series of
even absent in small specimens. thoastrocytoma, in particular the pres- 62 tumours {1238}. No IDH11 mutations
ence of a basal lamina surrounding indi- were detected in a series of 7 tumours
Immunophenotype
vidual cells. However, the expression of (by sequencing) {118} or in a series of
Although the essential nature of pleo-
neuronal markers {828} and CD34 {1316, 60 cases (by immunohistochemistry for
morphic xanthoastrocytoma is clearly
2083} in many pleomorphic xanthoastro- R132H-mutant IDH1) {1081}. These find-
and uniformly glial, with nearly invariable
cytomas, as well as the occasional as- ings molecularly distinguish pleomorphic
immunoreactivity for GFAP and S100
sociation with cortical dysplasia {1271}, xanthoastrocytoma from diffusely infiltrat-
protein {825,828}, the tumours have a
suggests a more complex histogenesis ing cerebral astrocytoma.
significant tendency to exhibit neuronal
and a possible origin from multipotent Although there are few data on the oc-
differentiation. Expression of neuronal
neuroectodermal precursor cells or from currence of BRAFfusions in pleomorphic
markers (including synaptophysin, neu-
a pre-existing hamartomatous lesion. xanthoastrocytoma, there was no evi-
rofilament, class III beta-tubulin, and
dence of 7q34 duplication, which is often
MAP2) has been reported with variable Genetic profile associated with BRAF fusion, in a series
frequency in tumours that have otherwise Complex karyotypes have been docu- of 10 cases analysed by microarray-
typical histological features of pleomor- mented, with gains of chromosomes 3 based comparative genomic hybridiza-
phic xanthoastrocytoma {828,2013}. In and 7 and alterations of the long arm of tion {1961}.
some cases, this biphenotypic glioneu- chromosome 1 {1495,2253,2254}, but
ronal appearance has been confirmed ul- these are not specific to pleomorphic Genetic susceptibility
trastructurally {1007}. CD34 is frequently There are no distinct associations with
Pleomorphic xanthoastrocytoma 97
Giannini C.
Anaplastic pleomorphic Paulus W.
Louis D.N.
xanthoastrocytoma Liberski P.P.
Figarella-Branger D.
Capper D.
are unknown. Although some anaplas- Prognosis and predictive factors survival rate for patients with tumour ne-
tic xanthoastrocytomas may develop A consistent relationship between mitotic crosis was worse than that for those with-
through malignant progression from activity and outcome in pleomorphic xan- out (42.2% vs 90.2%, P = 0.0002). The
WHO grade II pleomorphic xanthoastro- thoastrocytoma has emerged, whereas dataset was insufficient to detect a differ-
cytoma, the sequence of underlying ge-the relationship between necrosis and ence in survival between patients whose
outcome remains unclear {825,1081}.
netic events has not yet been determined. tumours had > 5 mitoses per 10 high-
The frequency of BRAFM600E mutation One study found that a mitotic count of power fields and necrosis (n = 14; 7 pa-
> 5 mitoses per 10 high-power fields (with
is lower in anaplastic pleomorphic xan- tients died and 6 cases recurred) and
thoastrocytoma (9 of 19 cases [47.4%] one high-power field covering 0.23 mm2) those whose tumours had > 5 mitoses
in one study) than in pleomorphic xan-can be used to establish the diagnosis. per 10 high-power fields but no necrosis
thoastrocytoma (30 of 40 cases [75.0%]In that study, significant mitotic activ- (n = 5; 2 patients died and 3 cases re-
ity (defined as > 5 mitoses per 10 high-
in a separate study), and its prognostic curred). Of the 2 patients whose tumours
significance is unknown {1081,2290}. power fields) and/or necrosis was en- had necrosis but not increased mitotic
BRAF V600E mutation status is not sig-countered in 31% of tumours at initial activity, one had no evidence of disease
presentation {1081}. These features were
nificantly different between paediatric after 10 years of follow-up; the other had
and adult cases {1081}. found to be associated with shorter sur- only limited follow-up {1 month), but was
vival [1081}. The 5-year overall survival still alive at that time. Between children
Genetic susceptibility rate for patients whose tumours showed
No distinct associations between ana- > 5 mitoses per 10 high-power fields was and adults, there were no significant
plastic pleomorphic xanthoastrocytoma significantly worse than that for patients differences in 5-year recurrence-free
and hereditary tumour syndromes have whose tumours showed < 5 mitoses per survival (67.9% vs 62.4%, P = 0.39) or
been reported. 5-year overall survival {87.4% vs 76.3%,
10 high-power fields (89.4% vs 55.6%, P = 0.83). The prognostic significance of
P = 0.0005). And the 5-year overall BRAFM600E mutation remains unknown.
Definition
A slow-growing, exophytic, intraventric-
ular glial neoplasm characterized by
clusters of bland to mildly pleomorphic,
mitotically inactive cells embedded in an
abundant fibrillary matrix with frequent
microcystic change.
Subependymomas are often detected in-
cidentally, by neuroimaging or at autopsy,
and have a very favourable prognosis
{1126,1211,1533,2794}. Some tumours
have the admixed histological features of
both subependymoma and ependymoma.
ICD-0 code 9383/1
Grading
Subependymoma corresponds histologi-
cally to WHO grade I.
Epidemiology
The true incidence of subependymoma
is difficult to determine, because these Fig. 3.02 A Subependymoma filling the right lateral ventricle, with displacement of the septum pellucidum to the
tumours frequently remain asymptomatic contralateral hemisphere. The tumour is sharply delineated and only focally attached to the ventricular wall; the
and are often found incidentally at autop- cut surface is greyish-white with some small haemorrhages; note the old cystic infarct in the left corpus caudatum
(arrowhead). B Large subependymoma filling the left ventricle and a smaller one in the right ventricle. C Posterior fossa
sy. In two studies, subependymomas ac- subependymoma in the caudal region of the fourth ventricle. Note the compression of the dorsal medulla (arrowheads).
counted for approximately 8% of ependy- D Third ventricle subependymoma (arrowheads).
mal tumours {1398,2274}, and in one of
the studies, they accounted for 0.51% of
Localization with motor and sensory deficits accord-
all CNS tumours resected at a single in-
Subependymomas are distinguished by ing to the affected anatomical segment.
stitution {1398}.
their intraventricular location, sharp de- Incidental detection of asymptomatic
Subependymomas develop in both sex-
marcation, slow growth, and usually non- subependymomas at autopsy is common
es and in all age groups, but occur most
invasive behaviour. The most frequent {2201}.
frequently in middle-aged and elderly
site is the fourth ventricle (accounting for
patients. The male-to-female ratio is ap- Imaging
50-60% of cases), followed by the lateral
proximately 2.3:1 {2056,2201}. Subependymomas present as sharply
ventricles (accounting for 30-40%). Less
common sites include the third ventricle demarcated nodular masses that are
and septum pellucidum. In rare cases, usually non-enhancing. Calcification and
tumours occur intraparenchymally in the foci of haemorrhage may be apparent.
cerebrum {1279}. In the spinal cord, sub- Intramedullary cases are typically ec-
ependymomas manifest as cervical and centric in location, rather than centrally
cervicothoracic intramedullary or (rarely) positioned as is typical of intraspinal
extramedullary masses {1130,2201}. ependymomas. The lesions are hypoin-
tense to hyperintense on both T1- and T2-
Clinical features weighted MRI, with minimal to moderate
Subependymomas may become clinical- enhancement {2056,2201}.
ly apparent through ventricular obstruc-
tion and increased intracranial pressure. Macroscopy
Spontaneous Intratumoural haemorrhage These tumours present as firm nodules of
has been observed {31,369}. Rare in- various sizes, bulging into the ventricular
traparenchymal tumours exhibit marked lumen. In most cases, the diameter does
Fig. 3.01 Age and sex distribution of subependymoma, oedema and are associated with sei- not exceed 1-2 cm. Intraventricular and
based on 167 cases; data from the Central Brain Tumor
zures {2056}. Spinal tumours manifest spinal subependymomas are generally
Registry of the United States (CBTRUS), 1995-2002.
well demarcated. Large subependymo- Immunophenotype a set of 41-year-old Identical twins {1799},
mas of the fourth ventricle may cause Immunoreactivity for GFAP is usually in a set of 22-year-old identical twins
brain stem compression. Rare cases present, although to various extents, and {464}, and in a brother and sister aged
arising in the cerebellopontine angle immunoreactivity can also be found for 28 and 31 years, respectively {430}. In a
have been described in both adults and neural markers of low specificity, such family with several brain tumours, three
children {1048}. as NCAM1 and neuron-specific enolase siblings developed subependymomas of
{2832}. Unlike in classic ependymomas, the fourth ventricle: two brothers (aged
Microscopy 27 and 57 years) and a sister (aged
EMA is rarely expressed in subependy-
Subependymomas are characterized by 49 years). In addition, a younger sibling
momas. One study of potential therapeu-
clusters of small uniform nuclei embedded (aged 13 years) had a pontine tumour
tic targets reported that TOP2B, MDM2,
in a dense fibrillary matrix of glial cell pro- of undetermined pathology and an el-
nucleolin, HIF1-alpha, and phosphoryl-
cesses with frequent occurrence of small der brother (aged 57 years) developed
ated STAT3 are frequently expressed in
cysts, particularly in lesions originating in a fourth ventricular ependymoma {1032}.
subependymomas {1329}.
the lateral ventricles. Tumour cell nuclei A prenatal, maldevelopmental origin of
appear isomorphic and resemble those of Cell of origin familial subependymomas has been
subependymal glia. In solid tumours, occa- Proposed cells of origin include sub- suggested {464}, but the occurrence in
sional pleomorphic nuclei may be encoun- ependymal glia {101,1716}, astrocytes a family with several brain tumours and
tered; however, nuclear variation is typical of the subependymal plate, ependymal in a father (aged 47 years) and son (aged
in multicystic tumours. Some subependy- cells {2205}, and a mixture of astrocytes 22 years) is more suggestive of a genetic
momas exhibit low-level mitotic activity, and ependymal cells {746,2257}. susceptibility {1032,2209}.
but this is exceptional. Calcifications and
Genetic profile Prognosis and predictive factors
haemorrhage can occur. Prominent tumour
A recent study using DNA methylation Subependymomas have a good progno-
vasculature may rarely be accompanied by
profiles of ependymomas from all age sis {1126}. To date, no recurrences after
microvascular proliferation. Occasionally,
groups and subependymomas from adult gross total resection have been reported
cell processes are oriented around ves-
patients to characterize the full range of {2257}. Complete excision may not be fea-
sels, forming ependymal pseudorosettes.
disease identified nine molecular groups sible for all tumours arising from the floor
In some cases, a subependymoma consti-
of ependymoma across three anatomical of the fourth ventricle; however, debulking
tutes the most superficial aspect of a clas-
sites: the supratentorial compartment, alone usually yields an excellent progno-
sic ependymoma or (more rarely) a tany-
posterior fossa, and spinal compartment sis, given that these tumours grow slowly
cytic ependymoma {1279}; such combined
{1880}. Groups dominated by subepen- and residual tumour may take decades to
tumours are classified as mixed ependymo-
dymomas were found to occur in all three manifest as a symptomatic mass {321}. Al-
ma-subependymoma and are graded on
of these anatomical locations. Posterior though recurrences are generally not ex-
the basis of the ependymoma component
fossa and spinal subependymomas har- pected with subtotally resected tumours
{2201}. In one rare example, the subepen-
boured chromosome 6 copy number al- {2028}, rare cases have been reported,
dymomatous element predominated and
terations, whereas supratentorial tumours and cerebrospinal fluid spread has been
seemed to signify a good overall prognosis
showed virtually none. The supratento- documented as well {2321,2677}. Mitotic
{2201}. Examples of subependymoma with
rial and posterior fossa subependymoma activity is usually low or absent. Scattered
melanin formation {2179}, rhabdomyosarco-
groups showed excellent overall survival. mitoses and cellular pleomorphism are
matous differentiation {2566}, and sarcoma-
tous transformation of vascular stromal ele- Genetic susceptibility of no clinical significance {2020,2201}.
ments {1532} have been reported. Familial occurrence of subependymo- KJ-67/MIE51 immunohistochemical studies
At the ultrastructural level, subependymo- mas is rare, but well documented. All have found proliferation index values of
mas show cells with typical ependymal published cases have been located in < 1%, compatible with the slow growth of
characteristics, including cilium formation the fourth ventricle. Reports have de- this entity, although one study of 2 cases
and microvilli, and sometimes with abun- scribed the simultaneous manifestation indicated that recurrence rate may corre-
dant intermediate filaments {101, 1716, of fourth ventricular subependymomas in late with proliferation index {1354}.
2274}.
Subependymoma 103
McLendon R.
Myxopapillary ependymoma Schiffer D.
Rosenblum M.K.
Wiestler O.D.
may recur repeatedly, as the tumour be- involve the cauda equina, and only rarely
comes entangled with spinal nerves. invade nerve roots or erode sacral bone.
Multifocal tumours have been described exhibiting spinal metastatic dissemina-
ICD-0 code 9394/1 {1748}. Myxopapillary ependymomas can tion at presentation {674,2108}.
occasionally be observed at other loca- Macroscopy
Grading
tions, such as the cervicothoracic spinal Myxopapillary ependymomas are lobu-
Histologically, myxopapillary ependymo-
cord {2396}, the fourth ventricle {1502}, lated, soft, and grey or tan. They are of-
ma corresponds to WHO grade I. How-
the lateral ventricles {2247}, and the brain ten encapsulated. Gelatinous alterations,
ever, this variant may have a more ag-
parenchyma {2698}. Subcutaneous sac- cyst formation, and haemorrhage may be
gressive biological behaviour in children
rococcygeal or presacral myxopapillary apparent.
and a poor outcome after incomplete
ependymomas constitute a distinct sub-
resection. Microscopy
group. They are thought to originate from
Epidemiology ectopic ependymal remnants {1089}. In classic cases, cuboidal to elongated
Myxopapillary variants account for Intrasacral variants can clinically mimic tumour cells are radially arranged in pap-
9-13% of all ependymomas {1398,2274}. chordoma. illary fashion around hyalinized fibrovas-
In the conus medullaris / cauda equina cular cores. Some examples show little
Clinical features or no papillary structuring and consist
region, myxopapillary ependymomas
Myxopapillary ependymomas are typi- largely of confluent, polygonal tumour
are the most common intramedullary
cally associated with back pain, often of cell sheets or fascicles of spindled cells.
neoplasm, with annual incidence rates of
long duration. Alcian blue-positive myxoid material ac-
about 0.08 cases per 100 000 males and
0.05 cases per 100 000 females {1863}. Imaging cumulates between tumour cells and
Myxopapillary ependymomas are typi- blood vessels, also collecting in micro-
cally sharply circumscribed and con- cysts (which help to identify largely solid,
trast-enhancing. Extensive cystic change non-papillary examples). Rounded eo-
and haemorrhage may be seen. sinophilic structures (so-called balloons)
that are periodic acid-Schiff-positive
Spread and exhibit spiculated reticulin staining
In a recent review of 183 patients with are seen in some cases. Mitotic activity
myxopapillary ependymomas, distant and the Ki-67 proliferation index are low
spinal metastases were found in 17 pa- {2019}. Histological features of anaplasia
tients {9.3%) and brain metastases in are most exceptional {98}.
11 {6.0%). Factors associated with dis- Ultrastructurally, the cells do not show
tant treatment failure included young polarity, but do show adherens junctions
age, lack of initial adjuvant radiotherapy, with cytoplasmic thickening and wide
Number of cases Number of cases
and incomplete excision {2711}. Paedi- spaces containing amorphous material
Fig. 3.04 Age and sex distribution of myxopapillary atric patients are particularly prone to or loose filaments {2076,2402}. Extracel-
ependymoma, based on 311 cases; data from the Central lular spaces, delineated by cells with
Brain Tumor Registry of the United States (CBTRUS), basal membranes, contain projected
1995-2002.
villi {2076}. Few cilia, complex interdigi- myxopapillary ependymomas, whereas survival rate of 98.4% after total or par-
tations, and abundant basement mem- labelling for CAM5.2, CK5/6, CK7, CK20, tial resection {2770}. Late recurrence
brane structures have been described or 34betaE12 has been reported as ab- and distant metastases can occur after
{2019}, with the distinctive feature of sent or exceptional in this setting {1427, incomplete resections in both adults and
some examples being aggregations of 2641}. children {35,674}. Children have had a
microtubules within endoplasmic reticu- less predictable outcome in some stud-
lum complexes {1018,1019}. The pres- Genetic profile ies, even with apparent gross total resec-
ence of adherens junctions and intra- A recent study using DNA methylation tion {2216,2426}. In a series of 183 cases,
cytoplasmic lumina with microvilli was profiles to characterize the full range of treatment failure occurred in approxi-
recently confirmed {2686}. disease identified nine molecular groups mately one third of the patients. Recur-
of ependymoma across three anatomical rence was mainly local and was more fre-
Immunophenotype quent in younger patients and those not
sites: the supratentorial compartment,
Diffuse immunoreactivity for GFAP dis- posterior fossa, and spinal compartment treated initially with adjuvant radiotherapy
tinguishes myxopapillary ependymomas {1388,2711}. Gross total resection plays
{1880}. Myxopapillary ependymomas
from metastatic carcinomas, chordomas, an important role in improving outcome,
were found in one molecular group from
myxoid chondrosarcomas, paraganglio- and adjuvant radiotherapy improves pro-
the spinal compartment. They were char-
mas, and schwannomas {1427,2641}. gression-free survival {1389,2578}.
acterized by polyploidy (in particular
Labelling for S100 or vimentin is also Although age seems to be the strongest
gains across multiple chromosomes) and
typical, and reactivity for CD99 and an excellent outcome. predictor of recurrence, expression of
NCAM1 is frequently seen {1427}. Im- EGFR has also been cited as a potential
munoreactivity for the AE1/AE3 cytoker- Prognosis and predictive factors biomarker of recurrence {2647}.
atin cocktail is a common feature of Prognosis is favourable, with a 5-year
Definition anaplastic ependymoma are consid- 0-14 years) to 4.5% (at 15-19 years) to
A circumscribed glioma composed of ered to correspond histologically to WHO 4.0% (at 20-34 years) {1863}. In children
uniform small cells with round nuclei in grades II and III, respectively. However, aged < 3 years, as many as 30% of all
a fibrillary matrix and characterized by no association between grade and bio- CNS tumours are ependymomas. In Can-
perivascular anucleate zones (pseu- logical behaviour or survival has been ada, a mean annual incidence of 4.6 cas-
dorosettes) with ependymal rosettes also definitively established {248,633,703}. es per 100 000 population was estimated
found in about one quarter of cases. Of the various studies of prognostic for ependymomas in infants {2046}. In
Classic ependymoma generally has a variables and outcome in ependymoma, the USA, ependymoma is more common
low cell density and a low mitotic count. those that have not found an association in Whites than in African-Americans, with
It very rarely invades adjacent CNS pa- between grade (II vs III) and progression- an incidence rate ratio of 1.67:1. No such
renchyma to any significant extent. Cilia free or overall survival outnumber those difference is found between Hispanic
and microvilli are seen on ultrastructural that have. The published ratios of grade II and non-Hispanic populations {1863}.
examination. to grade III tumours in series of ependy- In the spinal cord, ependymomas are
Classic ependymomas are mainly in- momas vary widely, from 17:1 to 1:7, and the most common neuroepithelial neo-
tracranial tumours; they do occur in the the explanation for such inconsistent data plasms, accounting for 50-60% of all
spinal cord, but the myxopapillary vari- is multifactorial {633,856,2557}. The inter- spinal gliomas in adults {2653}, but they
ant is more common at this site. Classic pretation of most histopathological varia- are rare in children {164}.
ependymomas occur in both adults and bles used in this classification for grading
Age and sex distribution
children, although most posterior fossa purposes is subjective, and ependymo-
tumours present in childhood. Ependy- mas are morphologically heterogeneous. Ependymomas can develop in patients
momas have a variable clinical outcome, For example, the significance of grading of any age, with reported patient ages
which is primarily dependent on extent of on the basis of focal microvascular prolif- ranging from birth to 81 years [http://
surgical resection, the use of irradiation eration or focally increased mitotic counts www.cbtrus.org]. However, incidence is
as an adjuvant therapy, and molecular within large areas of bland architectural greatly dependent on histological variant,
group {857,1880}. and cytological features is difficult to molecular group, and location. Posterior
Three distinct histopathological pheno- determine. There have been few studies fossa ependymomas are most common
types, which are classified as ependymo- of the prognostic significance of WHO among children, with a mean patient
ma variants (although without particular grade or individual pathological features age at presentation of 6.4 years {2295},
clinicopathological significance) can be across large trial cohorts in which proper and spinal tumours dominate a second
a prominent component of both classic multivariate analyses of prognostic vari- age peak at 30-40 years. Supratentorial
and anaplastic ependymoma: papillary ables can be performed, and there have ependymomas affect paediatric as well
ependymoma, clear cell ependymoma, been only three studies in which evalua- as adult patients. The overall male-to-
and tanycytic ependymoma. tion of histological variables was defined female ratio is 1.77:1, but this ratio varies
stringently and undertaken by several significantly across different anatomical
ICD-0 code 9391/3 observers {633,856,2557}. Due to these sites and molecular groups {1171,1880,
limiting factors, grading is almost never 2046}. In the USA, classic and anaplastic
Grading
used for therapeutic stratification of pa- ependymoma have an approximate com-
Traditionally, classic ependymoma and
tients with ependymoma. Given that spe- bined annual incidence of 0.29 cases in
cific genetic alterations and molecular males and 0.22 in females.
groups have recently been proposed as
prognostic or predictive factors for these Localization
tumours {1560,1880,2767}, the practice Ependymomas may occur along the
of histologically grading ependymoma ventricular system or spinal canal, in
may soon become obsolete altogether. the cerebral hemispheres, or at extra-
CNS sites. Overall, 60% of the tumours
Epidemiology develop in the posterior fossa, 30% in
the supratentorial compartment, and
Incidence 10% in the spinal canal [http://seer.
In the USA, ependymomas account for cancer.gov/archive/csr/1975_2004].
6.8% of all neuroepithelial neoplasms. The In adult patients, infratentorial and spi-
Age at diagnosis
incidence rate decreases with increasing nal ependymomas occur with almost
Fig. 3.07 Cumulative age distribution (both sexes) of
patient age at diagnosis, from 5.6% (at equal frequency, whereas infratentorial
ependymoma, based on 298 cases {2274}.
Ependymoma 107
Fig. 3.10 Ependymoma. A Ependymal rosettes are characterized by columnar tumour cells arranged around a central lumen; they are infrequent, but a diagnostic hallmark of
ependymoma {1291}. B Ependymal canals. C High tumour-cell density and perivascular pseudorosettes. D This ependymoma shows extensive hyalinization, which may precede
calcification {1291}.
ependymoma, but palisading necrosis located at the luminal surface, junctional other gliomas {1101,1865,2031}. Focal cy-
and microvascular proliferation are only complexes at the lateral surface, and tokeratin immunoreactivity can be seen in
focal features in this tumour, with its lack of a basement membrane at the some cases {2641}. Rarely, ependymo-
bland cytology and low mitotic count. internal surface. The cells may form mi- mas can express neuronal antigens {72,
The interface between tumour and CNS crorosettes into which microvilli and cilia 2036,2154}. L1CAM expression is evident
parenchyma is typically well demarcated, project. Junctional complexes (zonulae in supratentorial ependymomas with a
although evidence of brain tissue infiltra- adherentes) irregularly linked by zonu- C11orf95 rearrangement {1891}.
tion may occasionally be encountered. lae occludentes or gap junctions, as well
Cell of origin
Three distinct histopathological pheno- as cell processes filled with intermedi-
Stem cells isolated from ependymomas
types, which are classified as ependymo- ate filaments, may also be encountered
have a radial glia phenotype, suggesting
ma variants (although without particular {858}. A basal lamina may be present at
that radial glia cells are the histogenetic
clinicopathological significance) can be the interface between tumour cells and
source of these tumours {2526}. Further
a prominent component of both classic vascularized stroma.
research has implicated distinct groups
and anaplastic ependymoma: papillary
Immunophenotype of stem cells that are specific to anatomi-
ependymoma, clear cell ependymoma,
Immunoreactivity for GFAP is usually ob- cal site; cerebral neural stem cells and
and tanycytic ependymoma.
served in pseudorosettes, but is more adult spinal neural stem cells are poten-
Rare ependymomas have been reported
variable in other elements of the tumour, tial cells of origin for cerebral and spinal
with lipomatous metaplasia, widespread
such as rosettes and papillae. Ependy- ependymomas, respectively, and these
pleomorphic giant cells, extensive tu-
momas typically express S100 protein origins would explain the predominant
mour cell vacuolation, melanotic differen-
and vimentin {1285}. EMA Immunoreac- locations of these tumours in the differ-
tiation, signet ring cells, and neuropil-like
tivity can be found in most ependymo- ent age groups {1171,1891}. The impor-
islands.
mas, with expression along the luminal tance of anatomical site in ependymoma
Ultrastructure surface of some ependymal rosettes or biology is demonstrated by the molecu-
Ependymomas retain the characteristic manifesting as dot-like perinuclear or lar groups of the disease as defined by
ultrastructural properties of ependymal ring-like cytoplasmic structures {1241}. methylome profiling, which is considered
cells, such as cilia with a 9 + 2 microtubu- OLIG2 expression is characteristically to reflect histogenesis {1880}.
lar pattern, blepharoblasts and microvilli sparse in ependymomas compared with
Genetic profile ependymomas {1891}, characterize the a standardized incidence ratio of 3.70
Molecular alterations are very common in other two supratentorial groups: ST-EPN- {1722,2570}. However, ependymomas
ependymoma and comprise cytogenetic, RELA and ST-EPN-VAP1. The other two do not demonstrate mutations in ARC
genetic, epigenetic, and transcriptomic posterior fossa groups (PF-EPN-A and {1849}. In a Japanese family, two of four
changes. Ependymomas display a broad PF-EPN-B) match those previously called siblings developed a cervical spinal cord
range of cytogenetic aberrations, most group A and group B in some molecu- ependymoma and one had a schwan-
commonly gains of chromosomes 1q, 5, lar studies {1026,1560,2696,2767}. The noma. Neurofibromatosis type 2 was
7, 9, 11, 18, and 20 and losses of chro- final two molecular groups for the spinal excluded, and genetic analysis revealed
mosomes 1 p, 3, 6q, 6, 9p, 13q, 17, and cord (including the cauda equina) con- a common allelic loss at 22q11.2-qter in
22 {1267,1351}. Supratentorial tumours tain myxopapillary ependymomas and two of the affected siblings. The authors
preferentially show loss of chromosome classic ependymomas, respectively, who studied this family suggested the ex-
9 {372,888,1159,1171,2767,2860}; in par- and are termed SP-MPE and SP-EPN. istence of a tumour suppressor gene on
ticular, homozygous deletion of CDKN2A In infants and young children, posterior chromosome 22 related to the genesis of
has been recurrently demonstrated in su- fossa ependymomas mainly fall into the familial ependymomas {2827}.
pratentorial ependymomas {1639,2008, PF-EPN-A group, whereas PF-EPN-B
Prognosis and predictive factors
2526}. Gain of chromosome 1q has been tumours occur mainly in adolescents
The identification of clinicopathological
reported as a reproducible prognostic and adults. Copy number alterations,
variables of prognostic value in ependy-
marker in several trial cohorts, being as- particularly gains and losses of whole
momas is an important but challenging
sociated with poor outcome in posterior chromosomes and chromosome arms,
issue {2275}. In particular, the clinical util-
fossa tumours {1266,1351,2767}. Mono- characterize PF-EPN-B ependymomas,
ity of individual histopathological features
somy 22 and deletions or translocations whereas PF-EPN-A ependymomas show
or tumour grade remains highly contro-
of chromosome 22q are particularly com- few copy number alterations. Two molec-
versial {633,776}. Gain of chromosome
mon in spinal cord tumours and tumours ular groups, ST-EPN-RELA and PF-EPN-
1q has been reported to be a potential
associated with neurofibromatosis type 2 A, are associated with a particularly poor
outcome indicator among tested molecu-
{936}. The NF2 gene is involved in epen- prognosis {1880,2696,2767}.
lar markers {372,857,1266,1351,1639},
dymoma tumorigenesis, and NF2 muta- Posterior fossa ependymomas have a
and outcome correlates of molecular
tions occur frequently in spinal ependy- very low mutation rate and lack recurrent
groups may prove significant in the future
momas {207,621}. somatic mutations on analysis by whole-
{1560,1880,2696,2767}.
Using DNA methylation profiling, several genome sequencing methods {1560,
studies have provided support for the 1891}. Supratentorial ependymomas are Patient age and extent of resection
existence of distinct molecular groups characterized by a recurrent structural Children with ependymoma fare worse
among ependymomas {1049,1424,1560, variant, the C11orf95-RELA fusion gene, than adults. This difference may reflect
1880}. These groups show strong re- which is a by-product of chromothrip- the more frequent occurrence of paediat-
lationships to certain anatomical sites sis and occurs in 70% of paediatric su- ric tumours in the posterior fossa versus
(see Table 3.01, p. 110). In a large cohort pratentorial ependymomas. the predominantly spinal location for adult
(containing > 500 tumours), three groups tumours. Children aged < 1 year have a
Genetic susceptibility
were identified in each of the three CNS 5-year overall survival rate of 42.4% {791}.
Spinal ependymomas occur in neurofi-
compartments (i.e. supratentorial, poste- With increasing age, the 5-year overall
bromatosis type 2, indicating a role of the
rior fossa, and spinal) {1880}. Tumours survival rate improves, to 55.3% among
NF2 gene in these neoplasms. Other he-
with a subependymomatous morphology 1-4-year-olds, 74.7% among 5-9-year-
reditary forms of ependymoma are rarely
were classified into separate spinal, pos- olds, and 76.2% among 10-14-year-olds.
observed {309}. Two patients with Tur-
terior fossa, and supratentorial groups, Extent of surgical resection is consistent-
cot syndrome and ependymomas have
called SP-SE, PF-SE, and ST-SE, re- ly reported to be a reliable indicator of
been reported, and parental colon can-
spectively. Fusion genes involving either outcome; gross total resection is associ-
cer is associated with an increased risk
RELA or YAP1, as previously described ated with significantly improved survival
of ependymomas among offspring, with
for a large proportion of supratentorial
Ependymoma 109
Table 3.01 Key characteristics of the nine molecular groups of ependymoma; based on data from a single study {1880}
{238,1604,1644}. In the Children's Oncol- occur. Metastatic disease is associated and grade III ependymomas is so unreli-
ogy Group (COG) ACNS0121 trial, re- with a poor prognosis. able {633}.
section was an independent risk factor,
irrespective of pathological grade {776}. Histopathology Molecular groups
In another study, which included children One major and unresolved issue con- A molecular classification of the disease
aged < 3 years at presentation, a better cerns the accurate definition of anapla- will likely supersede attempts to use
5-year survival rate was achieved after sia, because an inconsistent relationship histopathological variables in the strati-
complete resection {43%) than after in- between pathological variables and out- fication of patients for adjuvant therapy.
complete resection {36%) {2046}. come has emerged over several dec- Nine molecular groups of ependymoma
ades of study {650,704,857,1643,2178, have recently been identified, three from
Tumour location 2778}. Of the features usually associated each principal anatomical compartment
Tumour site has been identified as an with anaplastic change in gliomas, only across the neuraxis {1880}. There is a
important prognostic factor. Supratento- mitotic index, several other indices of strong association between two of these
rial ependymomas are associated with proliferation, and foci of poorly differenti- groups, ST-EPN-RELA and PF-EPN-A,
better survival rates than are posterior ated tumour cells seem to be consistently and a poor outcome (Table 3.01).
fossa neoplasms, especially in children associated with survival in ependymoma,
{649,2060}. Spinal ependymomas have and not in all studies {857,1345,1398,
a significantly better outcome than do 2275,2557}. As a result, very few clini-
intracranial tumours, although late re- cal trials use grade to stratify therapy,
currences (> 5 years after surgery) can because the distinction between grade II
Fig. 3.12 Papillary ependymoma. A Discohesive growth, pseudopapillae, and perivascular pseudorosettes. B Finger-like projections lined by single or multiple layers of cuboidal
tumour cells with smooth contiguous surfaces. C This ependymoma variant is characterized by well-formed papillae in which a central vessel is covered by layers of tumour cells.
The differential diagnosis includes choroid plexus papilloma, the rare papillary meningioma, and metastatic carcinoma.
Ependymoma 111
Ellison D.W.
Ependymoma, RELA fusion-positive Korshunov A.
Witt H.
grade III. No grade I ependymoma has The C11orf95-RELA fusion is the most intact RELA gene, but probe separation (red/green)
been recorded as containing this genetic common structural variant found in occurs with rearrangement of the RELA gene.
Definition
A circumscribed glioma composed of
uniform small cells with round nuclei in
a fibrillary matrix and characterized by
perivascular anucleate zones (pseudoro-
settes), ependymal rosettes in about one
quarter of cases, a high nuclear-to-cyto-
plasmic ratio, and a high mitotic count.
A diagnosis of anaplastic ependymo-
ma can be confidently made when an
ependymal tumour shows a high cell
Fig. 3.17 Sagittal, gadolinium-enhanced, T1-weighted Fig. 3.18 Anaplastic ependymoma of the lateral ventricle
density and elevated mitotic count along-
MRI of an anaplastic ependymoma of the fourth ventricle. in a 4-year-old boy, with extensive involvement of the
side widespread microvascular prolif- right frontal lobe.
eration and necrosis. Like the classic
tumour, anaplastic ependymoma rarely In a recent study that will likely serve as and biological behaviour or survival has
invades adjacent CNS parenchyma to the basis for the future molecular classifi- been definitively established {248,633,
any significant extent. Cilia and microvilli cation of the disease {1880}, nine groups 703}. Of the various studies of prognostic
are seen on ultrastructural examination. of ependymoma were described (three variables and outcome in ependymoma,
Anaplastic ependymomas are mainly for each of the three major CNS ana- those that did not find an association be-
intracranial tumours; they are rare in the tomical compartments: the supratentorial tween grade (II vs III) and progression-
spinal cord. Anaplastic ependymomas compartment, posterior fossa, and spinal free or overall survival outnumber those
occur in both adults and children, al- compartment). The modal patient age at that did. The published ratios of grade II
though most posterior fossa tumours presentation, clinical outcome, and fre- to grade III tumours in series of ependy-
present in childhood. Clear cell, papil- quencies of histopathological variants momas vary widely, from 17:1 to 1:7, and
lary, or tanycytic morphology can be a and genetic alterations vary across these the explanation for such inconsistent
feature of both classic and anaplastic groups (see Table 3.01, p. 110). data is multifactorial {633,856,2557}.
ependymomas. Anaplastic ependymo- The interpretation of most histopathologi-
mas have a variable clinical outcome, ICD-0 code 9392/3 cal variables used in this classification
which is primarily dependent on extent of Grading for grading purposes is subjective, and
surgical resection and molecular group Traditionally, classic ependymoma and ependymomas are morphologically het-
{857,1880}. erogeneous. There have been few stud-
anaplastic ependymoma are consid-
In defining molecular groups of epen- ies of the prognostic significance of WHO
ered to correspond histologically to
dymoma, transcriptome or methylome WHO grades II and III, respectively. grade or individual pathological features
profiling has established the relevance of However, no association between grade in large trial cohorts in which proper mul-
anatomical site to ependymoma biology. tivariate analyses of prognostic variables
Fig. 3.19 Anaplastic ependymoma. A Poorly differentiated tumour cells with brisk mitotic activity. B Large foci of necrosis.
microvilli, hemidesmosomes, and basal and the intensity of immunostaining vary are consistently negative {2089}. The
lamina. Some have also been suggested depending on the antibody clone used proliferative potential of Chordoid gliomas
to contain secretory granules {389}. {196}. Staining for vimentin and CD34 corresponds to that of other low-grade
is also strong, whereas immunoreactiv- gliomas. The Ki-67 proliferation index is
Immunophenotype
ity for S100 protein, EMA, and cytokera- low, with values of 0-1.5% in one study
The most distinctive immunohistochemi-
tin is variable. Epidermal growth factor {272} and < 5% in other reports {2089}.
cal feature of Chordoid gliomas is their
receptors and merlin are expressed, R132H-mutant IDH1 immunostaining is
strong, diffuse reactivity for GFAP {272,
whereas nuclear accumulation of p53 is negative {196}.
2235}. These tumours consistently ex-
weak or absent. Neuronal and neuroen- Immunohistochemistry can be useful in
press TTF1 in most nuclei, although the
docrine markers (e.g. synaptophysin, the differential diagnosis of Chordoid gli-
percentage of immunoreactive nuclei
neurofilaments, and chromogranin-A) oma versus other Chordoid neoplasms.
Definition
An epilepsy-associated, stable or
slow-growing cerebral tumour primarily
affecting children and young adults; his-
tologically characterized by an angiocen-
tric pattern of growth, monomorphous
bipolar cells, and features of ependymal
differentiation.
Angiocentric glioma (also called mono-
morphous angiocentric glioma {2691}
and angiocentric neuroepithelial tumour Fig. 4.05 Angiocentric glioma. A T2-weighted, fluid-suppressed MRI demonstrates the neoplasm as a well-defined
{1467}) has an uncertain relationship to hyperintense mass in close proximity to the cingulate gyrus of the right frontal lobe. Note the lesion's primarily cortical
other neoplasms exhibiting ependymal localization. B The bright lesion with little mass effect is based largely in the amygdala.
differentiation. Examples with this pattern
have been reported as cortical ependy- involve children. Males and females are Spread
moma {1465}. Tumours harbouring both affected equally frequently. Angiocentric glioma has an infiltrative
angiocentric glioma and ependymoma Localization appearance, locally trapping neurons
patterns have also been reported {2623}. A superficial, cerebrocortical location is and other pre-existing parenchymal ele-
The relationship between angiocentric typical. ments. Extensions along parenchymal
glioma and classic ependymoma thus vessels and the subpial zone are com-
Clinical features mon {2691}.
remains to be defined.
Angiocentric gliomas are epilepto-
ICD-0 code 9431/1 genic lesions, with chronic and intrac- Macroscopy
table partial epilepsy being particularly Gross features have not been detailed.
Grading
characteristic. One temporal lobe example was de-
Angiocentric glioma corresponds histo-
scribed at surgery as producing hip-
logically to WHO grade I. Imaging
pocampal enlargement with darkening
On MRI, the superficial, if not cortically and induration of the amygdala. The grey
Synonym
based, lesion is well circumscribed, bright
Angiocentric neuroepithelial tumour (not matter-white matter boundary may be
on FLAIR images, and non-contrast-en-
recommended) blurred.
hancing. A cortical band of T1 -hyperinten-
Epidemiology sity is present in some cases. A stalk-like Microscopy
Incidence figures are not yet available extension to the subjacent lateral ventricle A unifying feature is the structure of re-
for this uncommon lesion. Most cases is another variable feature {1337}. markably monomorphic, bipolar spin-
died cells oriented around cortical blood
Fig. 4.06 Angiocentric glioma. A Elongated tumour cells forming occasionally perivascular pseudorosettes. B Perivascular rosettes.
Definition terized by the presence of focal or multi- was involved in 144 cases {81%) and the
A rare glial neoplasm composed of cells focal regions of high cellularity, anaplas- infratentorial in 33 cases {19%). The spi-
that are positive for GFAP and have tic nuclear features, increased mitotic nal cord is only rarely involved.
broad, non- or slightly tapering process- activity (> 5 mitoses per 10 high-power
Imaging
es radiating towards central blood ves- fields), microvascular proliferation, and
On CT and MRI, astroblastomas present
sels (astroblastic pseudorosettes) that necrosis with palisading. In most cases,
as well-demarcated, non-calcified, nod-
often demonstrate sclerosis. these high-grade features are found fo-
ular or lobulated masses with frequent
Astroblastoma mainly affects children, cally in the setting of a classic, better-
cystic change and conspicuous contrast
adolescents, and young adults, and oc- differentiated astroblastoma. The Ki-67
enhancement {2318}.
curs nearly exclusively in the cerebral proliferation index in these malignant as-
hemispheres. Neoplasms exhibiting troblastomas is typically > 10%. Macroscopy
foci of astroblastoma-type perivascular Astroblastoma is greyish pink or tan, and
Epidemiology
structuring but having components of its consistency depends on the extent of
These are unusual tumours, and uniform
otherwise conventional astrocytoma or associated collagen deposition. Foci of
diagnostic criteria have not been applied;
ependymoma should not be given this necrosis or haemorrhage do not neces-
therefore, definitive epidemiological data
designation. sarily indicate anaplasia.
are not available. However, astroblasto-
ICD-0 code 9430/3 mas seem to be most frequent in chil- Microscopy
dren, adolescents, and young adults. The Intermediate filament-laden cell pro-
Grading tumours may show a predominance in fe- cesses that form parallel or radial ar-
The biological behaviour of astroblas- males {2204}. One report on 116 cases rays terminating on vascular basement
toma varies. In the absence of sufficient from the published literature suggested a membranes, forming astroblastic pseu-
clinicopathological data, it would be pre- substantial {70%) female predominance dorosettes, are commonly observed
mature to establish WHO grade(s) at this {2447}, which is consistent with prior {1066}. These structures are composed
time. However, the literature has catego- conclusions {236,2539}; however, an- of elongated tumour cells containing
rized these tumours as either well differ- other study, which compiled 239 cases abundant eosinophilic cytoplasm, with a
entiated or malignant (anaplastic). In one from SEER data, found an approximately single, prominent process extending to
series, well-differentiated tumours had equal distribution among males and fe- a central blood vessel. Cross-sections
low mitotic activity {1 mitosis per 10 high- males {28}. of pseudorosettes have a radiating ap-
power fields) and an average Ki-67 pro- pearance, whereas longitudinal sections
Localization
liferation index of 3% {267}. Regional appear ribbon-like. The presence of so-
Astroblastomas typically involve the
(infarct-like) necrosis has been noted in called stout processes, which extend to
cerebral hemispheres {28,1066,2204,
30% of these tumours. Neither vascular central vessels, is critical to the defini-
2447}. Among 177 intracranial cases
proliferation nor spontaneous necrosis tion of astroblastoma. These distinctive
in the SEER data for which the site was
with palisading has been seen. broad or columnar cellular processes are
known, the supratentorial compartment
Malignant astroblastomas are charac-
Fig. 4.08 Astroblastoma. A Cells oriented to central vessels. B Pseudorosettes with sclerosis may take a papillary form.
Astroblastoma 121
accepted. Bailey and Cushing thought
these tumours arose from embryonic
cells programmed to become astrocytes
{109}. The presence of intermediate fila-
ments on ultrastructural examination and
a lack of evidence of neuronal or (in most
cases) ependymal differentiation, togeth-
er with positive staining for GFAP and
S100 protein, suggest that the tumour
may be derived from a cell most simi-
lar to an astrocyte. The tanycyte, a cell
with features intermediate between those
of astrocytes and ependymal cells, has
been suggested as a cell of origin for as-
troblastoma on the basis of ultrastructural
observations {1381,1387}.
Genetic profile
DNA copy number aberrations identified
by comparative genomic hybridization
have been described for 7 cases {267},
Fig. 4.09 Astroblastoma. A Central vessel of pseudorosette shows variable sclerosis. B Borders of astroblastoma
and the most common alterations iden-
with brain are generally well defined. C Hyaline sclerosis of central vessels is typical in astroblastomas. D Tumour cells tified in this small series included gains
strongly express GFAP. of chromosomes 19 and 20q, which fre-
quently occurred together. Less common
generally positive for GFAP, whereas fi- examining ultrastructural features {1381, were losses on chromosomes 10 and X,
brillarity is generally lacking in the tumour 1387} found cell body polarization with and a gain of 9q. Conventional cytoge-
stroma. Vascular hyalinization is a con- investing basement membranes, apical netic studies performed on 2 cases led to
spicuous feature of astroblastoma and cytoplasmic blebs capped by microvilli the same overall conclusion {265,1140}.
ranges from focal and mild to extensive with purse-string pedicular constrictions, Although the number of cases studied to
and severe. The combination of mild vas- and lamellar cytoplasmic interdigitations date is small, the findings are consistent
cular hyalinization and radiating tumour (called pleatings). Zonula adherens-type with the hypothesis that astroblastoma
cells produces a papillary architecture in junctions framing occasional microro- is distinct from conventional glial neo-
a subset of tumours. In mildly hyalinized settes and rare cilia were also identified plasms. A recent case report on a single
pseudorosettes, perivascular tumour in these cases. tumour noted that neither IDH1 nor IDH2
cells become separated from the central mutation was detected in the tumour
Immunophenotype
vessel by a greater distance and often {745}, and a report on a series of 9 cases
appear cuboidal. At low magnification, Cytoplasmic Immunoreactivity for vimen-
tin, S100, and GFAP is characteristic, al- of astroblastoma noted a lack of positive
more extensive vascular hyalinization immunostaining for R132H-mutant IDH1
though the extent of labelling (particularly
gives the impression of numerous pink in all cases {95}.
for GFAP) varies considerably {338,1984,
hyaline rings, with a paucity of interven-
2204}. Cell membranes may label for Prognosis and predictive factors
ing tumour cells. The interface with adja-
EMA {338,1140}, typically as a focal phe- In general, high-grade histology has
cent brain is well delineated and is char-
acterized by a pushing or non-infiltrative nomenon. Less-consistent immunolabel- been found to be associated with recur-
ling is reported with CAM5.2 {1140,1381, rence, progression, and worse prognosis
border. Focal infiltration of adjacent tis-
1984} and cytokeratin {1381}. Reactivity {236,2539}, although this association has
sues by tongues of neoplastic cells is
for neuron-specific enolase is variable recently been questioned {1135}. In one
seen occasionally, but diffuse infiltration
{338,1066,1984}, and studied cases have study, only a single recurrence was noted
of surrounding parenchyma is not. The
been negative for synaptophysin {1140}. in 14 informative cases treated by gross
reported Ki-67 proliferation index varies
from 1% to 18% {265,1140}. A relationship In isolated examples, neuronal cadher- total resection, at a mean follow-up of
in {1381} and cell adhesion molecules 24 months {265}. An analysis of the litera-
between proliferation index and outcome
(including CD44, NCAM1, GJB1, and ture suggested that gross total resection
has not been established in the literature,
GJB2) are positive {1381,1984}. Staining resulted in a 5-year survival rate of 95%
although an elevated index tends to be
for OLIG2 can be present {745}. {2447}, and gross total resection of even
associated with high-grade histology.
Compelling evidence of neuronal differ- Cell of origin high-grade astroblastoma may result in a
entiation has not been reported, and no The histogenesis of astroblastoma is con- favourable outcome {236}. Data from the
ependymal features have been encoun- troversial, and the entity is not universally SEER registry indicate that infratentorial
tered in most studied cases. Two studies location may portend improved outcome.
Fig. 5.01 Age versus localization of choroid plexus tumours, Fig. 5.03 A Macroscopic appearance of choroid plexus papilloma showing cauliflower-like appearance. B Choroid
based on a compilation of 264 published cases {2777}. plexus papilloma arising in the posterior third ventricle producing partial obstruction with ventricle dilatation.
Macroscopy cobblestone-like surface. Rarely, choroid carcinomas, limiting its usefulness {41}.
Choroid plexus papillomas are circum- plexus papillomas can acquire unusual Most choroid plexus tumours demon-
scribed cauliflower-like masses that may histological features, including oncocytic strate variably positive staining for S100,
adhere to the ventricular wall, but are change, mucinous degeneration, melani- possibly related to older patient age and
usually well delineated from brain paren- zation and tubular glandular architecture better prognosis {1916}. Membranous
chyma. Cysts and haemorrhages may of tumour cells, neuropil-like islands, and expression of the inward rectifier potas-
occur. Intraoperative observations in rare degeneration of connective tissue (e.g. sium channel KIR7.1 has been found in
atypical choroid plexus papillomas dem- xanthomatous change; angioma-like in- normal choroid plexus (in 34 of 35 sam-
onstrate a highly vascular tumour with crease of blood vessels; and bone, car- ples) and in choroid plexus papilloma (in
a propensity to bleed {2494}, and this tilage, or adipose tissue formation) {87, 12 of 18 cases) but not in 100 cases of
feature is also observed in some typical 299,960}. other primary brain tumours and cerebral
choroid plexus papillomas. metastases {958}. Another study found
Immunophenotype
KIR7.1 in 30 of 30 choroid plexus tumours
Microscopy Nearly all choroid plexus tumours ex-
and the glutamate transporter EAAT1 in
Delicate fibrovascular connective tissue press cytokeratins and vimentin {594,
32 of 35 cases, whereas these markers
fronds are covered by a single layer of 912}. Most demonstrate positive staining
were absent in 4 endolymphatic sac tu-
uniform cuboidal to columnar epithelial for CK7, and positivity for CK20 is less
mours {2284}. EAAT1 has also been de-
cells with round or oval, basally situat- common. In one study, none of the tu-
scribed to differentiate between neoplas-
ed monomorphic nuclei. Mitotic activity mours were found to be CK20-positive
tic and non-neoplastic choroid plexus,
is absent or very low (< 2 mitoses per when CK7-negative {1088}. EMA is often
because expression in the non-neoplas-
10 high-power fields). Brain invasion with negative or only weakly and focally posi-
tic choroid plexus was seen in only 4% of
cell clusters or single cells, high cellu- tive {594,1610}; strong positive staining
cases {180}.
larity, necrosis, nuclear pleomorphism, for EMA favours other neoplasms. Tran-
and focal blurring of the papillary pat- sthyretin is positive in normal choroid Genetic profile
tern are unusual, but can occur. Choroid plexus and in most choroid plexus tu- No large-scale sequencing studies of
plexus papilloma closely resembles non- mours {1916}, but staining may be nega- choroid plexus papilloma have been pub-
neoplastic choroid plexus, but the cells tive or variable among choroid plexus lished to date. TP53 mutations are rare in
tend to be more crowded, elongated, or papillomas and choroid plexus carcino- choroid plexus papillomas (present in
stratified in comparison with the normal mas, and is also seen in some metastatic < 10% of cases) {2483}. Both classic cy-
togenetic and genome-wide array-based
approaches demonstrated hyperdiploidy
in choroid plexus papilloma {598,1648,
2123}. In a series of 36 choroid plexus tu-
mours, MGMT promoter methylation was
found in all cases {961}.
Genetic susceptibility
Choroid plexus papilloma is a major dia-
gnostic feature of Aicardi syndrome, a
genetic but sporadic condition presum-
ably linked to the X chromosome and de-
fined by the triad of total or partial agen-
Fig. 5.05 Choroid plexus papilloma. Immunohistochemistry for the potassium channel KIR7.1. A Choroid plexus esis of the corpus callosum, chorioretinal
tumour cells in cerebrospinal fluid. B Typical membranous labelling of the apical cell surface of tumour cells.
Definition Etiology
A frankly malignant epithelial neoplasm Most choroid plexus carcinomas occur
most commonly occurring in the lateral sporadically, but they can also occur in
ventricles of children, showing at least association with hereditary syndromes
four of the following five histological fea- such as Aicardi syndrome {2488} or
tures: frequent mitoses, increased cellu- (more frequently) Li-Fraumeni syndrome
lar density, nuclear pleomorphism, blur- (LFS) {1379} (see p. 310).
ring of the papillary pattern with poorly
Localization
structured sheets of tumour cells, and
The great majority of choroid plexus car-
necrotic areas.
cinomas are located within and around
Choroid plexus carcinoma frequently in- Fig. 5.08 A large choroid plexus carcinoma in the lateral
the lateral ventricles {1415}.
vades neighbouring brain structures and ventricle with extensive invasion of brain tissue.
Almost all choroid plexus carcinomas re- in virtually all choroid plexus carcinomas. recommended that any patient with a
tain nuclear positivity for SMARCB1 and Both classic cytogenetic and genome- choroid plexus carcinoma be tested for
SMARCA4. wide array-based approaches demon- a TP53 germline mutation, even in the
strate either hyper- or hypodiploidy in absence of a family history of LFS {864}.
Genetic profile
choroid plexus carcinomas {1648,2123, Choroid plexus carcinoma has also been
Choroid plexus carcinomas are char-
2843}. TP53 mutations in choroid plexus described in rhabdoid tumour predispo-
acterized by complex chromosomal al- sition syndrome, a familial cancer syn-
carcinoma are associated with increased
terations that are related to patient age
genomic instability {2483}, in particular drome caused by germline mutation in the
{2198}. No large-scale sequencing stud-
hypodiploidy {1648}. SMARCB1 gene {2327}; however, these
ies of choroid plexus carcinoma have
cases most likely constitute intraventricu-
been published to date. About 50% of Genetic susceptibility
lar atypical teratoid/rhabdoid tumours
all choroid plexus carcinomas harbour About 40% of choroid plexus carcino-
rather than choroid plexus carcinomas.
TP53 mutations. The combination of the mas occur in the setting of germline TP53
TP53-R72 variant and the MDM2SNP309 mutations / LFS {2483}. Within the spec- Prognosis and predictive factors
polymorphism, which is associated with trum of tumours occurring in the setting The 3-year and 5-year progression-free
reduced TP53 activity, was observed of LFS, choroid plexus carcinomas are survival rates of choroid plexus carcinoma
in the majority (> 90%) of patients with among the less frequent manifestations. have been reported as 58% and 38%, re-
TP53-wildtype choroid plexus carcino- Flowever, the link to this inherited tumour spectively, and the overall survival rates as
mas {2483}, implicating p53 dysfunction syndrome is so strong that it has been 83% and 62%. Deaths from disease be-
yond 5 years were also noted {2844}. Only
extent of surgery had a significant impact
on survival for choroid plexus carcinoma.
The use of adjuvant radiation therapy in
patients with choroid plexus carcinoma
undergoing surgery was not found to be
associated with improved overall survival
{351}. Some children with choroid plexus
carcinomas have been found to have
TP53 gene mutations in association with
LFS, and several recent studies have sug-
gested that the absence of TP53 muta-
tions as identified by immunohistochemi-
cal staining is associated with a more
favourable outcome compared with p53-
positive tumours {878,2483,2844}. One
of these studies also suggested that the
prognosis of TP53-mutant tumours may
be improved with intensive chemotherapy
{2844}. A more recent study demonstrat-
ed on multivariate analysis that choroid
plexus carcinomas with loss of chromo-
some arm 12q were associated with a
Fig. 5.10 Choroid plexus carcinoma. A Pleomorphism. B High mitotic activity. C Solid growth, high cellular density, significantly shorter survival than were tu-
and focal membranous staining for KIR7.1. D Infiltration of neighbouring brain tissue. Immunochemistry for transthyretin
mours without this alteration {2198}.
(HR).
Fig. 6.05 Dysembryoplastic neuroepithelial tumour. A Mucin-rich cortical nodule with columnar architecture. B The so-called specific glioneuronal element is characterized by
oligodendrocyte-like cells embedded in a mucoid matrix with interspersed floating neurons.
element. It may show a patchy pattern variants of DNT have been described. markers including S100 protein and the
{531}, owing to the juxtaposition of foci of These non-specific histological forms ac- glial transcription factor OLIG2. They
tumour and of easily recognizable cortex. counted for 20-50% of the DNTs included can also express myelin-oligodendro-
Other tumour components are absent. in three studies {537,1903,2610}. Because cyte glycoprotein, indicating oligoden-
they lack the specific glioneuronal ele- droglial differentiation {2781}, as well
Complex form
ment, these variants of DNT are often in- as NOGO-A {1600}. GFAP is absent in
In this variant, glial nodules, which give
distinguishable from gangliogliomas or oligodendrocyte-like cells, whereas the
the tumour its characteristic multinodular
other gliomas by conventional histology, scattered stellate astrocytes within the
architecture, are seen in association with
particularly when the cortical topography specific glioneuronal element are positive
the specific glioneuronal element. The
of the tumour is not apparent on non-rep- for GFAP. Floating neurons can be visuak
heterogeneous appearance of these tu-
resentative samples. Immunohistochem- ized by the nuclear NeuN epitope {2772,
mours is due to the presence of additional
istry and molecular features can help to 2773}. Variable expression of MAP2 can
histological components resembling as-
exclude typical diffuse astrocytomas and be found in oligodendrocyte-like cells, but
trocytic or oligodendrocytic differentia-
oligodendrogliomas of adulthood (see Ge- staining is typically faint, and the strong
tion. These constituent cell populations
netic profile). Criteria for the differentiation perinuclear expression found in diffuse
can vary from case to case, as well as
of such diffuse and non-specific variants oligodendrogliomas is not detectable
from area to area within the same tumour.
of DNT from other long-term epilepsy-as- {224}. The oncofetal antigen CD34 has
The glial components seen in the complex
sociated tumours such as gangliogliomas been described with variable incidences
form of DNTs have a highly variable ap-
are not well established, and the concept in DNTs {222,414,2543}. DNT cells should
pearance. They may form typical nodules
of additional histological variants of DNT not label with antibodies against mutant
or may show a relatively diffuse pattern.
remains controversial. A novel classifica- IDH1 {356} or K27M-mutant H3.3 {150}.
They may closely resemble conventional
tion scheme for long-term epilepsy-asso- Varying proportions of DNTs have been
categories of gliomas or may show unusu-
ciated tumours has been proposed that described to stain with antibodies against
al features. They often mimic pilocytic as-
includes these variants as well as mixed V600E-mutant BRAF protein {414,2543}.
trocytomas and may show nuclear atypia,
tumours {219}. It awaits further molecu- The Ki-67 proliferation index of DNTs has
rare mitoses, or microvascular-like pro-
lar-diagnostic and clinicopathological been reported to vary from 0% to 8% fo-
liferation and ischaemic necrosis. Their
confirmation. cally {530,531,537,1903,2026,2515}.
microvascular network can vary from
meagre to extensive and may include glo- Cortical dysplasia Differential diagnosis
merulus-like formations. In these vessels, Focal cortical dysplasia is found in DNTs
The histological diagnosis of DNT may
the endothelial cells may be hyperplastic {2543}. It should be diagnosed only in be difficult, in particular with limited ma-
and mitotically active. Within the glial com- areas of cortical abnormalities without terial. En bloc resection during epilepsy
ponents, frankly hamartomatous (usually tumour cell infiltration and classified as
surgery is therefore recommended {219}.
calcified) vessels are common {531,537, focal cortical dysplasia Type lllb accord-
The typical columnar architecture of the
2078}. Malformative vessels can cause ing to the classification proposed by the
specific glioneuronal element can be
haemorrhage {536,689,1860,2412,2542}. International League Against Epilepsy obscured when the samples are not ad-
(ILAE) {225}. equately oriented, and due to its semiliq-
Non-specific and diffuse forms
uid consistency, this element can be lost
On the basis of their similar clinical pre- Immunophenotype
as a result of inadvertent surgical aspira-
sentation, cortical topography, neuro- The so-called specific glioneuronal el-
tion and/or fragmentation during fixation.
radiological features, and stability on ement shows a consistent pattern in
It is therefore important that the diagno-
long-term preoperative imaging follow- immunohistochemistry. The small oli-
sis of DNT be considered in any case
up, non-specific and diffuse histological godendrocyte-like cells express glial
in which all of the following features are
Definition
A rare, well-differentiated, slow-growing
neuroepithelial neoplasm composed of
irregular clusters of mostly mature neo-
plastic ganglion cells, often with dysplas-
tic features.
The stroma consists of non-neoplastic
glial elements. Transitional forms be-
tween gangliocytoma and ganglioglioma
exist, and the distinction of these two en-
tities is not always possible.
ICD-0 code 9492/0
Grading
Gangliocytoma corresponds histologi-
cally to WHO grade I.
Epidemiology
Gangliocytomas are rare tumours pre-
dominantly affecting children. The rela-
tive incidence reported in epilepsy surgi-
cal series ranges from 0% to 3.2% {2541}.
Localization
Like gangliogliomas, these tumours can
occur throughout the CNS. Dysplastic
cerebellar gangliocytoma (Lhermitte-
Duclos disease) is discussed in sepa- Fig. 6.08 Gangliocytoma. A Focal accumulation of multipolar, dysplastic neurons. B Clusters of mature neurons are
embedded in an otherwise normal brain matrix. C Stellate ramification of GFAP-positive astrocytes is compatible with
rate sections of this volume (see pp. 142, non-neoplastic nature in a gangliocytoma.
314). Gangliocytoma of the pituitary is re-
viewed in the volume WHO classification
of tumours of the endocrine organs. may show a lower degree of differentia- Genetic profile
tion, but the presence of mitotically active Genetic data specifically addressing
Clinical features neuroblasts is not compatible with the gangliocytomas have not been reported.
Gangliocytomas share the clinical fea- diagnosis of gangliocytoma and should A close genetic relationship to gangli-
tures of gangliogliomas. prompt the differential diagnosis of CNS oglioma seems possible.
Imaging ganglioneuroblastoma (see p. 207). The
Genetic susceptibility
Radiological data specifically addressing stroma consists of non-neoplastic glial el- Dysplastic cerebellar gangliocytoma
gangliocytoma have not been reported. ements but may be difficult to distinguish
(Lhermitte-Duclos disease), which is as-
from a low-cellularity glial component of
Microscopy sociated with Cowden syndrome, is cov-
a ganglioglioma. A network of reticulin
Gangliocytomas are composed of irregu- fibres may be present, particularly in a ered in separate sections of this volume
lar groups of large, multipolar neurons perivascular location. (see pp. 142, 314). No distinct genetic
(often with dysplastic features). Binucle- susceptibility factors have been reported
ated neurons are commonly observed. Immunophenotype for classic gangliocytoma.
The density of dysplastic ganglion cells is The neoplastic ganglion cells are typically
Prognosis and predictive factors
typically low; it may be close to the den- positive (to various degrees) for synapto- Gangliocytomas are benign tumours with
sity of neurons in grey matter, but is high- physin, neurofilament, chromogranin-A, favourable outcome. Specific prognos-
er in some cases. Some ganglionic cells and MAP2. The neuronal nuclear antigen
tic or predictive factors have not been
NeuN is often only weakly expressed, or
reported.
may be negative.
Fig. 6.09 Multinodular and vacuolating neuronal tumour of the cerebrum. A On MRI, the tumour presents as a superficial lesion with a high T2 signal (arrowhead) and (B) with a
somewhat nodular appearance on T1-weighted images. C Nodular pattern. Nissl stain. D Small neurons are neurofilament-positive.
Gangliocytoma 137
Becker A.J.
Ganglioglioma Wiestler O.D.
Figarella-Branger D.
Blümcke I.
Capper D.
Definition
A well-differentiated, slow-growing glio-
neuronal neoplasm composed of dys-
plastic ganglion cells (i.e. large cells with
dysmorphic neuronal features, without
the architectural arrangement or cytolog-
ical characteristics of cortical neurons) in
combination with neoplastic glial cells.
Gangliogliomas preferentially present in
the temporal lobe of children or young
adults with early-onset focal epilepsy.
Intracortical cystic structures and a cir-
cumscribed area of cortical (and sub-
cortical) signal enhancement are charac-
teristic on FLAIR and T2-weighted MRI.
BRAF V600E mutation occurs in approxi- Fig. 6.11 Ganglioglioma. A Relatively small enhancing nodule and a large, associated septated cyst in a 15-year-
mately 25% of gangliogliomas, whereas old male. The cyst wall is not enhancing. B Coronal T2-weighted imaging shows a cortical/subcortical lesion with
IDH mutation or combined loss of chro- intracortical cysts, bony remodelling, and a hypointense portion suggesting calcification (arrow).
mosomal arms 1p and 19q exclude a di-
agnosis of a ganglioglioma. The progno- The available data indicate that ganglio-
sis is favourable, with a recurrence-free gliomas and gangliocytomas together
survival rate as high as 97% at 7.5 years. account for 0.4% of all CNS tumours and
1.3% of all brain tumours {1207,1552}.
ICD-0 code 9505/1
There are no population-based epide-
Grading miological data on gangliogliomas.
Most gangliogliomas correspond his- Patient age at presentation ranges from
tologically to WHO grade I. Some gan- 2 months to 70 years. Data from several
gliogliomas with anaplastic features in large series with a total of 626 patients
their glial component (i.e. anaplastic indicate a mean/median patient age at
gangliogliomas) are considered to cor- diagnosis of 8.5-25 years. The male-
Fig. 6.12 Ganglioglioma of the right temporal lobe also
respond histologically to WHO grade III to-female ratio is 1.1-1.9:1 {1428,2027, involving the hippocampla formation.
{1552,1570} (see p. 141). Criteria for WHO 2541,2774}. In a survey conducted by the
grade II have been discussed but not es- German Neuropathological Reference duration from 1 month to 50 years before
tablished {1552,1570}. Center for Epilepsy Surgery of 212 chil- diagnosis, with a mean/median duration
Epidemiology dren with gangliogliomas, the mean pa- of 6-25 years {1428,2027,2774}. For tu-
tient age at surgery was 9.9 years and mours involving the brain stem and spinal
48% of the patients were girls. cord, the mean durations of symptoms
Localization
These tumours can occur throughout the Table 6.01 Localization of gangliogliomas
Ganglioglioma 139
Fig. 6.14 Ganglioglioma. A Showing the typical biphasic pattern of irregularly oriented, dysplastic, and occasionally binucleated neurons and neoplastic glial cells. B Prominent
dysplastic neuronal component and perivascular inflammatory exudates. C Biphasic composition of dysplastic neurons and neoplastic glial cells. D Occasionally, gangliogliomas
develop a reticulin fibre network apart from the vasculature.
Fig. 6.15 Ganglioglioma. A GFAP expression. B Synaptophysin expression. C Strong expression of V600E-mutant BRAF protein.
Fig. 6.16 Anaplastic ganglioglioma. A Dysplastic, occasionally binucleated neurons and mitoses within a relatively
cellular and pleomorphic astroglial matrix. B The same tumour contains palisading tumour cells around necrotic foci.
0 10 20 30 40 50 60 70
Age at diagnosis
Fig. 6.17 Cumulative age distribution of Cowden Fig. 6.19 Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease). A Macroscopy with delineated enlargement
syndrome (both sexes) in 75 cases. of cerebellar folia (arrowheads). B Low-power microscopy showing enlargement and distortion of cerebellar cortex.
Advanced techniques (including FDG- Immunophenotype have a germline mutation in PTEN, includ-
PET {972}, MR spectroscopy {679}, and The dysplastic neuronal cells are immu- ing intragenic mutations, promoter muta-
diffusion-weighted imaging {1686}) have nopositive for synaptophysin. Antibod- tions, and large deletions/rearrangements
also been used to characterize Lher- ies specific to the Purkinje cell antigens {1499,1589,2865}. Pilot data suggest
mitte-Duclos disease. Infiltrating medul- LEU4, PCP2, PCP4, and calbindin have that a subset of individuals with Cowden
loblastomas have been reported to mimic been found to label a minor subpopula- syndrome and Cowden syndrome-like
dysplastic cerebellar gangliocytoma on tion of large atypical ganglion cells, but not symptoms but without PTEN mutations
imaging {602,1686}. to react with the majority of the neuronal instead have germline variants of SDHB
elements, suggesting that only a small (on 1p35-36) or SDHD (on 11q23), both of
Spread
proportion of neurons are derived from a which have been shown to affect the same
Dysplastic cerebellar gangliocytoma can
Purkinje cell source {926,2351}. Immuno- downstream signalling pathways as PTEN
recur locally, but it does not spread to other
histochemistry also demonstrates loss of (AKT and MAPK) {1782}.
structures in the brain or outside of the
PTEN protein expression in most dysplas-
CNS. Genetic susceptibility
tic cells and increased expression of phos-
Dysplastic cerebellar gangliocytoma
Macroscopy phorylated AKT and S6, reflecting aberrant
(Lhermitte-Duclos disease) is a compo-
The affected cerebellum displays a dis- signalling that is predicted to result in in-
nent of Cowden syndrome (also called
crete region of hypertrophy and a coarse creased cell size and lack of apoptosis {3,
PTEN hamartoma syndrome). Cowden
gyral pattern that extends into deeper lay- 2864}. Undetectable or very low prolifera-
syndrome is an autosomal dominant dis-
ers. Dysplastic cerebellar gangliocytomas tive activity has been reported in the few
order characterized by multiple hamar-
are usually confined to one hemisphere, cases analysed with proliferation markers
tomas involving tissues derived from all
but they can occasionally be multifocal. {3,926}.
three germ cell layers. The classic hamar-
Microscopy Cell of origin toma associated with Cowden syndrome
The dysplastic gangliocytoma of Lher- It remains unclear whether Lhermitte- is trichilemmoma. People with Cowden
mitte-Duclos disease causes diffuse en- Duclos disease is hamartomatous or syndrome also have a high risk of breast
largement of the molecular and internal neoplastic in nature. Malformative histo- and thyroid carcinomas, mucocutaneous
granular layers of the cerebellum, which pathological features, very low or absent lesions, non-malignant thyroid abnor-
are filled by ganglionic cells of various size proliferative activity, and the absence malities, fibrocystic disease of the breast,
{3}. An important diagnostic feature is the of progression support classification as gastrointestinal hamartomas, early-on-
relative preservation of the cerebellar ar- hamartoma. However, recurrent growth set uterine leiomyomas, macrocephaly,
chitecture; the folia are enlarged and dis- has occasionally been noted, and dys- and mental retardation. The syndrome is
torted but not obliterated. A layer of abnor- plastic gangliocytomas can develop in caused by germline mutations of the PTEN
mally myelinated axon bundles in parallel adult patients with previously normal MRI gene. A subset of individuals with Cowden
arrays is often observed in the outer mo- scans {3,926,1580}. It has been sug- syndrome and Cowden syndrome-like
lecular layer. Scattered cells morphologi- gested that the primary cell of origin is the symptoms but without germline PTEN mu-
cally consistent with granule neurons are cerebellar granule neuron {926}, and that tations have been found to harbour germ-
also sometimes found under the pia or in a combination of aberrant migration and line variants of SDHB or SDHD {245}.
the molecular layer. The resulting structure hypertrophy of granule cells is responsi-
Prognosis and predictive factors
of these dysmorphic cerebellar folia has ble for formation of the lesions {3}. Murine
Although several recurrent Lhermitte-Du-
been referred to as inverted cerebellar cor- transgenic models based on localized
clos disease lesions have been reported,
tex. Purkinje cells are reduced in number PTEN loss support this hypothesis {1401}.
no clear prognostic or predictive factors
or absent. Calcification and ectatic vessels
Genetic profile have emerged. However, patients should
are commonly present within the lesion.
Approximately 85% of Cowden syndrome be followed for other potential manifesta-
Vacuoles are sometimes observed in the
cases, as strictly defined by the Interna- tions of Cowden syndrome, particularly
molecular layer and white matter {3}.
tional Cowden Consortium (ICC) criteria, breast cancer in female patients.
Definition
A benign glioneuronal tumour composed
of a prominent desmoplastic stroma with
a neuroepithelial population restricted
either to neoplastic astrocytes - desmo-
plastic infantile astrocytoma (DIA) - or to
astrocytes together with a variable mature
neuronal component - desmoplastic in-
fantile ganglioglioma (DIG) - sometimes
with aggregates of poorly differentiated
cells {1533}. Fig. 6.22 A Desmoplastic infantile astrocytoma. Coronal contrast-enhanced T1-weighted MRI in a 10-month-old child
DIA and DIG typically occur in infants, with a large head, showing a mixed cystic and solid mass in the left cerebral hemisphere. The solid portion enhances
most often as a large and cystic lesion strongly, abutting and thickening the adjacent meninges. B Desmoplastic infantile ganglioglioma. Postcontrast axial
involving the superficial cerebral cortex MRI demonstrating a superficial enhancing component of a desmoplastic infantile ganglioglioma together with a large
septated cystic component that enlarges the skull and displaces the midiine.
and leptomeninges, often attached to
dura.
also stressed the presence of immature more than one lobe; preferentially the
ICD-0 code 9412/1 neuroepithelial cell aggregates. Because frontal and parietal, followed by the tem-
both lesions have similar clinical, neu- poral, and (least frequently) the occipital.
Grading roimaging, and pathological features
Clinical features
(including a favourable prognosis), they
DIA and DIG correspond histologically to The signs and symptoms are of short
are now categorized together as DIA and
WHO grade I. duration and include increasing head
DIG in the WHO classification.
circumference, tense and bulging fonta-
Synonyms and historical annotation nelles, lethargy, and the setting-sun sign.
Epidemiology
DIA was first described in the literature Occasionally, patients present with sei-
DIAs and DIGs are rare neoplasms of
by Taratuto et al. {2514}, as superficial
early childhood. Their incidence can only zures, focal motor signs, or skull bossing
cerebral astrocytoma attached to dura
be estimated from their frequency in insti- over the tumour.
with desmoplastic stromal reaction. It
tutional series. One series of 6500 CNS
was included in the first edition of the Imaging
tumours from patients of all ages reported
WHO classification in 1993 under the On CT, DIAs and DIGs present as large,
22 cases of DIG (0.3%) {2628}. In a se-
term “desmoplastic cerebral astrocytoma hypodense cystic masses with a solid
ries of CNS intracranial tumours limited to
of infancy” {1290}. In 1987, VandenBerg isodense or slightly hyperdense super-
children, 6 DIAs were found, accounting
et al. {2629} described desmoplastic ficial portion that extends to the overly-
for 1.25% of all paediatric brain tumours
supratentorial neuroepithelial tumours ing meninges and displays contrast en-
{2514}. In studies limited to brain tumours
of infancy with divergent differentiation hancement. The cystic portion is usually
of infancy, DIA and DIG accounted for
(DIG), occurring in the same clinical set- located deep in the cerebrum, whereas
15.8% of the tumours {2875}.
ting. Unlike DIA, DIG was described as the solid portion is peripheral. On MRI,
The age range for 84 reported cases of
having a neuronal component with vari- T1-weighted images show a hypointense
DIA/DIG was 1-24 months, with a medi-
able differentiation, and this description cystic component with an isointense pe-
an age of 6 months and a male-to-female
ripheral solid component that enhances
ratio of 1.5:1 {1533}. The large majority
with gadolinium. On T2-weighted imag-
of infantile cases present within the first
es, the cystic component is hyperintense
year of life. Several non-infantile cas-
and the solid portion is heterogeneous.
es, with patient ages ranging from 5 to
Oedema is usually absent or modest
25 years, have more recently been re-
{2571}.
ported. There is a strong male predomi-
nance in the non-infantile cases reported Macroscopy
to date {1928}. These tumours are large (measuring as
much as 13 cm in diameter) and have
Localization
deep uniloculated or multiloculated cysts
Fig. 6.21 Age distribution (months, both sexes) of DIAs and DIGs invariably arise in the su-
filled with clear or xanthochromic fluid.
desmoplastic infantile astrocytoma and ganglioglioma, pratentorial region and commonly involve
based on 84 published cases.
The solid superficial portion is primarily cell population in DIA. In DIG, neoplastic angiomatoid vessels, but microvascular
extracerebral, involving leptomeninges astrocytes are predominant, but a neo- proliferation is not evident {539,1538}.
and superficial cortex. It is commonly plastic neuronal component with variable Electron microscopy
attached to the dura, firm or rubbery in differentiation is also present, most often
consistency, and grey or white in colour. taking the form of ganglion cells {2628}. Astrocytic tumour cells are characterized
There is no gross evidence of haemor- In addition to this desmoplastic lepto- by intermediate filaments that are typi-
rhage or necrosis. meningeal component, both DIA and cally arranged in bundles and by scat-
DIG contain a population of poorly differ- tered cisternae of rough endoplasmic re-
Microscopy entiated neuroepithelial cells with small, ticulum and mitochondria. An extensive
The diagnostic features are those of a round, deeply basophilic nuclei and mini- basal lamina surrounds individual tumour
slow-growing superficial neuroepithelial mal surrounding cytoplasm. This imma- cells. Fibroblasts containing granular en-
tumour composed of a dominant desmo- ture component, lacking desmoplasia, doplasmic reticulum and well-developed
plastic leptomeningeal component and may predominate in some areas. A cor- Golgi complexes are also apparent,
most often containing a variable poorly tical component devoid of desmoplasia particularly in collagen-rich areas {539,
differentiated neuroepithelial component. may also be observed; this component 1538}. The neuronal cells of DIG contain
The desmoplastic leptomeningeal com- is often multinodular, with some nodules dense-core secretory granules and may
ponent consists of a mixture of fibroblast- being microcystic. develop small processes containing neu-
like spindle-shaped cells, often with a There is a sharp demarcation between rofilaments. In neuronal cells, immuno-
wavy pattern with abundant connective the cortical surface and the desmo- electron microscopy has shown filamen-
tissue, intermixed with slightly pleomor- plastic tumour, although Virchow-Robin tous reactivity to neurofilament heavy
phic neoplastic neuroepithelial cells spaces in the underlying cortex are often polypeptide in cell bodies and processes
with eosinophilic cytoplasm arranged in filled with tumour cells. Calcifications are lacking a basal lamina.
fascicles or demonstrating storiform or common, but mononuclear inflammatory
whorled patterns {2514,2629}. Reticulin Immunophenotype
infiltrates are usually lacking. Mitotic ac-
impregnations show a prominent reticu- In the desmoplastic leptomeningeal
tivity and necrosis are uncommon and
lin-positive network surrounding almost component, fibroblast-like cells express
are mostly restricted to the population
every cell and mimicking a mesenchymal vimentin, most express GFAP, and a few
of poorly differentiated neuroepithe-
tumour. Astrocytes are the sole tumour express SMA. Most neuroepithelial cells
lial cells {2628}. Some tumours contain
also react with GFAP. Astrocytes largely and DIG {99,1538}. The absence of the identified the BRAF V600E mutation in
predominate in this component. Anti- genetic alterations typical of most dif- 2 of 18 DIAs/DIGs {808,1315}. The au-
bodies to collagen IV react in a reticulin- fuse astrocytomas suggests that diffuse thors of both studies concluded that this
like pattern around the tumour cells {99, astrocytomas are not related to these activating mutation was an uncommon
1538}. Expression of neuronal markers neoplasms. finding in DIA/DIG.
(e.g. synaptophysin, neurofilament heavy
Genetic profile Prognosis and predictive factors
polypeptide, and class III beta-tubulin)
Classic cytogenetic analysis has been Most studies indicate that gross total
is observed in neoplastic neuronal cells;
carried out on only a limited number of resection results in long-term survival in
mostly in ganglion cells, but also in cells
cases, in which either a normal karyo- cases of DIA and DIG. In one study of
lacking overt neuronal differentiation on
type or non-clonal abnormalities were 8 patients with DIA (median follow-up:
routine stains {1918}. In the poorly dif-
described {393}. A comparative genomic 15.1 years), 6 patients survived to the
ferentiated neuroepithelial component,
hybridization study of 3 cases of DIA and end of follow-up (the other 2 died peri-
cells react with GFAP {1776} and vimen-
DIG did not reveal any consistent chromo- operatively) {2514}. In another study, no
tin, but also with neuronal markers and
somal gains or losses {1369}. One case deaths or evidence of tumour recurrence
MAP2 {1918,2628}. Desmin expression
of DIG showed a loss on 8p22-pter, and were observed among 14 patients with
may be encountered, but epithelial mark-
one DIA showed a gain on 13q21. A more DIG (median follow-up: 8.7 years) {2628}.
ers (e.g. cytokeratins and EMA) are not
recent genome-wide DNA copy number Thus, surgery alone, with total removal,
expressed.
analysis of 4 DIAs and 10 DIGs found seems to provide local tumour control.
The Ki-67 proliferation index ranges
that large chromosomal alterations were In cases of subtotal resection or biopsy,
from < 0.5% to 5%, with the majority of
rare, but demonstrated focal recurrent most tumours are stable or regrow only
reported values being < 2% {1369}. In
losses at 5q13.3, 21 q22.11, and 10q21.3 slowly. There have been reports of radio-
the unusual DIAs and DIGs that show
{832}. Frequent gains were seen at 7q31, logical regression of some tumours after
histological anaplasia, mitotic activity is
which includes the gene for hepatocyte subtotal resection {2500}. Dissemination
readily identified and a KI-67 proliferation
growth factor receptor (MET), and less- of these tumours through the cerebrospi-
index as high as 45% has been reported
frequent gains were noted at 4q12 (KDR, nal fluid has been reported, but should
{547,1963}.
KIT, and PDGFRA) and 12q14.3 (MDM2). be considered a rare event {527,547}.
Cell of origin No evidence of KIAA1549-BRAF fusions Long-term tumour control can be
The exact cellular origins of DIAs and was noted in these cases. Unsupervised achieved by total surgical resection of DIA
DIGs have not been established. The clustering and principal component and DIG despite the presence of prim-
presence of primitive small-cell popula- analysis of the copy number alterations itive-appearing cellular aggregates with
tions that express both glial and neuronal in this group of DIAs and DIGs did not mitotic activity or foci of necrosis. Among
proteins might suggest that these are separate the tumours based on histologi- the DIGs that show foci of frank anaplasia
progenitor cells to the better-differentiat- cal class, suggesting that they constitute (i.e. with high mitotic rate, microvascular
ed neuroepithelial components and sup- a single molecular genetic entity with a proliferation, and perinecrotic palisading
ports the hypothesis that DIAs and DIGs spectrum of histological features {832}. tumour cells), there have been reports of
are embryonal neoplasms programmed Early molecular studies of DIA did not un- long-term survival after gross total resec-
to progressive maturation. The special- cover any LOH on chromosomes 10 and tion {2451,2500}. Tumour progression
ized subpial astrocytes of the developing 17 or any TP53 mutations {1538}. More re- has been reported in DIGs that could
brain have been suggested as a poten- cently, the mutational status of BRAF has not be completely resected, especially in
tial cell of origin, given that they are su- been investigated in two relatively large those with a high proliferation index and
perficially localized and form a continu- series of DIAs and DIGs. In one study, anaplastic features. Histological features
ous, limiting basal lamina, similar to the BRAF V600E mutations were found in 1 of of glioblastoma have been described in
abundant basal lamina production of DIA 14 tumours. In the other, pyrosequencing the recurrence {547,1523,1963}.
Definition 1998, but was previously described un- emotional affect have also been encoun-
A low-grade biphasic neoplasm with as- der other designations, including “pseu- tered. Haemorrhage as the initial pre-
trocytic and neuronal differentiation and dopapillary ganglioglioneurocytoma” sentation has been reported {303,1888}.
histopathological features including a and “pseudopapillary neurocytoma with Some cases are asymptomatic and dis-
pseudopapiitary structure composed of glial differentiation" {1274}. covered incidentally, even when the tu-
flat to cuboidal astrocytes that are pos- mour is large (as large as 6 cm in one
itive for GFAP lining hyalinized vessels, Epidemiology case) {572,586,1324}.
interpapillary collections of synapto- Incidence Imaging
physin-positive neurocytes, and occa- PGNTs are rare neoplasms, accounting Radiologically, a cystic component is
sional ganglion cells; with low mitotic for < 0.02% of intracranial tumours {22}. typical, but the tumours can be broadly
activity and infrequent necrosis or micro-
Age and sex distribution classified into four groups: cysts with
vascular proliferation.
mural nodules, masses that are cystic
Papillary glioneuronal tumour (PGNT) is The median patient age at diagnosis is only, mixed cystic and solid masses, and
a rare glioneuronal tumour that preferen- 23 years (range: 4-75 years). A recent re- masses that are solid only {2285}. The
tially occurs in the supratentorial com- view of the literature showed that 35% of tumours are usually located in the white
partment in young adults, with no sex patients were aged < 18 years and 60% matter, frequently near the ventricle {65,
preference. A circumscribed cystic or were aged < 26 years. No sex predilec- 2285}. On MRI, the solid portion is isoin-
solid mass with contrast enhancement tion has been found {2285}. tense or hypointense on T1-weighted
is characteristic on MRI. A novel translo-
Localization images and diffusion-weighted images,
cation, t(9;17)(q31;q24), which results in
PGNTs are typically located in the cere- and hyperintense on T2-weighted images
an SLC44A1-PRKCA fusion oncogene,
bral hemispheres, often in proximity to and FLAIR images {65,1439}. Most of the
is present in a high proportion of cases.
the ventricles, and with a predilection for tumours {85%) have no (or only minimal)
The prognosis is good.
the temporal lobe {283,1324,2022}. Oc- peritumoural oedema, even when they
ICD-0 code 9509/1 casionally, they grow intraventricularly are large in volume {2285,2606}. About
{572,2011}. On MRI and CT, the tumours 10% of the reported cases showed overt
Grading
present as demarcated, solid to cystic, or occult signs of intratumoural haemor-
Most PGNTs correspond histologically
contrast-enhancing masses with little rhage {169}. Calcification has also been
to WHO grade I and behave in a manner
mass effect. A cystic or mural nodule ar- reported in some cases {2505,2757}.
consistent with this grade {2285}, but a
minority of cases show atypical histologi- chitecture may be seen. Spread
cal features or late biological progression Clinical features To date, leptomeningeal or cerebrospinal
{1102,1139,1731}. The principal manifestations include fluid seeding has not been reported.
headaches and seizures. Rarely, neu- Only one case has shown primary ex-
Synonyms and historical annotation
rological deficits, such as disturbances traneural metastases, which involved
PGNT was established as a clinicopatho-
of vision, gait, sensation, cognition, and bilateral pleura, pericardium, and the left
logical entity by Komori et al. {1324} in
Fig. 6.25 Papillary glioneuronal tumour. A T2-weighted MRI shows a solid and cystic mass in the right frontal lobe. B This mass is hypointense on T1-weighted MRI. C Peripheral
enhancement is noted in the solid portion on postcontrast T1 -weighted MRI. D 1C-methionine PET reveals that this mass has high uptake in the peripheral portion.
breast and occurred 4.5 years after initial The background can be fibrillary or mi- Electron microscopy
resection {250}. crocystic. Neurocytes often resemble The limited ultrastructural studies on
oligodendrocyte-like cells {1324,1484, these tumours have identified three cell
Macroscopy 1731}. Interpapillary neuronal cells show types: astrocytic, neuronal, and poorly
PGNTs are usually composed of solid considerable variation in size and shape differentiated {257,1324,1731}. Astrocytes
and cystic elements {2285}. Almost all {1324,2633}. Vascular structures can be contain cytoplasmic bundles of interme-
cases are supratentorial. Most occur prominent and occasionally manifest diate filaments and are separated from
within the cerebral hemisphere (espe- as a mass of hyalinized material without vascular adventitia by a basal lamina.
cially the frontal or temporal lobe), but much intervening tumour {2583}. Neurons are characterized by neuronal
some are intraventricular {1731}. They are In addition to neuronal cells, minigemi- processes filled with parallel microtu-
usually grey and friable and may be cal- stocytes with eccentrically located nu- bules, their terminations with clear vesi-
cified. Rare cases have presented with clei and eosinophilic cytoplasm are cles, and occasional synapses. Poorly
extensive haemorrhage, mimicking a occasionally observed in interpapillary differentiated cells are polygonal and
cavernoma {169}. spaces {1102,2509}. At the periphery of contain dense bodies and free ribo-
Microscopy the lesion, scattered tumour cells are in- somes but no intermediate filaments in
termingled with gliotic brain tissue, which the cytoplasm. Minigemistocytes with
Histopathology contains Rosenthal fibres, eosinophilic numerous bundles of glial filaments have
PGNT is characterized by a prominent granular bodies, haemosiderin pigment, also been reported {1102}.
pseudopapillary architecture, a single and microcalcifications {1324,2583}.
or pseudostratified layer of flattened or Immunophenotype
These glial elements lack both nuclear
cuboidal glial cells with round nuclei and The cytoplasm and processes of flat-
atypia and mitotic activity. Microvascular
scant cytoplasm around hyalinized blood tened to cuboidal cells covering hyalin-
proliferation or necrosis is exceptional,
vessels, and intervening collections of ized vessels are immunostained by anti-
even in cases with relatively increased
neurocytes and medium-sized gan- bodies to GFAP, S100 protein, and nestin
proliferative activity {1484}, although
glion cells with accompanying neuropil. {1324,1484,2509}. In some cases, oligo-
there have been a few reports of exam-
dendrocyte-like cells that are positive for
ples with frank anaplasia {9,1102}.
OLIG2 and negative for GFAP surround
Fig. 6.27 Papillary glioneuronal tumour. A GFAP-positive cells around blood vessels. B Many of interpapillary cells show 0LIG2 Immunoreactivity. C NeuN positivity is found in
some interpapillary cells. D Ganglioid cells and neurocytes show NFP Immunoreactivity.
this layer {2509}. The minigemistocytes differentiation is presumed, with paraven- Prognosis and predictive factors
demonstrate intense immunoreactivity tricular examples possibly deriving from In most cases, gross total resection with-
for GFAP. The neuronal cells and neuropil the subependymal matrix {1324}. out adjuvant therapy results in long-term
stain with antibodies to synaptophysin, recurrence-free survival. Therefore, sur-
Genetic profile / genetic susceptibility gical removal is the main prognostic fac-
neuron-specific enolase, and class III
The translocation t(9;17)(q31;q24), result- tor. Anaplastic features (e.g. mitoses, mi-
beta-tubulin {1324,2509}. The majority of
ing in an SLC44A1-PRKCA fusion onco- crovascular proliferation, necrosis, and a
the neuronal cells are positive for NeuN;
gene, is present in a high proportion of high proliferation rate) have been report-
however, NFP expression is mostly con-
cases. The prognosis is good. ed in rare cases and were variably asso-
fined to large ganglion cells, and chro-
To date, no familial or syndrome- ciated with aggressive behaviour {1139,
mogranin-A expression is absent {1324}.
associated cases of PGNTs have been 1772}. There have been no reported cas-
Proliferation reported. An initial series of 6 patients es that progressed or recurred after sur-
The Ki-67 proliferation index generally reported no 1p abnormalities in PGNTs gery when the Ki-67 proliferation index
does not exceed 1-2%, but cases dis- {2509}. Recently, an FGFR1 N546K mu- was < 5.0% {1888}. Flowever, > 20 cases
playing elevated activity (ranging from tation was observed in a single PGNT have been reported to have atypical fea-
10% to > 50%) have been reported {250}. {800}. Another study described recurrent tures, with an elevated Ki-67 proliferation
SLC44A1-PRKCA fusions {278}. To date, index (of > 5.0%). Of these tumours, 50%
Cell of origin
comparative genomic hybridization has eventually progressed or recurred {9,22,
An origin from multipotent precur-
not revealed an aberration profile char- 250,1102,1139,1439,1888,1976}.
sors capable of divergent glioneuronal acteristic of this tumour {670,1731}.
Definition
A neoplasm composed of two distinct
histological components: one containing
uniform neurocytes forming rosettes and/
or perivascular pseudorosettes and the
other being astrocytic in nature and re-
sembling pilocytic astrocytoma.
Rosette-forming glioneuronal tumour is
slow-growing, preferentially affects young
adults, and occurs predominantly in the
fourth ventricle, but can also affect other
sites such as the pineal region, optic chi-
asm, spinal cord, and septum pellucidum.
ICD-0 code 9509/1
Grading Fig. 6.29 Rosette-forming glioneuronal tumour. A T1-weighted MRI shows low intensity of the tumour mass and focal
Rosette-forming glioneuronal tumour gadolinium enhancement. B T2-weighted MRI demonstrates a relatively hyperintense midline tumour occupying the
corresponds histologically to WHO fourth ventricle and involving cerebellar vermis.
grade I, and its generally favourable
postoperative course is consistent with Imaging and wall or floor of the fourth ventricle. An
this grade. On MRI, rosette-forming glioneuronal intraventricular component is typical, oc-
tumour presents as a relatively circum- casionally with aqueductal extension.
Epidemiology scribed, solid tumour showing T2-hyper-
Rosette-forming glioneuronal tumour is Microscopy
intensity, T1-hypointensity, and focal/mul-
known to be rare, but specific popula- Rosette-forming glioneuronal tumours
tifocal gadolinium enhancement.
tion-based incidence rates are not yet are generally demarcated, but limited
available. Spread infiltration may be seen. They are char-
Localization outside of the fourth ventricle acterized by a biphasic neurocytic and
Localization (e.g. in the pineal region, optic chiasm, glial architecture {1119,1325,2033}. The
Rosette-forming glioneuronal tumours spinal cord, and septum pellucidum) has neurocytic component consists of a uni-
arise in the midline, usually occupy the been described. In rare cases, dissemi- form population of neurocytes forming
fourth ventricle and/or aqueduct, and nation throughout the ventricular system neurocytic rosettes and/or perivascu-
can extend to involve adjacent brain can occur {58,68,2285,2803}. lar pseudorosettes. Neurocytic rosettes
stem, cerebellar vermis, pineal gland, feature ring-shaped arrays of neurocytic
or thalamus. Secondary hydrocephalus Macroscopy nuclei around delicate eosinophilic neu-
may be seen. Localization outside the Rosette-forming glioneuronal tumour ropil cores. Perivascular pseudorosettes
fourth ventricle (e.g. in the pineal region, most commonly involves the cerebellum feature delicate cell processes radiating
optic chiasm, spinal cord, and septum
pellucidum) has been described, and
in rare cases, dissemination throughout
the ventricular system can occur {58,68,
2285,2803}.
Clinical features
Patients most commonly present with
headache (a manifestation of obstructive
hydrocephalus) and/or ataxia. Cervical
pain is occasionally experienced. Rare
cases are asymptomatic and discovered
as incidental imaging findings.
Fig. 6.30 Rosette-forming glioneuronal tumour consists of two components: neurocytic (left) and astrocytic (right).
towards vessels. Both patterns, when form surface contacts with perikarya and Genetic profile
viewed longitudinally, may show a colum- other cytoplasmic processes. PIK3CA and FGFR1 mutations (in hotspot
nar arrangement. Neurocytic tumour cells codons Asn546 and Lys656) have been
have spherical nuclei with finely granular found in rosette-forming glioneuronal tu-
Immunophenotype mours {340,629,804,2547}. Despite the
chromatin and inconspicuous nucleoli,
Immunoreactivity for synaptophysin is histological similarity between rosette-
scant cytoplasm, and delicate cytoplas-
present at the centres of neurocytic ro- forming glioneuronal tumours and pilocyt-
mic processes. These neurocytic struc-
settes and in the neuropil of perivascular ic astrocytomas, KIAA1549-BRAF fusions
tures may lie in a partly microcystic,
pseudorosettes {1119,1325,2033}. Both and BRAF V600E mutations have not
mucinous matrix. The glial component
the cytoplasm and processes of neuro- been described in rosette-forming glio-
of rosette-forming glioneuronal tumour
cytic tumour cells may express MAP2 neuronal tumour {629,803,807,1220}, and
typically dominates and in most areas
and neuron-specific enolase. In some the tumour has not shown evidence of
resembles pilocytic astrocytoma. Astro-
cases, NeuN positivity can be observed IDH1/2 mutations {629,2392,2547,2801}
cytic tumour cells are spindle to stellate
in neurocytic tumour cells. GFAP and or 1p/19q codeletion {2694,2801}. Mass
in shape, with elongated or oval nuclei
S100 immunoreactivity is present in the spectrometry array mutation profiling with
and moderately dense chromatin. Cyto-
glial component, but absent in rosettes a panel covering multiple hotspots for
plasmic processes often form a compact
and pseudorosettes. The Ki-67 prolifera- single-nucleotide variants did not reveal
to loosely textured fibrillary background.
tion index is low: < 3% in reported cases. mutations in AKT1, AKT2, AKT3, EGFR,
In some areas, the glial component may
be microcystic, containing round to oval, Cell of origin GNAQ, GNAS, KRAS, MET, NRAS, or
oligodendrocyte-like cells with occasion- Neuroimaging, histological findings, and RET {629}.
al perinuclear haloes. Rosenthal fibres, molecular evidence indicate that rosette- Genetic susceptibility
eosinophilic granular bodies, microcal- forming glioneuronal tumour may arise One reported patient with rosette-form-
cifications, and haemosiderin deposits from brain tissue surrounding the ven- ing glioneuronal tumour had a type I Chi-
may be encountered. Overall, cellularity tricular system. For cases affecting the ari malformation {1325}. Rosette-forming
is low. Mitoses and necroses are absent. fourth ventricle, an origin from the sub- glioneuronal tumours have also been
Vessels may be thin-walled and dilated or ependymal plate or the internal granule described in patients with neurofibroma-
hyalinized. Thrombosed vessels and glo- cell layer of cerebellum has been sug- tosis type 1 {2263}, as well as Noonan
meruloid vasculature may also be seen. gested {1325,2547}. syndrome {1220}.
Ganglion cells are occasionally present,
but adjacent, perilesional cerebellar cor- Prognosis and predictive factors
tex does not show dysplastic changes. The clinical outcome of these generally
H1047R benign lesions is favourable in terms of
Electron microscopy
survival, but disabling postoperative defi-
Astrocytic cells of the glial component
cits have been reported in approximately
contain dense bundles of glial filaments.
half of cases. In rare cases, tumour dis-
Rosette-forming neurocytic cells are in-
semination and progression is possible
timately apposed and feature spherical
{58,2285}.
nuclei with delicate chromatin, cytoplasm
containing free ribosomes, scattered
profiles of rough endoplasmic reticulum,
prominent Golgi complexes, and occa-
sional mitochondria. Loosely arranged cy-
toplasmic processes form the centres of
rosettes and contain aligned microtubules
as well as occasional dense-core gran-
ules. Presynaptic specializations may be Fig. 6.32 Rosette-forming glioneuronal tumour. Detection
of a missense mutation in exon 20 of PIK3CA by Sanger
seen, and mature synaptic terminals may
sequencing.
Fig. 6.34 Diffuse leptomeningeal glioneuronal tumour. A Diffuse leptomeningeal thickening (arrows) is a consistent feature on postmortem studies; parenchymal cysts may also be
encountered in some cases, usually in a superficial location. B Note the extensive intraventricular involvement, as well as the parenchymal cysts. C Extensive spinal leptomeningeal
involvement.
Fig. 6.36 Diffuse leptomeningeal glioneuronal tumour. A The tumour cells are GFAP-negative. B Tumour cells show extensive nuclear immunoreactivity for OLIG2. C Diffuse
leptomeningeal glioneuronal tumour with anaplastic features. The Ki-67 proliferation index is elevated, suggestive of a more aggressive clinical behaviour.
nerve roots and infiltration of basal cranial nests in the leptomeninges, with desmo- observed. Rosenthal fibres are usually
nerves and ganglia may also be seen. plastic and myxoid changes commonly absent. The intraparenchymal compo-
present. A storiform pattern may be ob- nent resembles a diffusely infiltrative
Microscopy
served in desmoplastic areas. Mitotic glioma, mostly oligodendroglioma-like,
Cerebrospinal fluid examination demon-
activity is usually low, and other histo- although astrocytic features occasionally
strates elevated protein levels, although
logical features of anaplasia are absent predominate.
cytology is often negative {2149,2294}.
in most cases. However, rare examples
Therefore, the diagnosis usually requires Immunophenotype
show histological evidence of anaplasia
a meningeal tumour biopsy. Histological- The oligodendroglial-like tumour cells
either at primary presentation or after
ly, diffuse leptomeningeal glioneuronal typically express OLIG2, MAP2, and
tumour progression {2149}. Anaplastic
tumours are low- to moderate-cellularity S100 protein {2030,2149}. GFAP immuno-
features include brisk mitotic activity (de-
neoplasms composed of relatively mono- positivity in tumour cells is seen in < 50%
fined as > 4 mitoses per 10 high-power
morphic oligodendroglial-like tumour of the cases and is often restricted to a
fields) {2149}. Areas of necrosis are usu-
cells with uniform, medium-sized round minor proportion of neoplastic cells. Ex-
ally absent on biopsies but have been
nuclei and inconspicuous nucleoli. Like pression of synaptophysin is detectable
detected in individual cases at autopsy
in oligodendroglioma, artificial perinu- in as many as two thirds of the tumours,
{2149}. A small subset of tumours contain
clear haloes and cytoplasmic swelling and is particularly common in those con-
ganglion or ganglioid cells. Neuropil as-
are commonly seen in formalin-fixed, taining neuropil aggregates and ganglion
sociated with ganglion cells and neuro-
paraffin-embedded tissue sections. The cells. Immunostaining for NeuN, neurofil-
pil-like islands have also been observed.
tumour cells grow diffusely or in small aments, EMA, and R132H-mutant IDH1 is
Rarely, eosinophilic granular bodies are
Fig. 6.38 Diffuse leptomeningeal glioneuronal tumour. DNA copy number profile determined by 450k methylation bead array analysis; note the deletion of 1p and the circumscribed
gains on 5p and 7q in a case with KIAA1549-BRAF fusion.
Definition
An uncommon intraventricular neoplasm
composed of uniform round cells with a
neuronal immunophenotype and low pro-
liferation index.
Central neurocytoma is usually located in
the region of the foramen of Monro, pre-
dominantly affects young adults, and has
a favourable prognosis.
Grading
Central neurocytoma corresponds histo-
logically to WHO grade II. The tumours
are usually benign, but some recur, even
after total surgical removal. Because the Fig. 6.40 Central neurocytoma. A Large intraventricular tumour of the lateral ventricle with hypointensity on T1-
prognostic values of anaplastic features weighted MRI. B Strong contrast enhancement on T1 -weighted MRI after gadolinium injection.
Fig. 6.42 Central neurocytoma. A Round monomorphic cells and vascularized thin-walled capillaries. B Central neurocytoma with anaplastic histological features. Microvascular
proliferation associated with mitotic activity.
Proliferation including MYCN gain. A transcriptomic necessary after gross total resection,
The Ki-67 proliferation index is usually low study showed overexpression of genes many authors have recommended post-
(< 2%), but higher values can occur in atyp- involved in the WNT signalling pathway, operative radiotherapy after incomplete
ical central neurocytomas {2053,2478}. calcium function, and maintenance of resection to prevent recurrence {1907}.
neural progenitors {2637}. These genes The prognostic relevance of atypical
Cell of origin
may contribute to central neurocytoma histological features in central neurocy-
The cell of origin is still unknown. Because tomas and any consequent treatment
tumorigenesis.
of the frequent involvement of the septum
Central neurocytomas have not been re- strategy is more controversial; there have
pellucidum and the predominant neu-
ported to exhibit 1p/19q codeletion, with been reports of central neurocytoma de-
ronal differentiation of the tumour, central
the exception of a single case of atypical void of anaplastic histological features
neurocytoma was first thought to derive
neurocytoma located in the insular cortex but associated with adverse outcome
from the nuclei of the septum pellucidum
{1718}. {2638}.
{967}. However, given the evidence for Shorter recurrence-free intervals have
Prognosis and predictive factors
both glial and neuronal differentiation in
been reported by some authors for cen-
some tumours, central neurocytoma may The clinical course of central neurocy-
tral neurocytomas with a Ki-67 prolifera-
toma is usually benign, with the extent of
in fact derive from neuroglial precursor
tion index of > 2% or 3% {1561,2478},
resection being the most important prog-
cells with the potentiality of dual differ-
but this was not found by others {2638}.
nostic factor. Craniospinal dissemination
entiation. These tumours could originate
Anaplastic histological features are not
is exceptional {643,2567}. In a meta-
from the subependymal plate of the lat- generally associated with poor progno-
eral ventricles {2662}. An origin fromanalysis of 310 cases of central neuro-
sis. However, a mitotic count of > 3 mi-
circumventricular organs has also beencytoma, the local control rates at 3 and
toses per 10 high-power fields has been
proposed {1186}. 5 years after gross total resection were
found to be a predictor of higher risk of
95% and 85%, respectively, versus 55%
Genetic profile recurrence {1462,2638}. In one multicen-
and 45% after subtotal resection {2052}.
Central neurocytomas contain numerous tre study of 71 patients, incomplete re-
Although most clinical studies support section was predictive of poor outcome
DNA copy number alterations {1350},
the assumption that radiotherapy is not
{2638}.
Definition
A tumour composed of small uniform
cells that demonstrate neuronal differen-
tiation but are not IDH-mutant, and that
presents throughout the CNS, without
apparent association with the ventricular
system.
Extraventricular neurocytoma is usually
well circumscribed and slow-growing,
and shares most histological features
with central neurocytoma. Because Fig. 6.44 Extraventricular neurocytoma. A Hyperintense frontal mass on T2-weighted MRI. B Hypointense mass with
some tumours (including pilocytic as- no contrast enhancement is seen on T1-weighted MRI after gadolinium administration.
trocytomas, dysembryoplastic neuroepi-
thelial tumours, gangliogliomas, papillary literature ranges from 1 to 79 years, with extraventricular neurocytomas have
glioneuronal tumours [PGNTs], oligo- the median age in the fourth decade of been associated with seizures, head-
dendrogliomas with neurocytic features, life {938,2470}. aches, visual disturbances, hemiparesis,
and diffuse leptomeningeal glioneuronal There does not seem to be a signifi- and cognitive disturbances; thalamic
tumours) show synaptophysin expres- cant relationship between sex and the and hypothalamic lesions with increased
sion, synaptophysin expression is not incidence of extraventricular neurocy- intracranial tension; and spinal lesions
sufficient to establish a diagnosis of ex- toma. The male-to-female ratio is about with motor, sensory, and sphincter dys-
traventricular neurocytoma. Strong and 1:1, with a slight female predominance function {769,2470}.
diffuse OLIG2 expression is not com- seen in some series and a slight male
Imaging
patible with a diagnosis of extraventricu- predominance seen in others {269,769,
On MRI, extraventricular neurocytoma
lar neurocytoma. Some entities that are 938}. However, because most cases re-
presents as a solitary, well-demarcated
genetically well defined (e.g. IDH-mutant ported before 2012 were not screened
mass of non-specific signal intensity and
and 1p/19q-codeleted oligodendroglio- for IDH mutations, it is difficult to be cer-
variable contrast enhancement, with a
ma and PGNTs) should be excluded by tain of the diagnosis of extraventricular
cystic component in 58% of cases, mild
appropriate genetic testing. However, the neurocytoma.
perilesional oedema in 51.5%, and cal-
genetic characteristics of extraventricular
Etiology cification in 34% {269,1518,2822}. The
neurocytoma are not yet well defined.
No specific etiology has been impli- solid component is predominantly isoin-
ICD-0 code 9506/1 cated in the genesis of extraventricular tense on T1-weighted images, but may
neurocytoma. be hypointense. On T2-weighted and
Grading
FLAIR images, the signal is predomi-
Extraventricular neurocytomas corre- Localization
nantly hyperintense.
spond histologically to WHO grade II. The cerebral hemispheres are the most
There have been suggestions for further common site for extraventricular neu- Spread
grading on the basis of mitotic rate, Ki-67 rocytoma (affected in 71% of cases). Extraventricular neurocytoma spread is
proliferation index, and the presence or The tumours most often affect the fron- particularly rare, although craniospinal
absence of vascular proliferation and/or tal lobes (in 30% of cases), followed by dissemination can occur as remote me-
necrosis {769}. The term “atypical” has the spinal cord (in 14%). These tumours tastasis or along the surgical route {938}.
been used for lesions with an elevated can occur in the thalamus, hypothalamic Cases of diffuse leptomeningeal neuroep-
mitotic rate and Ki-67 proliferation index region, cerebellum, and pons, with iso- ithelial tumour have been reported mainly
{1213}. There is some evidence that lated cases reported in cranial nerves, in children. These cases share with ex-
each the cauda equina, the sellar region, and traventricular neurocytoma some histolog-
of these factors is associated with risk of even outside the craniospinal compart- ical and immunohistochemical features,
recurrence, but definitive grading criteria ment {769,2470}. including proliferation of a uniform popula-
have not yet been established. tion of oligodendrocyte-like cells express-
Clinical features
ing synaptophysin but not R132H-mutant
Epidemiology The clinical presentation varies accord-
IDH1 {2294}. These tumours represent a
Extraventricular neurocytoma can pres- ing to the location of the tumour and
new entity (see Diffuse leptomeningeal
ent in patients of any age. The patient whether it exerts a mass effect. Cerebral
glioneuronal tumour, p. 152).
age at diagnosis of cases reported in the
Macroscopy essential for the diagnosis of extraven- mandatory, to rule out diffuse glioma with
Some examples are well circumscribed tricular neurocytoma and is present in neurocytic differentiation {356,2822}. Be-
(sometimes with a cyst-mural nodule oligodendroglioma-like cells and larger cause 1p/19q codeletion is a hallmark of
configuration), whereas others are more neurons. Clusters of neurosecretory oligodendroglioma, it is likely that pre-
infiltrative and therefore less discrete. granules are visualized by chromogranin- sumed extraventricular neurocytomas
A staining in some cases with ganglion exhibiting 1p/19q codeletion are in fact
Microscopy cells. In lesions with a glial component, oligodendrogliomas {2147}. The differen-
A wide variety of histopathological ap- these cells may be positive for GFAP. tial diagnosis also includes ganglioglio-
pearances have been reported in this R132-mutant IDH1 protein is absent {21, ma, dysembryoplastic neuroepithelial
histologically heterogeneous lesion, 2822}. Expression of OLIG2 has been tumour, and even PGNT, so it is recom-
which is usually more complex than the reported in some cases, but a more con- mended to test for BRAF V600E mutation
highly cellular, cytologically monomor- vincing example was immunonegative for and for SLC44A1-PRKCA fusion, a recur-
phous central neurocytoma {269,816}. this marker. IDH and 1p/19q status were rent genetic alteration reported in PGNT
Tumours with the dense cellularity and not reported for these cases {1714,1832}. {278}.
neuropil islands common in central neu- To date, neither high-throughput geno-
rocytoma are diagnostically straightfor- Cell of origin typing nor sequencing studies have
ward, but uncommon. More often, the There is no consensus on the putative been carried out. Microarray-based com-
tumours are less cellular and have an cell of origin. Extraventricular neurocy- parative genomic hybridization has been
oligodendroglioma-like appearance due toma may arise from mislocated neural performed in 2 cases, revealing distinct
to small, uniform round cells with arte- progenitor cells in the brain parenchyma profiles, with loss and gain of multiple
factually cleared cytoplasm embedded {269}. These neural progenitor cells dif- chromosomal loci {1732}.
in a fibrillar matrix. Unlike in central neu- ferentiate into distinct cell lineages (neu-
rocytoma, ganglion cell differentiation is rocytic and astrocytic) in this particular Prognosis and predictive factors
common. Ganglioid cells - neurons inter- microenvironment {1876}. Although extraventricular neurocytoma
mediate in size between ganglion cells is generally benign and has a low rate of
Genetic profile recurrence, outcomes are known to vary
and neurocytes - are also frequent. Hya-
Although deletion of chromosome arms considerably. In one study, the presence
linized vessels and calcifications may be
1p and 19q (either in isolation or in com- of 1p/19q codeletion was a poor prog-
present. A glial astrocytic component is
bination) has been found in extraven- nostic factor {2147}. Gross total resection
uncommon, and can be difficult to distin-
tricular neurocytoma, neither IDH1/2 has been associated with a low rate of
guish from reactive gliosis. Cases with a
mutation nor MGMT methylation has recurrence {269,769,1213}. Subtotally re-
convincing ganglion cell component can
been reported {21,356,1206,1718,1732}. sected lesions are often stable, but recur-
be labelled ganglioneurocytoma.
Therefore, if extraventricular neurocyto- rence is possible {269,769,1213}.
Immunophenotype ma is suspected on pathological exami-
Immunoreactivity for synaptophysin is nation, investigation for IDH mutation is
Definition
A rare cerebellar neoplasm with ad-
vanced neuronal/neurocytic differentia-
tion and focal lipoma-like changes.
Cerebellar liponeurocytoma affects
adults, has low proliferative activity, and
usually has a favourable prognosis. How-
ever, recurrence can occur and malig-
nant progression has been reported.
ICD-0 code 9506/1
Grading
Cerebellar liponeurocytoma corresponds
histologically to WHO grade II. Recur-
rences have been reported in almost
50% of cases. Recurrent tumours may Fig. 6.47 Cerebellar liponeurocytoma. A T1 -weighted MRI (with gadolinium) of a recurrent liponeurocytoma, presenting
as an irregular, strongly enhancing lesion in the right cerebellar hemisphere. Reprinted from Jenkinson MD et al. {1153}.
display increased mitotic activity, an in-
B Axial T1-weighted MRI after gadolinium administration shows areas of prominent hypointense signal within a well-
creased Ki-67 proliferation index, vascu-
demarcated isodense tumour {53}.
lar proliferation, and necrosis {817,1900,
2054}. The time to clinical progression
liponeurocytoma have been reported in Enhancement with gadolinium is usu-
is often long (mean: 6.5 years), but in
the English-language literature {1790}. ally heterogeneous, with areas of tumour
some cases relapse occurs within a few
The mean patient age is 50 years (range: showing variable degrees of enhance-
months {1153}.
24-77 years), with peak incidence in the ment. On T2-weighted MRI, the tumour
Synonyms third to sixth decades of life. There is no is slightly hyperintense to the adjacent
The terms “neurolipocytoma” {635}, “me- significant sex predilection {1044,1908}. brain, with focal areas of marked hyperin-
dullocytoma” {817}, “lipomatous glioneu- tensity. Associated oedema is minimal or
Localization
rocytoma” {57}, and “lipidized mature absent {34}. Fat-suppressed images may
Cerebellar liponeurocytoma most com-
neuroectodermal tumour of the cerebel- be helpful in supporting a preoperative
monly involves the cerebellar hemi-
lum’’ {866} have been proposed. The diagnosis {53}.
spheres, but can also be located in the
term “cerebellar liponeurocytoma” is now
paramedian region or vermis and extend Microscopy
widely accepted and is supported by ge-
to the cerebellopontine angle or fourth Cerebellar liponeurocytoma is a very rare
netic analyses that indicate that this le-
ventricle {1790}. adult cerebellar neoplasm composed of
sion is a rare but distinct clinicopathologi-
a uniform population of small neurocytic
cal entity {1044,1790,2400}. Clinical features
cells arranged in sheets and lobules and
Headache and other symptoms and
Epidemiology with regular round to oval nuclei, clear
signs of raised intracranial pressure (ei-
More than 40 cases of cerebellar cytoplasm, and poorly defined cell mem-
ther from the lesion itself or due to ob-
branes. The histological hallmark of this
structive hydrocephalus) are common entity is focal accumulation of lipid-laden
presentations. Cerebellar signs, includ-
cells that resemble adipocytes but con-
ing ataxia and disturbed gait, are also
stitute lipid accumulation in neuroepithe-
common {1867}.
lial tumour cells.
Imaging Electron microscopy shows dense-core
On CT, the tumour is variably isodense and clear vesicles, microtubule-contain-
or hypodense, with focal areas of marked ing neurites, and (occasionally) synapse-
hypoattenuation corresponding to fat like structures {766,817}.
density {53,1790}. On T1-weighted MRI, The growth fraction of the small-cell com-
the tumour is isointense to hypointense, ponent, as determined by the Ki-67 pro-
with patchy areas of hyperintensity corre- liferation index, is usually in the range of
Age at diagnosis
sponding to regions of high lipid content. 1-3%, but can be as high as 6%, with a
Fig. 6.46 Age distribution of cerebellar liponeurocytoma,
mean value of 2.5% {635,1200,2400}. In
based on 25 published cases.
Fig. 6.49 Cerebellar liponeurocytoma. A Small tumour cells and neoplastic cells with lipomatous differentiation express MAP2; similarly, liponeurocytomas also express synaptophysin.
B Expression of the astrocytic marker GFAP is observed in most cases, but only focally. C The Ki-67 proliferation index (as determined by nuclear MIB1 monoclonal antibody staining)
is usually low.
the adipose component, the Ki-67 prolif- 2054}. Similarly, the lipidized component tent expression of neuronal markers, in-
eration index is even lower. Features of may be markedly reduced or even ab- cluding neuron-specific enolase, syn-
anaplasia such as nuclear atypia, necro- sent {2054} in recurrent lesions. aptophysin, and MAP2. Focal GFAP
sis, and microvascular proliferation are expression by tumour cells, which in-
Immunophenotype dicates astrocytic differentiation, is ob-
typically absent in primary lesions, but
may be found in recurrent tumours {817, Immunohistochemically, there is consis- served in most cases {2400}. One report
Fig. 6.50 Cerebellar liponeurocytoma. Electron microscopy shows dense-core and clear vesicles, microtubule-containing neurites, and occasionally synapse-like structures.
Fig. 6.53 A Intraoperative aspect of a spinal paraganglioma attached to the filum terminate. B Macroscopic aspect
Number of cases Number of cases of a spinal paraganglioma attached to a nerve root. A well-circumscribed, solid tumour, partly attached to a spinal root;
Fig. 6.52 Age and sex distribution of spinal formalin fixed.
paraganglioma, based on 71 published cases.
Paraganglioma 165
encompassing the lobules, their long
processes are often so attenuated that
they are not visible on routine light mi-
croscopy and can be detected only on
immunostains for S100 protein. Approxi-
mately 25% of all cauda equina paragan-
gliomas are so-called gangliocytic para-
gangliomas, containing mature ganglion
cells and a Schwann cell component
{313}. Ependymoma-like perivascular
formations are also common. Some tu-
mours show architectural features remi-
niscent of carcinoid tumours, including
angiomatous, adenomatous, and pseu-
dorosette patterns {2395}. Tumours com-
posed predominantly of spindle {1712}
and melanin-containing cells (called mel-
anotic paragangliomas) {773,1712} have
also been described at this site, as has
oncocytic paraganglioma {1889}. Foci of
haemorrhagic necrosis may occur, and Fig. 6.56 This paraganglioma shows subcapsular haemosiderin, visualized with Peris Prussian blue stain.
scattered mitotic figures can be seen.
Neither these features nor nuclear pleo-
morphism is of prognostic significance Gangliocytic paragangliomas containing syndromes caused by any SDH muta-
{2395}. a variable mixture of epithelioid neuroen- tion. Although SDHB immunohistochem-
docrine cells, Schwann cell-like cells, istry has become part of the routine as-
Ultrastructure and scattered ganglion cells can show sessment of paragangliomas in many
The distinctive ultrastructural feature of cytokeratin positivity in the epithelioid centres {1655}, it is probably of limited
chief cells is the presence of dense-core cells {894,2328}. Expression of 5-HT value in cauda equina paragangliomas
(neurosecretory) granules measuring and various neuropeptides (e.g. soma- given the very low rate of SDH mutations
100-400 nm (mean: 140 nm). Sustentac- tostatin and met-enkephalin) has been {1420,1955}.
ular cells are characterized by an elon- demonstrated in paragangliomas of the Sustentacular cells show inconsistent
gated nucleus with marginal chromatin, cauda equina region {1712,2395}. Loss (sometimes only focal) S100 protein re-
increased cytoplasmic electron density, of SDHB expression is considered a sur- activity {313} and usually show staining
relative abundance of intermediate fila- rogate marker for familial paraganglioma for GFAP as well. Chief cells may also
ments, and lack of dense-core granules
{647,2395}.
Immunophenotype
Consistent with their neuroendocrine
differentiation, the chief cells of para-
gangliomas are immunoreactive for the
commonly used neuroendocrine mark-
ers chromogranin-A and synaptophysin
{1303,1655,2395}. The diagnosis of para-
ganglioma in other sites is confirmed by
positivity for tyrosine 3-monooxygenase,
the rate-limiting enzyme in catechola-
mine synthesis {1655}. However, this test
is usually not required for cauda equina
paragangliomas, because it distinguish-
es paragangliomas from other neuroen-
docrine carcinomas, which are not con-
sidered in the differential diagnosis in
this location. Whereas paragangliomas
in other sites are cytokeratin-immunon-
egative, those arising from the cauda
equina can show positivity for cytokerat-
ins, typically in the form of perinuclear
immunoreactivity {432,894,1655,2438}. Fig. 6.57 Paraganglioma Immunophenotype. A Chromogranin. B Synaptophysin. C Spinal paragangliomas express
cytokeratins. D S100 is expressed by sustentacular cells and occasional chief cells.
Paraganglioma 167
Nakazato Y.
Pineocytoma Jouvet A.
Vasiljevic A.
abundant delicate tumour cell processes. is characterized by large ganglion cells annulate lamellae, cilia with a 9 + 0 mi-
Pineocytomatous rosettes are not seen and/or multinucleated giant cells with bi- crotubular pattern, microtubular sheaves,
in normal pineal gland. In pineocytoma, zarre nuclei {240,997,1384,1638,2279}. fibrous bodies, vesicle-crowned rodlets,
poorly defined lobules may be seen, but The mitotic activity of this pattern is still heterogeneous cytoplasmic inclusion,
a conspicuous lobular architecture is in- low, despite the tumours’ ominous nu- and membrane whorls, as well as mito-
stead a feature of normal pineal gland. clear appearance. The stroma of pineo- chondrial and centriolar clusters. Mem-
Most nuclei are round to oval, with incon- cytoma consists of a delicate network of brane-bound dense-core granules and
spicuous nucleoli and finely dispersed vascular channels lined by a single layer clear vesicles are present in the cyto-
chromatin. Cytoplasm is moderate in of endothelial cells and supported by plasm and cellular processes. The cellu-
quantity and homogeneously eosino- scant reticulin fibres. Microcalcifications lar processes show occasional synapse-
philic. Processes are conspicuous and are occasionally seen but usually corre- like junctions.
short, often ending in club-shaped ex- spond to calcifications of the remaining
Immunophenotype
pansions that are optimally demonstrated pineal gland.
Pineocytoma cells usually show strong
by neurofilament immunostaining or sil-
Electron microscopy immunoreactivity for synaptophysin, neu-
ver impregnation. Mitotic figures are lack-
Ultrastructurally, pineocytomas are com- ron-specific enolase, and NFP. Variable
ing (with < 1 mitosis per 10 high-power
posed of clear and various numbers of staining has also been reported for other
fields) in all but occasional large speci-
dark cells joined with zonulae adherentes neuronal markers, including class III be-
mens {1187}. Pineocytomatous rosettes
{968,997,1185,1674}. The cells extend ta-tubulin, microtubule-associated pro-
vary in number and size. Their anucleate
tapering processes that occasionally ter- tein tau, UCHL1, chromogranin-A, and
centres are composed of delicate, en-
minate in bulbous ends. Their cytoplasm the neurotransmitter 5-HT
meshed cytoplasmic processes resem-
is relatively abundant and contains well- {477,1185,1187,
bling neuropil {240,1187,1811,2279}. The
developed organelles. Pineocytoma 1384,1811,2809}. Photosensory differen-
nuclei surrounding the periphery of the
cells share numerous ultrastructural fea- tiation is associated with immunoreactiv-
rosette are not regimented. A pleomor-
tures with normal mammalian pinealo- ity for S-arrestin and rhodopsin {1638,
phic cytological variant is encountered
cytes, such as paired twisted filaments, 1811,1933}. In pleomorphic variants, the
in some pineocytomas {701}. This variant
Fig. 7.05 Pleomorphic pineocytoma. A Pleomorphism and gangliocytic differentiation. B Mono- and multinucleated ganglion cells.
Pineocytoma 171
Fig. 7.06 Pineocytoma. A Pineocytomatous rosettes show intense Immunoreactivity for synaptophysin. B The cytoplasm and processes of tumour cells show intense Immunoreactivity
for NFP. C Pleomorphic cells often show Immunoreactivity for NFP.
ganglioid cells usually express several pinealocytes predominate. To a vari- the RB1 gene and pineocytoma has not
neuronal markers, especially NFP. able extent, pineal parenchymal tumours been established. A microarray analysis
mimic the developmental stages of the of pineocytoma has shown high-level ex-
Proliferation pression of genes coding for enzymes
human pineal gland. In tissue culture,
In most cases, mitotic figures are very related to melatonin synthesis (i.e. TPH1
pineocytoma cells are also capable of
rare or absent {702,1187,1217}. The mean and ASMT) and genes involved in retinal
synthesizing 5-HT and melatonin {700}.
Ki-67 proliferation index is < 1% {91,702, The immunoexpression of CRX and phototransduction (i.e. OPN4, RGS16,
1217}. and CRB3). These reactivities indicate
ASMT in pineocytoma is an additional
Cell of origin indication that these tumours are biologi- bidirectional neurosecretory and photo-
The histogenesis of pineal parenchymal cally linked to pinealocytes {754,2241}. sensory differentiation {698}.
tumours is linked to the pinealocyte, a CRX is a transcription factor involved in
Genetic susceptibility
cell with photosensory and neuroendo- the development and differentiation of
No syndromic associations or genetic
crine functions. The ontogeny of the hu- pineal cell lineage, and ASMT is a critical
susceptibilities have been demonstrated.
man pineal gland recapitulates the phy- enzyme for the synthesis of melatonin (a
The occurrence of pineocytoma in sib-
togeny of the retina and the pineal organ hormone produced by the pineal gland).
lings was reported in one family {796}.
{1675}. During the late stages of intrauter-
Genetic profile
ine life and the early postnatal period, the Prognosis and predictive factors
Conventional cytogenetic studies based
human pineal gland consists primarily of The clinical course of pineocytomas is
on karyotypes are rare. Karyotype analy-
cells arranged in rosettes similar to those characterized by a tong interval {4 years
sis of 3 pineocytomas demonstrated
of the developing retina. These feature in one series) between the onset of symp-
a pseudodiploid or hypotriploid profile
abundant melanin pigment as well as toms and surgery {240}. No strictly clas-
with various numerical and structural ab-
cilia with a 9 + 0 microtubular pattern. By sified pineocytomas have been shown
normalities, including loss of all or part
the age of 3 months, the number of pig- to metastasize {677,2278}. The reported
of chromosome 22, toss or partial dele-
mented cells gradually decreases so that 5-year survival rate of patients with pine-
tion of chromosome 11, toss of chromo-
pigment becomes undetectable by his- ocytoma ranges from 86% to 91% {677,
some 14, and gain of chromosomes 5
tochemical methods {1675}. As differen- 2278}. In one series, the 5-year event-
and 19 {162,525,2061}. However, no
tiation progresses, cells that are strongly free survival rate was 100% {677}. Extent
chromosomal gains or tosses were found
immunoreactive for neuron-specific eno- of surgery is considered to be the major
by comparative genomic hybridization
lase accumulate. By the age of 1 year, prognostic factor for pineocytoma {465}.
analysis {2122}. A relationship between
Fig. 7.07 Pineocytoma. A In a pineocytomatous rosette, tumour cells surround an eosinophilic fibrillated core. B Argyrophilic tumour cell processes end with club-shaped
expansions in the pineocytomatous rosettes (Bodian silver impregnation). C Ultrastructure of a pineocytomatous rosette, showing numerous cell processes filled with clear vesicles,
dense-core granules, and mitochondria.
Definition anaplasia” {2586}, and “pineoblastoma pineal gland into the posterior third ven-
A tumour of the pineal gland that is in- with lobules” {240}. These terms have ob- tricle, with compression of the corpora
termediate in malignancy between pineo- scured the value of the designation, and quadrigemina and compromise of cere-
cytoma and pineoblastoma and is com- they are not recommended. brospinal fluid flow through the aqueduct.
posed of diffuse sheets or large lobules In earlier studies, no true PPTID group Compression of the superior colliculus by
of monomorphic round cells that appear was identified. However, mixed pineo- the expanding mass may cause ocular
more differentiated than those observed cytoma-pineoblastoma was sometimes movement abnormalities (i.e. Parinaud
in pineoblastomas. described as an intermediate tumour be- syndrome), including paralysis of upward
Pleomorphic cytology may be present. tween pineocytoma and pineoblastoma gaze, pupillary abnormalities (i.e. slightly
Pineal parenchymal tumours of interme- {1638,2279}. By definition, this tumour is dilated pupils that react to accommoda-
diate differentiation (PPTIDs) occur main- composed of clearly delineated areas of tion but not to light), and nystagmus re-
ly in adults (mean patient age: 41 years), pineoblastoma admixed with well-demar- tractorius {69,195,757,2319}. A rare case
and show variable biological and clini- cated areas of pineocytoma. Neoplastic of apoplectic haemorrhage of a PPTID
cal behaviour, from low-grade tumours cells lack the so-called intermediate mor- with sudden-onset symptoms has been
with frequent local and delayed recur- phology that is required for a diagnosis reported {2684}.
rences to high-grade tumours with risk of of PPTID. Mixed pineocytoma-pineo-
craniospinal dissemination. Accordingly, Imaging
blastoma should not be included in the
mitotic activity, Ki-67 proliferation index, On imaging, PPTIDs usually present as
PPTID group, but rather belongs in the
and neuronal and neuroendocrine differ- bulky masses with local invasion. They
pineoblastoma group (see Pineoblasto-
entiation are also variable, and reported are more rarely circumscribed. On CT, the
ma, p. 176).
5-year overall survival rates range from tumours may show occasional peripheral
39% to 74% {677,1187}. Epidemiology so-called exploded calcifications {1321}.
PPTIDs account for approximately 45% On MRI, PPTIDs are heterogeneous and
ICD-0 code 9362/3 of all pineal parenchymal tumours, with mostly hypointense on T1-weighted im-
a range of 21-54% in most recent series ages and hyperintense on T2-weighted
Grading
{91,1105,2809,2868}. Earlier reported in- images. On both CT and MRI, postcon-
The biological behaviour of pineal paren-
cidence rates of PPTID were even more trast enhancement is usually marked and
chymal tumour of intermediate differen-
variable, from 0% to 59%, reflecting the heterogeneous {1105,1321}.
tiation is variable and may correspond to
general ignorance of this pineal paren-
WHO grades II or III, but definite histolog- Spread
chymal tumour, the frequent misdiag-
ical grading criteria remain to be defined. PPTIDs have a potential for local recur-
nosis of the entity, and/or the inclusion
rence and craniospinal dissemination
Synonyms and historical annotation of mixed pineocytoma-pineoblastomas
{677,1105,2708,2835}. Local recurrence
The category of PPTID was first clearly and other unusual pineal parenchymal tu-
occurs in approximately 22% of cases
introduced in 1993 by Schild et al. {1185, mours in this group {240,1187,1638,1811}.
{677}. Craniospinal dissemination may be
1674,2279}. PPTIDs have been reported PPTIDs can occur in patients of any age,
observed at the time of diagnosis (in 10%
under various names, such as “malignant but most frequently affect adults, with
of cases) or may occur during the course
pineocytoma” {997}, “pineocytoma with a mean patient age of 41 years (range:
of the disease (in 15% of cases) {677}.
1-83 years) {754,1105,1187,2809}. There
is a slight female preponderance, with a Macroscopy
male-to-female ratio of 0.8:1. The gross appearance of PPTIDs is simi-
lar to that of pineocytomas. They are cir-
Localization
cumscribed, soft in texture, and lacking
PPTIDs are localized in the pineal region. gross evidence of necrosis. An irregular
tumour surface was observed by endos-
Clinical features copy in a case with spinal metastasis
{1105}.
The clinical presentation is similar to that
of other pineal parenchymal tumours. Microscopy
The main symptoms are headaches and PPTID may exhibit two architectural
vomiting, related to increased intracranial patterns: diffuse (neurocytoma- or oli-
Fig. 7.08 Age distribution of pineal parenchymal tumours pressure caused by obstructive hydro- godendroglioma-like) and/or lobulated
of intermediate differentiation, based on 142 published cephalus. Hydrocephalus is the con-
cases, both sexes. sequence of tumoural extension of the
(with vessels delineating vague lobules) wide range of reported mitotic counts nuclear NeuN staining in PPTID {1217,
{1187}. Transitional cases also exist, de- reflects the difficulty in making the 1487,2684}. ASMT-positive cells are sig-
fined as tumours in which typical pineo- diagnosis (often in a small biopsy); there nificantly more numerous in PPTIDs than
cytomatous areas are associated with a were 0 mitoses per 10 high-power fields in pineoblastomas {754}. In pleomorphic
diffuse or lobulated pattern more consist- in 54% of cases, 1-2 in 28%, 3-6 in 15%, variants, the ganglioid cells usually ex-
ent with PPTID. PPTIDs are characterized and rarely > 6 {1187}. press several neuronal markers, espe-
by moderate to high cellularity. The neo- In the PPTID group, the mean Ki-67 pro- cially NFP {701,1384}.
plastic cells usually harbour round nuclei liferation index is usually significantly dif-
Cell of origin
showing mild to moderate atypia and a ferent from those of pineocytomas and
Pineal parenchymal tumours arise from
so-called salt-and-pepper chromatin. pineoblastomas, ranging from 3.5% to
pinealocytes or their precursor cells, and
The cytoplasm of cells is more easily 16.1% {91,1105,2122,2835,2868}.
the close kinship among pineocytoma,
distinguishable than in pineoblastoma.
Immunophenotype PPTID, and pineoblastoma is evidenced
A pleomorphic cytological variant may
Immunohistochemistry shows synapto- by several shared clinical, morphologi-
be encountered in PPTIDs as well as in
physin positivity {91,754,1105,1187}. Vari- cal, and genetic features {698,1187,1674,
pineocytomas {701,1384}. This variant is
able labelling is also seen with antibod- 2279}. The immunoexpression of cone-
characterized by bizarre ganglioid cells
ies to NFP and chromogranin-A {1185, rod homeobox (CRX) and acetylseroto-
with single or multiple atypical nuclei and
1187,2586,2809}. GFAP and S100 pro- nin methyltransferase (ASMT) proteins
abundant cytoplasm. Mitotic activity is
tein are usually expressed in astrocytic in PPTID is an additional indication that
low to moderate.
interstitial cells {91,1187}. Ganglion cells PPTIDs are biologically linked to pinealo-
Proliferation in pleomorphic variants may also ex- cytes {754,2241}. CRX is a transcription
PPTID is a potentially aggressive neo- press S100 protein {1187}. Like in other factor involved in the development and
plasm. In a large published series, the pineal parenchymal tumours, there is no differentiation of pineal cell lineage, and
Fig. 7.10 Pineal parenchymal tumour of intermediate differentiation. A Diffuse pineal parenchymal tumour of intermediate differentiation. This tumour is composed of round cells with
a conspicuous cytoplasm and round to oval nuclei with delicate chromatin. B Pleomorphic cells in a low-grade pineal parenchymal tumour of intermediate differentiation.
ASMT is a critical enzyme for the synthe- Prognosis and predictive factors spinal dissemination {28%) {677}. The
sis of melatonin (a hormone produced by Compared with pineoblastomas, PPTIDs low-grade and high-grade prognostic
the pineal gland). are more likely to present with local- groups also showed a significantly differ-
ized disease, and they have a better ent mean Ki-67 proliferation index {5.2%
Genetic profile vs 11.2%) {702}. Although an associa-
prognosis, with a median overall survival
By comparative genomic hybridization, tion has been found in some studies be-
of 165 months (vs 77 months for pineo-
frequent chromosomal changes have blastoma) and a median progression- tween NFP immunopositivity and a bet-
been identified in PPTIDs. An average of ter prognosis, the use of this criterion to
free survival of 93 months (vs 46 months
3.3 gains and 2 losses has been report- assess prognosis in pineal parenchymal
for pineoblastoma) {1549}. In one study,
ed {2122}. The most common chromo- tumours remains controversial {91,1187,
prognosis was related to mitotic count
somal imbalances in PPTID are 4q gain, 2835}. In another study, PPTIDs in the
and to neuronal differentiation as as-
12q gain, and 22 loss. In one RT-PCR low-risk group (defined by < 3 mitoses
sessed by anti-NFP immunohistochem-
analysis, the expression of four genes istry {677,1187}. Low-grade PPTIDs were per 10 high-power fields and a Ki-67 pro-
(PRAME, CD24, POU4F2, and HOXD13) liferation index of < 5%) had better over-
defined as tumours showing < 6 mitoses
in high-grade PPTID was high, almost to all survival and progression-free survival
per 10 high-power fields and expression
the levels seen in pineoblastoma, and in than did PPTIDs in the high-risk group
of NFP in numerous cells {1187}. In this
contrast to the low expression of these (defined by > 3 mitoses per 10 high-
group, the 5-year overall survival rate
genes in pineocytoma and low-grade power fields or a Ki-67 proliferation index
was 74%. Recurrences occurred in 26%
PPTID {698}. One analysis showed ex- of patients and most were mainly local of > 5%) {2835}. The relevance of these
pression of EGFRvlll in a PPTID without criteria (mitotic count, NFP immunoex-
and delayed {677}. High-grade PPTIDs
concomitant EGFR qene amplification pression, and Ki-67 proliferation index)
were defined as tumours showing < 6
{1487}. requires confirmation by further studies;
mitoses per 10 high-power fields but no
Genetic susceptibility or only rare expression of NFP, or show- consequently, there are currently no rec-
No syndromic associations or genetic ing > 6 mitoses per 10 high-power fields ommended criteria for grading PPTID
susceptibilities have been reported for and NFP expression in numerous cells (see Grading, p. 173). Transformation of
PPTID. {1187}. In this group, the 5-year overall PPTID into pineoblastoma has been rare-
survival rate was 39%. Risk of recur- ly reported {1050,1272}.
rence was higher {56%), as was risk of
an occasional small nucleolus, scant cy- Mixed pineocytoma-pineob/astoma pineoblastoma because of their pineal
toplasm, and indistinct cell borders. The Mixed tumours are somewhat contro- localization, primitive neuroectodermal
diffuse growth pattern is interrupted only versial neoplasms showing a biphasic tumour-like component, and highly ag-
by occasional rosettes. Pineocytomatous pattern with distinct alternating areas gressive clinical course. Historically,
rosettes are lacking, but Homer Wright resembling pineocytoma and pineoblas- pineal anlage tumours were named af-
and Flexner-Wintersteiner rosettes may toma. Most importantly, areas resembling ter their shared histological features with
be seen. Flexner-Wintersteiner rosettes pineocytoma must be distinguished from melanotic neuroectodermal tumour of
indicate retinoblastic differentiation, as overrun normal parenchyma {997,1638, infancy (or retinal anlage tumour, a be-
do highly distinctive but infrequently oc- 1811,2279}. nign tumour typically located in the max-
curring fleurettes. Mitotic activity varies, illa with local aggressiveness). Despite
Pineal anIage tumours shared features with pineoblastomas,
but is generally high, and necrosis is
Pineal anlage tumours are extremely rare pineal anlage tumours have a distinct
common {997,1187,1674,2279}.
neoplasms of the pineal region. They are morphology. They are characterized by
often considered a peculiar variant of a combination of neuroectodermal and
Fig. 7.16 Pineoblastoma. A Nuclear expression of SMARCB1 (also called INI1). B Variable synaptophysin expression is a frequent finding. C Cytoplasmic expression of NFP may
be focally observed, but is rare.
Pineoblastoma 177
Fig. 7.17 Pineal anlage tumour. A Striated muscle cells. B Tubular structures composed of epithelioid cells containing melanin pigment. C Ganglion cells may be seen. D Area
resembling pineoblastoma with sheets of small blue round cells.
heterologous ectomesenchymal compo- abundant euchromatin as well as hetero- and includes reactivity for neuronal,
nents. The neuroepithelial component chromatin. The cytoplasm is scant and glial, and photoreceptor markers. Posi-
is characterized by pineoblastoma-like contains polyribosomes, few profiles of tivity for synaptophysin, neuron-specific
sheets or nests of small blue round cells, rough endoplasmic reticulum, and small enolase, NFP, class III beta-tubulin, and
neuronal ganglionic/glial differentiation, mitochondria, as well as occasional mi- chromogranin-A may also be seen, as
and/or melanin-containing epithelioid crotubules, intermediate filaments, and may S-arrestin staining {1187,1638,1811,
cells. The ectomesenchymal component lysosomes {1587,1674,1811}. Dense-core 1933,2809}. Reactivity for GFAP should
contains rhabdomyoblasts, striated mus- granules are rarely seen in the cell body prompt the exclusion of entrapped reac-
cle, and/or cartilaginous islands {29,177, {1587,1674}. Cell processes, which are tive astrocytes. SMARCB1 is consistently
2288}. Given these distinctive character- poorly formed and short, may contain mi- expressed in pineoblastomas {1669,
istics, it is likely that pineal anlage tumour crotubules as well as scant dense-core 2497}.
constitutes a separate entity. granules {1587}. Bulbous endings are
not seen {1674}. Junctional complexes of Cell of origin
Proliferation Pineoblastomas share morphological
zonula adherens and zonula occludens
The mean Ki-67 proliferation index in and immunohistochemical features with
type may be present between cells and
pineoblastoma ranges from 23.5% to cells of the developing human pineal
processes {1185,1587,1674,1811}. Syn-
50.1% {91,702,754,2122}. gland and retina. Evidence of this ontoge-
apses are absent {1811}. Cilia with a
netic concept includes the expression of
Electron microscopy 9 + 0 microtubular pattern are occasion-
ally seen {1587}. Rarely, cells radially ar- ASMT, CRX, S-arrestin, and rhodopsin in
Characterized by a relative lack of sig-
pineal parenchymal tumours {754,1638,
nificant differentiation, the fine structure ranged around a small central lumen are
2241} and the occasional association
of pineoblastoma is similar to that of encountered {1811}.
between bilateral retinoblastoma and
any poorly differentiated neuroectoder-
Immunophenotype pineoblastoma (a condition called trilat-
mal neoplasm. The cells are round to
The Immunophenotype of pineoblasto- eral retinoblastoma syndrome) {544}. The
oval, with slightly irregular nuclei and
mas is similar to that of pineocytomas occasional progression from lower-grade
Pineoblastoma 179
Jouvet A.
Papillary tumour of the pineal region Vasiljevic A.
Nakazato Y.
Paulus W.
Hasselblatt M.
other series, increased proliferative activ- present in some cells {512,696,1184}. that papillary tumours of the pineal region
ity (defined as a Ki-67 proliferation index may originate from remnants of the spe-
of > 10%) was observed in 39% and 40% Immunophenotype cialized ependymal cells of the subcom-
of cases, respectively {696,984}. High The most distinctive immunohistochemi- missural organ {1184}. Further evidence
proliferative activity has been linked to cal feature of papillary tumours of the for a putative origin from specialized
younger patient age {699}. pineal region is their reactivity for kerat- ependymocytes of the subcommissural
ins (KL1, AE1/AE3, CAM5.2, and CK18), organ comes from the high levels of ex-
Electron microscopy pression in papillary tumour of the pineal
On electron microscopy, papillary tu- particularly in papillary structures. GFAP
expression is less common than in region of genes expressed in the sub-
mours of the pineal region show com- commissural organ, including ZFHX4,
bined ependymal, secretory, and neu- ependymomas. Papillary tumours of the
pineal region also stain for vimentin, S100 SPDEF, RFX3, TTR, and CALCA {698,
roendocrine features. Papillary tumours 986}. Papillary tumours of the pineal re-
of the pineal region are usually com- protein, neuron-specific enolase, MAP2,
NCAM1, and transthyretin {957,2344}. gion have a claudin expression profile
posed of alternating clear and dark epi- similar to that of the subcommissural or-
thelioid cells adjoined at the apical region Focal membrane or dot-like EMA staining
as encountered in ependymomas is rare gan in human fetuses (i.e. claudin-1 and
by well-formed intercellular junctional -3 positivity and claudin-2 negativity) and
complexes. Apical poles of cells show {957,1184,1383}. NFP immunolabelling is
never seen, whereas the neuroendocrine rats (i.e. claudin-3 positivity) {696,2474}.
numerous microvilli with occasional cilia.
The nuclei are oval, indented, or irregu- markers synaptophysin and chromogra- Genetic profile
lar and are frequently found at one pole nin-A are sometimes weakly and focally In two comparative genomic hybridiza-
of the cell. Interdigitated ependymal-like expressed {1184}. Most papillary tumours tion studies, recurrent chromosomal
processes are seen at the basal pole of of the pineal region are characterized by imbalances included losses of chro-
some cells and are bordered by a base- the absence of staining for membranous mosome 10 (in 7 of 8 cases) as well as
ment membrane. Zonation of organelles KIR7.1, cytoplasmic stanniocalcin-1, cad- gains on chromosomes 4 (in 6 of 8 cas-
may be observed. The cytoplasm is usu- herin-1, and claudin-2, markers that are es) and 9 (in 7 of 8 cases) {902,957}. On
ally rich in organelles, which include nu- frequently present in choroid plexus tu- high-resolution copy number analysis,
merous clear and coated vesicles, mito- mours {696,699,957}. losses affecting chromosome 10 were
chondria, and rare dense-core vesicles. Cell of origin observed in all 5 cases examined; losses
Rough endoplasmic reticulum is abun- Immunohistochemical findings (i.e. cy- of chromosomes 3, 14, and 22 and gains
dant, and dilated cisternae filled with a tokeratin positivity) and ultrastructural of whole chromosomes 8, 9, and 12 were
granular secretory product may be seen. demonstration of ependymal, secretory, observed in > 1 case. These findings
Perinuclear intermediate filaments are and neuroendocrine organelles suggest were confirmed in a recent study that
Fig. 7.21 Papillary tumour of the pineal region. A CK18 is expressed in the epithelial-like neoplastic cells. Immunoexpression may be diffuse (as in this example) or may predominate
in perivascular areas. B Expression of CK18 predominates in perivascular areas. C NCAM1 (also called CD56) is usually strongly expressed, whereas only faint and focal
immunopositivity is reported in choroid plexus tumours.
Introduction respective cell signalling pathways. The 2016 WHO classification of medulloblastomas
In this update of the WHO classifica- four principal groups emerged from clus- Medulloblastomas, genetically defined
tion, medulloblastomas are classified tering analyses following transcriptome,
Medulloblastoma, WNT-activated
according to molecular characteristics microRNA, and methylome profiling, and
in addition to histopathological features. there is excellent concordance across Medulloblastoma, SHH-activated and TP53-mutant
The molecular classification relates to these platforms for the assignment of Medulloblastoma, SHH-activated and
the clustering of medulloblastomas into individual tumours {142,1804}. There are TP53-wildtype
groups on the basis of transcriptome or also significant associations between the Medulloblastoma, non-WNT/non-SHH
methylome profiling and has been intro- four groups and specific genetic altera- Medulloblastoma, group 3
duced because of its increasing clinical tions and clinicopathological variables.
Medulloblastoma, group 4
utility {1804}. A histopathological classifi- In the updated WHO classification, WNT-
cation has also been retained, due to its activated medulloblastomas (accounting Medulloblastomas, histologically defined
clinical utility when molecular analysis is for -10% of cases) and SHH-activated Medulloblastoma, classic
limited or not feasible. medulloblastomas (-30% of cases) are
Desmoplastic/nodular medulloblastoma
Transcriptome profiling studies of medul- listed separately from non-WNT/non-
loblastomas indicate that these tumours SHH tumours, which comprise group 3 Medulloblastoma with extensive nodularity
can be separated into several distinct tumours (-20% of cases) and group 4 Large cell / anaplastic medulloblastoma
molecular clusters {2524}, which by tumours (-40% of cases). Group 3 and Medulloblastoma, NOS
consensus have been distilled into four group 4 medulloblastomas are listed as
principal groups: WNT-activated medul- provisional variants, because they are
loblastomas, SHH-activated medullo- not as well separated as WNT-activated Medulloblastoma has always been con-
blastomas, group 3 medulloblastomas, and SHH-activated medulloblastomas sidered to be an embryonal tumour of
and group 4 medulloblastomas. in molecular clustering analyses and by the cerebellum. However, WNT-acti-
Tumours in the WNT-activated and SHH- current clinical laboratory assays {448, vated medulloblastomas are thought
activated groups show activation of their 1335}. to arise from cells in the dorsal brain
stem {831}, although not all brain stem
Table 8.01 Medulloblastoma subtypes characterized by combined genetic and histological parameters embryonal tumours are WNT-activated
Genetic profile Histology Prognosis medulloblastomas.
The established morphological variants of
Low-risk tumour; classic morphology found
Classic medulloblastoma (i.e. desmoplastic/nod-
in almost all WNT-activated tumours
Medulloblastoma, WNT-activated Large cell / anaplastic ular medulloblastoma, medulloblastoma
Tumour of uncertain clinicopathological
(very rare) with extensive nodularity, and large cell or
significance
anaplastic medulloblastomas) have their
Classic Uncommon high-risk tumour own particular clinical associations {619,
Large cell / anaplastic High-risk tumour; prevalent in children 1603,1626,1627}. Large cell and ana-
Medulloblastoma, SHH-activated, aged 7-17 years plastic medulloblastomas were listed as
Desmoplastic/nodular
TP53-mutant Tumour of uncertain clinicopathological separate variants in the previous version
(very rare)
significance of the classification, but because nearly
Classic Standard-risk tumour
all large cell tumours also demonstrate
an anaplastic component and both vari-
Tumour of uncertain clinicopathological
Medulloblastoma, SHH-activated, Large cell / anaplastic ants are associated with a poor outcome,
significance
they are commonly considered for clinical
Low-risk tumour in infants; prevalent in
TP53-wildtype Desmoplastic/nodular purposes as being in a single combined
infants and adults
category of large cell / anaplastic medul-
Extensive nodularity Low-risk tumour of infancy loblastoma {2208,2664}. This association
Medulloblastoma,
Classic Standard-risk tumour and its designation have been recog-
non-WNT/non-SHH, group 3
Large cell / anaplastic High-risk tumour
nized in the update of the classification.
The molecular and morphological variants
Standard-risk tumour; classic morphology
Classic of medulloblastoma listed in the new clas-
Medulloblastoma, found in almost all group 4 tumours
sification demonstrate particular relation-
non-WNT/non-SHH, group 4
Tumour of uncertain clinicopathological ships {631}. All true desmoplastic/nodular
Large cell / anaplastic (rare)
significance
medulloblastomas and medulloblastomas
Predominant Classic
Classic Desmoplastic / nodular Large cell / anaplastic Classic
pathological variant(s) Large cell / anaplastic
MYCN amplification
Frequent copy number PTCH1 deletion MYC amplification MYCN amplification
Monosomy 6 GLI2 amplification
alterations 10q loss isodicentric 17q isodicentric 17q
17p loss
PTCH1 mutation
CTNNB1 mutation PVT1-MYC KDM6A
Frequent genetic SMO mutation (adults)
DDX3X mutation TP53 mutation GFI1/GFI1B structural GFI1/GFI1B structural
alterations SUFU mutation (infants)
TP53 mutation variants variants
TERT promoter mutation
CD133+/lineage-
Cerebellar granule neuron cell precursors of the external neural stem cells
Lower rhombic lip
Proposed cell of origin granule cell layer and cochlear nucleus (Cerebellar granule neuron Unknown
progenitor cells
(Neural stem cells of the subventricular zone)* cell precursors of the ex-
ternal granule cell layer)*
with extensive nodularity align with the into an integrated diagnosis that brings its origins in cells of the dorsal brain stem
SHH-activated molecular group. Virtually together molecular group, histopatholog- that are derived from the lower rhombic
all WNT-activated tumours have classic ical variant, and specific genetic altera- lip. Medulloblastoma variants show a
morphology. Most large cell / anaplastic tion to enhance the level of diagnostic broad range of morphological features,
tumours belong either to the SHH-activat- precision. including neurocytic and ganglionic dif-
ed group or to group 3. Immunohistochemical assays that work ferentiation, and distinct biological be-
on formalin-fixed paraffin-embedded tis- haviours. In making a diagnosis medul-
Integrated diagnosis
sue and are readily available worldwide loblastoma, it is important to exclude
This updated classification is intended to
can be used to discern some genetically histopathologically similar entities that
encourage an integrated approach to di-
defined variants of medulloblastoma and arise in the posterior fossa, such as high-
agnosis {1535}. When molecular analysis
genetic alterations with clinical utility grade small cell gliomas, embryonal
is feasible, combined data on both mo-
{1240}. However, the updated classifica- tumour with multilayered rosettes, and
lecular group and morphological variant
tion does not make specific recommen- atypical teratoid/rhabdoid tumours.
provide optimal prognostic and predic-
dations regarding the merits of the vari-
tive information. This approach is further Grading
ous methods for determining molecular
enhanced when specific genetic data Irrespective of their histological or genetic
groups or genetic alterations.
are integrated into the diagnosis, e.g. by characterization, medulloblastomas cor-
the inclusion of TP53 gene status in the Definition respond histologically to WHO grade IV.
classification. An embryonal neuroepithelial tumour
SHH-activated medulloblastomas are arising in the cerebellum or dorsal brain
a heterogeneous group; a tumour with stem, presenting mainly in childhood
TP53 mutation and large cell / anaplastic and consisting of densely packed small
morphology has an abysmal progno- round undifferentiated cells with mild to
sis, in contrast to SHH-activated and moderate nuclear pleomorphism and a
TP53-wildtype medulloblastomas with high mitotic count.
extensive nodularity, which have a good Medulloblastoma is the most common
clinical outcome if treated appropriately CNS embryonal tumour and the most
{2870}. common malignant tumour of childhood.
Some molecular genetic alterations cur- It is now classified into molecular (i.e.
rently used in the risk stratification of me- genetic) variants as well as morphologi-
dulloblastomas, such as MYC amplifica- cal variants, all with clinical utility. Most
tion, are not included in the classification, medulloblastomas arise in the cerebel- Fig. 8.01 Cumulative age distribution of medulloblastoma
but could nevertheless be incorporated (both sexes), based on 831 cases (2008-2015). Data
lum, but the WNT-activated variant has
from the Brain Tumor Reference Center, Bonn.
Medulloblastoma 185
Fig. 8.02 Medulloblastoma. A Sagittal section. The tumour occupies mostly the lower part of the cerebellum. В Typical gross postmortem appearance of a medulloblastoma in the
cerebellar midline, occupying the cerebellar vermis. C Diffuse CSF seeding by a medulloblastoma into the basal cisterns and meninges.
Fig. 8.03 A Numerous medulloblastoma metastases of various sizes on the falx cerebri and the inner surface of the Fig. 8.04 infiltration by a cerebellar medulloblastoma of
dura mater covering the left cerebral hemisphere. Some smaller dural metastases are present on the contralateral side. the subarachnoid space. Note the clusters of tumour cells
В Multiple nodules in the cauda equina of the spinal cord representing CSF drop metastases of a medulloblastoma. in the molecular layer, particularly in the subpial region.
activation. Small foci of necrosis can be immunostainlng of highly differentiated, striated myogenic cells. C Biphasic pattern of small undifferentiated embryonal
cells and large rhabdomyoblasts immunostaining for myoglobin. D Melanotic cells commonly appear as tubular
grossly evident, but extensive necrosis is
epithelial structures, which are immunopositive for HMB45 and cytokeratins.
rare. In disseminated medulloblastoma,
discrete tumour nodules are often found
in the craniospinal leptomeninges or setting of a classic or large cell / anaplas- express no neural antigens, the expres-
cerebrospinal fluid pathways. tic tumour and are no longer considered sion of markers of neuronal differen-
distinct histopathological variants. These tiation is common. Immunoreactivity for
Microscopy are the rare (accounting for < 1% of synaptophysin, class III beta-tubulin, or
Several morphological variants of medul- cases) medulloblastoma with myogenic NeuN is demonstrated at least focally in
loblastoma are recognized, alongside differentiation (previously called medullo- most medulloblastomas. Homer Wright
the classic tumour: desmoplastic/nodular myoblastoma) and medulloblastoma rosettes and nodules of neurocytic dif-
medulloblastoma, medulloblastoma with with melanotic differentiation (previously ferentiation are immunopositive for these
extensive nodularity, and large cell / ana- called melanocytic medulloblastoma). markers. In contrast, expression of NFPs
plastic medulloblastoma. Their specific Although these tumours are very rare, it is rare. GFAP-immunopositive cells are
microscopic architectural and cytological is not uncommon for their phenotypes to often found among the undifferentiated
features are described in the correspond- occur together. embryonal cells of a medulloblastoma;
ing sections of this volume. A dominant in addition to a conventional embryonal however, they generally show the typical
population of undifferentiated cells with a element, medulloblastoma with myogen- spider-like appearance of reactive as-
high nuclear-to-cytoplasmic ratio and mi- ic differentiation contains a variable num- trocytes and tend to be more abundant
totic figures is a common feature, justify- ber and distribution of spindle-shaped near blood vessels. These cells are usu-
ing the designation “embryonal”, but it is rhabdomyoblastic cells and sometimes ally considered to be entrapped astro-
important to consider other entities in the large cells with abundant eosinophilic cytes, although the observation of similar
differential diagnosis. High-grade small cytoplasm {2211,2383}. Occasionally, cells in extracerebral metastatic deposits
cell gliomas and some ependymomas elongated differentiated strap cells, with raises the possibility that at least some
have an embryonal-like cytology, and the cross-striations of skeletal muscle, are well-differentiated neoplastic astro-
elements of the embryonal tumour with are evident. cytes. Cells showing GFAP immunore-
multilayered rosettes or atypical teratoid/ Medulloblastoma with melanotic differen- activity and the cytological features of
rhabdoid tumour can be identical to me- tiation contains a small number of mel- bona fide neoplasia can be observed
dulloblastoma. Any of these entities can anin-producing cells, which sometimes in approximately 10% of medulloblasto-
be confused with medulloblastoma, es- form clumps {730,1965}. These may ap- mas. In medulloblastoma with myogenic
pecially in small biopsies, so determining pear entirely undifferentiated (like other differentiation, cells demonstrating myo-
a tumour’s immunophenotype or genetic embryonal cells) or have an epithelioid genic differentiation are immunopositive
profile is an important part of working phenotype. Epithelioid melanin-produc- for desmin or myogenin, but not alpha-
through the differential diagnosis. ing cells may form tubules, papillae, or SMA. In medulloblastomas with mel-
Two distinctive morphological variants of cell clusters. anotic differentiation, melanin-producing
medulloblastoma are described in this cells express HMB45 or melan-A, and
section, because they may occur in the Immunophenotype
the clumps of epithelioid cells associated
Although a few medulloblastomas
with focal melanin production generally
Medulloblastoma 187
show immunoreactivity for cytokeratins. Genetic susceptibility syndrome {249A), and Nijmegen break-
Nuclear SMARCB1 and SMARCA4 ex- Medulloblastomas occur in the setting age syndrome {1058A).
pression is retained in all medulloblasto- of several inherited cancer syndromes: Genetic susceptibility to medulloblas-
ma variants; the loss of expression of one naevoid basal cell carcinoma syndrome toma has been documented in monozy-
of these SWI/SNF complex proteins in the (also called Gorlin syndrome; see p. 319), gotic twins {434}, siblings, and relatives
context of an embryonal tumour is char- Li-Fraumeni syndrome; see p. 310), mis- {1065,2666}. Association with other brain
acteristic of atypical teratoid/rhabdoid match repair cancer syndrome (Turcot tumours {673} and Wilms tumour {1846,
tumour. syndrome, p. 317), Rubinstein-Taybi 2062} has also been reported.
Fig. 8.07 A Non-WNT medulloblastoma often shows beta-catenin immunoreactivity restricted to the plasma membrane and cytoplasm. В WNT-activated medulloblastoma. Nuclear
immunoreactivity for beta-catenin indicates activation of the WNT pathway. C WNT-activated medulloblastoma. Immunoreactivity for beta-catenin manifests as groups of positive
nuclei in some WNT-activated medulloblastomas.
Fig. 8.11 Histopathological features of the classic medulloblastoma. A Typical syncytial arrangement of undifferentiated tumour cells. B Area with Homer Wright (neuroblastic)
rosettes. C Arrangement of tumour cells in parallel rows (spongioblastic pattern).
Fig. 8.12 Medulloblastoma. A Focal expression of synaptophysin. B Focal GFAP staining of tumour cells. C Clusters of medulloblastoma cells expressing retinal S-antigen.
Fig. 8.14 The developing human posterior fossa. EGL, Fig. 8.15 Cumulative age distribution of 180 cases (both
external granule layer; VZ, ventricular zone. sexes). Data from the Brain Tumor Reference Center, Bonn.
such as the skeletal system. At diagno- Microscopy hyperchromatic and moderately pleo-
sis, metastatic disease is found less fre- Desmoplastic/nodular medulloblastoma morphic nuclei, which produce a dense
quently with desmoplastic/nodular me- is characterized by nodular, reticulin- intercellular reticulin fibre network {818,
dulloblastomas than with other variants. free zones (so-called pale islands) sur- 1234}. In rare cases, this defining pat-
rounded by densely packed, undiffer- tern is not present throughout the en-
entiated, highly proliferative cells with tire tumour and there is instead a more
Fig. 8.17 Desmoplastic/nodular medulloblastoma. A Pale nodular areas surrounded by densely packed hyperchromatic cells. B Reticulin silver impregnation showing the reticulin-
free pale islands. C MIB1 monoclonal antibody staining shows that the proliferative activity predominates in the highly cellular, intermodal areas. D Neuronal differentiation, shown
by immunoreactivity for neuron-specific enolase, occurs mainly in the pale islands.
Fig. 8.20 Medulloblastoma with extensive nodularity. A Multinodular and gyriform pattern. В in a 1-month-old girl, the gadolinium-enhanced sagittal T1-weighted MRI shows a huge
lesion involving both cerebellar hemispheres and the vermis. The lesion has a multinodular and gyriform pattern of enhancement. C Note the downward herniation of the tumour
through the foramen magnum (arrow) and the marked effacement of the cisternal spaces of the posterior fossa. There is also supratentorial hydrocephalus and macrocrania.
maturation into tumours dominated by members of the SHH pathway. Most cas- SL/FOrelated naevoid basal cell carcino-
ganglion cells {419,538}. es harbour a SUFU mutation {294}. How- ma syndrome, neuroimaging surveillance
ever, a recent study of 4 medulloblasto- is recommended {2376}. Families with
Immunophenotype children that present with MBEN should
mas with extensive nodularity found a
Like in desmoplastic/nodular medullo- be offered genetic counselling because of
PTCH1 mutation in 2 of the tumours and
blastomas, the neuropil-like tissue and the high frequency of naevoid basal cell
an SUFU and SMO mutation in one each
the differentiated neurocytic cells within carcinoma syndrome {787,2376}.
of the other 2 tumours {1333}.
nodules are strongly immunoreactive for
synaptophysin and NeuN and the Ki-67 Genetic susceptibility Prognosis and predictive factors
proliferation index is much higher in in- In the majority of cases, naevoid basal cell Medulloblastoma with extensive nodular-
ternodular areas {1627}. Activation of the carcinoma syndrome is caused by germ- ity has an excellent outcome in the ma-
SHH pathway can be demonstrated by line mutations of PTCH1. In a few cases, jority of cases {787,1603,2208}. In an in-
immunohistochemistry for specific targets germline mutations instead occur in SUFU ternational meta-analysis of survival and
such as GAB1 {631} or TNFRSF16 {1402}. {2376} or PTCH2 {667,747}. Naevoid basal prognostic factors in infant medulloblas-
cell carcinoma syndrome is diagnosed in toma, the progression-free and overall
Cell of origin survival rates of 21 cases of medulloblas-
5.8% of all patients with medulloblastoma,
Medulloblastoma with extensive nodu- toma with extensive nodularity at 8 years
but in 22.7% of patients with a desmo-
larity, like most SHH-activated medul- were 86% and 95%, respectively {2208}.
plastic/nodular tumour variant and 41%
loblastomas, seems to be derived from Metastatic disease at presentation did
of patients with medulloblastoma with
ATOH1-positive cerebellar granule neu- not affect the favourable prognosis, sug-
extensive nodularity. The risk of medullo-
ron precursors {2310,2817}. gesting that a diagnosis of medulloblas-
blastoma in PTCH1-related naevoid basal
Genetic profile cell carcinoma syndrome is approximately toma with extensive nodularity confers
Medulloblastoma with extensive nodular- 2%, and the risk is 20 times the value in a better outcome regardless of adverse
ity carries mutations in genes encoding SUFU-related naevoid basal cell carcino- clinical features {2208}.
ma syndrome {294,1333}. In children with
Fig. 8.22 Large cell / anaplastic medulloblastoma. A,B Increased nuclear size, pleomorphism, and prominent nucleoli. Tumour “cell wrapping" is also evident (B).
Most paediatric CNS embryonal tumours and females, with a male-to-female ratio
previously classified as embryonal tumour Of 1.1:1 {801,1349,2403}. histopathological features with intracrani-
with abundant neuropil and true rosettes, al ETMR but disclose striking molecular
Localization diversity and consequently deserve a
ependymoblastoma, and medulloepithello-
ETMRs develop in both the supratento- separate nosological designation {1129,
ma are included in this group {1349,2403}.
rial and infratentorial compartments. The 1345A).
However, any CNS embryonal tumour with
most common site is the cerebral hemis
C19MC amplification or fusion qualifies for
phere (affected in 70% of cases), with Clinical features
this designation, including those without
frequent involvement of the frontal and The most common clinical manifestations
distinctive histopathological features.
parietotemporal regions {801,1349}. Oc- are symptoms and signs of increased in-
ICD-0 code 9478/3 casionally, these tumours can be very tracranial pressure (i.e. headache, vom-
large, involving multiple lobes and even iting, nausea, and visual disturbances).
Grading both cerebral hemispheres. An infraten- Focal neurological signs (i.e. ataxia or
Like other CNS embryonal tumours, torial location is less frequent, with either weakness) are more common in older
C19MC-altered ETMR corresponds his- children and in cases with infratentorial
cerebellum or brain stem affected in 30%
tologically to WHO grade IV. location.
of cases. Tumour protrusion into the ce-
Epidemiology rebellopontine cistern may be observed.
Imaging
The true incidence of C19MC-altered Some extracranial tumours (e.g. Intraocu- CT and MRI usually show contrast-
ETMR is difficult to determine due to the lar medulloepithelioma and sacrococ-
enhancing large tumour masses,
cygeal ependymoblastoma) share some
Fig. 8.24 Embryonal tumour with abundant neuropil and true rosettes. Blphaslc histological pattern: areas of small Fig. 8.25 Multilayered rosette: a key diagnostic feature of
embryonal cells with multilayered rosettes and neuropil-like areas with neoplastic neurocytic cells. embryonal tumours with multilayered rosettes.
Fig. 8.27 ETMR, with morphology of embryonal tumour with abundant neuropil and true rosettes. A Synaptophysin expression within neuropil areas. B Vimentin expression.
C Intense LIN28A immunoreactivity.
sometimes containing cysts or calcifica- debris. The cells facing the lumen have a structures in the otherwise paucicellular
tion. The radiological differential diagno- defined apical surface with a prominent neuropil-like areas, and rarely , neoplas-
sis of these lesions includes other CNS internal limiting membrane in some ro- tic ganglion cells can be found between
embryonal tumours, desmoplastic in- settes. The nuclei of the rosette-forming the cells composing the layers of the
fantile ganglioglioma and supratentorial cells tend to be pushed away from the rosettes.
anaplastic ependymoma. lumen towards the outer cell border. In
Ependymoblastoma
most tumours, a defined outer mem-
Spread This pattern of ETMR features sheets
brane around rosettes is lacking. There
The tumour may be locally and widely and clusters of poorly differentiated cells
are three histological patterns found in
infiltrative. Widespread leptomeningeal incorporating numerous multilayered
ETMR , C91MC-altered. On the basis of
dissemination, extracranial invasive rosettes, but typically lacks a neuropil-
their molecular commonality, these are
growth in the soft tissues, and extracra- like matrix and ganglion cell elements.
now considered to constitute either vari-
nial metastases have all been reported Rosettes are intermixed with small to
ous points along a morphological spec-
{1300,1349,2771|. medium-sized embryonal cells that have
trum or diverse differentiation within a
a high nuclear-to-cytoplasmic ratio and
Macroscopy single tumour entity, rather than distinct
variably developed fibrillary processes.
ETMR is usually greyish pink, and well nosological categories {1191,1349}.
circumscribed, with areas of necrosis Medulloepithelioma
and haemorrhage and minute calcifica- Embryonal tumour with abundant This pattern of ETMR typically presents
tions. Some tumours are cystic. Wide- neuropil and true rosettes as a distinct cerebral mass in young
spread leptomeningeal dissemination This pattern of ETMR shows a biphasic children. It is characterized by papillary,
and extraneural metastases are frequent architecture featuring dense clusters of tubular, and trabecular arrangements of
in the terminal stage of disease. small cells with round or polygonal nu- neoplastic pseudostratified epithelium
clei, scanty cytoplasm, and indistinct cell with an external (periodic acid—Schiff—
Microscopy bodies, as well as large, paucicellular, positive and collagen IV-positive) limit-
Rosettes are a frequent and characteris- fibrillar/neuropil-like areas, infrequently ing membrane, resembling the primitive
tic histopathological feature of C19MC- containing neoplastic neurocytic and neural tube. On the luminal surface of
altered embryonal tumours. They are ganglion cells {618,801}. In some cases, these tubules, cilia and blepharoblasts
multilayered and mitotically active struc- the neuropil has a fascicular quality. Hy- are absent. Mitotic figures are abundant
tures consisting of pseudostratified neu- percellular areas contain numerous mi- and tend to be located near the lumi-
roepithelium with a central, round, or toses and apoptotic bodies. In the aggre- nal surface. In zones away from tubular
slit-like lumen. The lumen of the rosette gates of small cells, multilayered rosettes and papillary structures, there are large
is either empty or filled with eosinophilic are often present. In some cases, these sheets of poorly differentiated cells with
rosettes are observed as highly cellular
Fig. 8.32 Cytogenetic profile (methylation array) prototypic for ETMR: amplification of C19MC (arrow) and gain of
chromosome 2.
Medulloepithelioma
immunolabelling is uniformly high among generally reactive astrocytes. Groups of
Definition embryonal cells. LIN28A is expressed by neurocytic cells express synaptophysin
A CNS embryonal tumour with a promi- medulloepitheliomas that lack C19MC or NeuN. Ki-67 immunolabelling is high
nent pseudostratified neuroepithelium amplification {2403}. in embryonal cells, but lower elsewhere.
that resembles the embryonic neural
tube in addition to poorly differentiated
neuroepithelial cells.
Even though medulloepithelioma is a CNS neuroblastoma CNS ganglioneuroblastoma
very rare tumour, a significant propor-
tion of those analysed genetically have Definition Definition
not shown C19MC alterations {2403}. A CNS embryonal tumour characterized A CNS embryonal tumour characterized
Although a diagnostic genetic signature by poorly differentiated neuroepithelial by poorly differentiated neuroepithelial
has yet to be defined for such tumours, cells, groups of neurocytic cells, and a cells and groups of neurocytic and gan-
they are grouped as a tumour entity, dis- variable neuropil-rich stroma. glion cells.
tinct from ETMR. This exceedingly rare tumour shows a This rare tumour shows varying degrees
distinctive pattern of differentiation, not of neuronal differentiation, but dystrophic
ICD-0 code 9501/3 unlike some peripheral neuroblastomas. ganglion cells are a prominent element.
Microscopy
Medulloepithelioma consists of sheets of ICD-0 code 9500/3 ICD-0 code 9490/3
embryonal cells interspersed to a vari-
able extent by tubular and trabecular ar- Microscopy Microscopy
rangements of a neoplastic pseudostrati- Zones of neurocytic differentiation are Varying degrees of neuronal differentia-
fied neuroepithelium, which appears found among sheets of densely packed tion characterize this tumour, which also
similar to embryonic neural tube. This primitive embryonal cells. Neurocytic dif-contains sheets of primitive embryonal
has a periodic acid-Schiff-positive ex- cells. Neurocytic and ganglion cells, the
ferentiation manifests as cells with slightly
ternal limiting membrane, and its luminal larger nuclei and variably distinct cyto- latter occasionally binucleated, are usu-
surface lacks cilia and blepharoblasts. ally present as small groups, rather than
plasm set against a faintly fibrillar matrix at
Neural differentiation may occasionally dispersed diffusely among the embryo-
lower density than the embryonal cells. Ar-
be found in the form of cells with a dys- chitectural features include Homer Wright nal cells. Dispersed cells with a neuronal
trophic neuronal or astrocytic morphol- morphology and appearing to form a
rosettes, palisading patterns of cells, and
ogy. Mitotic figures are readily found. pattern are more likely to be entrapped
regions of necrosis with granular calcifica-
tion. Exceptionally, a Schwannian stroma neurons. Mitotic figures and apoptotic
Immunophenotype may be present. bodies are readily found among embryo-
Embryonal cells in medulloepithelioma nal cells. Architectural features include
rarely show immunoreactivity for neu- Immunophenotype
Homer Wright rosettes, palisading pat-
ronal markers, such as synaptophysin The embryonal cells may be immunoneg- terns of cells, and regions of necrosis
and NFPs, and GFAP-positive tumour ative for neural markers, such as synap-
with granular calcification.
cells are exceptional. The neuroepithe- tophysin or GFAP, but some might show
lium may show patchy expression of cy- weak expression of synaptophysin. Very Immunophenotype
tokeratins and, less often, EMA. Ki-67 rarely, GFAP expression is found in a few Embryonal cells may be immunon-
tumour cells, but GFAP-positive cells are egative for neural markers, such as
Other CNS embryonal tumours 207
Fig. 8.34 CNS ganglioneuroblastoma. A Nodule of admixed neurocytic and ganglion cells among embryonal cells. B Embryonal cells next to large cells with variable neurona
differentiation embedded in a fibrillary stroma.
synaptophysin or GFAP, but some usually used. Embryonal tumours such as me- cells with round to oval nuclei and a high
show weak expression of synaptophysin. dulloepitheliomas, ependymoblastomas, nuclear-to-cytoplasmic ratio. Commonly
Groups of neurocytic and ganglion cells and embryonal tumours with abundant encountered features include frequent
express synaptophysin, NFPs, MAP2, neuropil and true rosettes, which exhibit mitoses and apoptotic bodies. More
and NeuN. Ki-67 immunolabelling is high alterations at the 19q13C19MC locus and tightly packed regions with angular or
in embryonal cells, but lower elsewhere. were previously included within the broad moulded cells may also be identified,
CNS PNET designation, are now consid- and Homer Wright rosettes can be found.
ered to be a distinct genetically defined Necrosis and vascular endothelial prolif-
entity, called embryonal tumour with eration may also be seen. Calcification
CNS embryonal tumour, NOS multilayered rosettes (ETMR), C19MC- is relatively common within degenerative
altered. Molecular genetic advances regions. A fibrous stroma is occasionally
Definition now permit the improved classification present and can vary from a delicate lob-
A rare, poorly differentiated embryonal of other CNS embryonal tumours as ular framework to dense fibrous cords.
neoplasm of neuroectodermal origin that well; for example, the diagnosis of atypi- Some variants of CNS embryonal tumour
lacks the specific histopathological fea- cal teratoid/rhabdoid tumour is made by display distinctive architectural or cyto-
tures or molecular alterations that define demonstrating mutation of SMARCB1 logical features. The latter often mani-
other CNS tumours. or SMARCA4 or loss of expression of fests as neuronal differentiation.
ICD-0 code 9473/3 SMARCB1 (INI1) or SMARCA4 (BRG1).
Other high-grade undifferentiated neural
Immunophenotype
CNS embryonal tumours, NOS, are neoplasms that are composed of small
CNS embryonal tumour can show vari-
characterized by poorly differentiated uniform cells and enter the differential di-
able expression of divergent neuroepithe-
neuroepithelial cells with a variable ca- agnosis of CNS embryonal tumour often
lial markers, including proteins associated
pacity for divergent differentiation along have their own molecular signatures (see
with both glial differentiation (GFAP) and
neuronal, astrocytic, myogenic, or mel- Table 8.03, p. 206). neuronal differentiation (synaptophysin,
anocytic lines. CNS embryonal tumours Malignant gliomas with primitive neuronal
NFP, and NeuN) {875}. Expression of these
can have histological features overlap- components, though rare, constitute
markers is typically present in a thin rim
ping those of other brain tumours, many a separate entity and were initially de-
of cytoplasm, although NeuN is nuclear.
of which have been reclassified from this scribed in adults {1099,1625,1946,2343}.
Antibodies that recognize GFAP may also
group through the identification of unique This entity is considered a variant of glio-
label reactive astrocytes. However, poorly
molecular biomarkers. blastoma rather than a CNS embryonal
differentiated regions of the neoplasm
The current definition of CNS embryonal tumour (see p. 33). often predominate, in which no immuno-
tumour, NOS, is more circumscribed than histochemical signs of neural differentia-
in prior WHO classifications, in which Microscopy tion are apparent. The Ki-67 proliferation
the umbrella designation “CNS primitive CNS embryonal tumours are poorly dif- index is typically variable, but a very high
neuroectodermal tumour (PNET)” was ferentiated neoplasms composed of
growth fraction, often with > 50% of immu-
nopositive tumour cells, is usual.
staining for their proteins or by other ap- ly in the ventricular system, suprasellar image demonstrates a heterogeneously enhancing left
propriate means. Tumours with this mor- region, or pineal gland. Infratentorial tu- cerebellar mass.
phology but lacking this molecular genet- mours can be located in the cerebellar
ic confirmation should be classified as hemispheres, cerebellopontine angle,
CNS embryonal tumours with rhabdoid and brain stem, and are relatively preva-
features (p. 212). lent in the first 2 years of life. Infrequently,
AT/RT arises in the spinal cord. Seeding
of AT/RT via the cerebrospinal fluid path-
ICD-0 code 9508/3 ways is common and is found in as many
as one quarter of all patients at presenta-
Grading tion {1002}. Infratentorial localization is
AT/RT corresponds histologically to WHO very rare in adult patients diagnosed with
grade IV. AT/RT {646}.
Epidemiology Clinical features Fig. 8.37 AT/RT with multiple haemorrhages, arising in
In several large series, AT/RTs account- The clinical presentation is variable, de- the right cerebellopontine angle.
ed for 1-2% of all paediatric brain tu- pending on the age of the patient and the
mours {2116,2783}. AT/RT is very rare in location and size of the tumour. Infants,
adult patients {2063}. However, due to in particular, present with non-specific variably contrast-enhancing, and lepto-
the preponderance of cases in children signs of lethargy, vomiting, and/or failure meningeal dissemination can be seen in
aged < 3 years, AT/RTs are estimated to to thrive. More specific problems include as many as a quarter of cases at presen-
head tilt and cranial nerve palsy, most tation {1659}.
commonly sixth and seventh nerve pare- Macroscopy
sis. Headache and hemiplegia are more These tumours (and their deposits along
commonly reported in children aged the cerebrospinal fluid pathways) gen-
> 3 years. erally have a gross appearance similar
Imaging to that of medulloblastoma and other
CT and MRI findings are similar to those CNS embryonal tumours. They tend to
in patients with other embryonal tumours. be soft, pinkish-red, and often appear
AT/RTs are isodense to hyperintense on to be demarcated from adjacent paren-
FLAIR images and show restricted diffu- chyma. They typically contain necrotic
sion. Cystic and/or necrotic regions are foci and may be haemorrhagic. Those
apparent as zones of heterogeneous with significant amounts of mesenchy-
signal intensity. Almost all tumours are mal tissue may be firm and tan-white
Fig. 8.35 Age and sex distribution of atypical teratoid/
in some regions. Tumours arising in the
rhabdoid tumour, based on 73 cases {1002,2530}.
cerebellopontine angle wrap themselves perikaryon {202,916}. A frequently en- necrosis and haemorrhage are common-
around cranial nerves and vessels and countered artefact in these cells is cyto- ly encountered in these tumours.
invade brain stem and cerebellum to plasmic vacuolation. Rhabdoid cells may
various extents. Rarely, AT/RT can show Immunophenotype
be arranged in nests or sheets and often
bony involvement {2697}. AT/RTs demonstrate a broad spectrum
have a jumbled appearance. However,
of immunohistochemical reactivities that
these cells are the exclusive or predomi-
Microscopy align with their histological diversity.
nant histopathological finding in only a
AT/RTs are heterogeneous lesions that However, the rhabdoid cells character-
minority of cases.
can often be difficult to recognize solely istically demonstrate expression of EMA,
Most tumours contain variable compo-
on the basis of histopathological criteria SMA, and vimentin. Immunoreactivities
nents with primitive neuroectodermal,
{324,2172}. The most striking feature in for GFAP, NFP, synaptophysin, and cy-
mesenchymal, and epithelial features. A
many cases is a population of cells with tokeratins are also commonly observed.
small-cell embryonal component is the
classic rhabdoid features, eccentrically In contrast, germ cell markers and mark-
most commonly encountered, present in
located nuclei containing vesicular chro- ers of skeletal muscle differentiation are
two thirds of all tumours. Mesenchymal
matin, prominent eosinophilic nucleoli, not typically expressed. Immunohisto-
differentiation is less common and typi-
abundant cytoplasm with an obvious eo- chemical staining for expression of the
cally presents as areas with spindle cell
sinophilic globular cytoplasmic inclusion, SMARCB1 protein (INI1) has been shown
features and a basophilic or mucopoly-
and well-defined cell borders. The cells to be a sensitive and specific test for the
saccharide-rich background. Epithelial
typically fall along a spectrum ranging diagnosis of AT/RT. In normal tissue and
differentiation is the least common histo-
from those with a classic rhabdoid phe- most neoplasms, SMARCB1 is a consti-
pathological feature. It can take the form
notype to cells with less striking nuclear tutively expressed nuclear protein; in AT/
of papillary structures, adenomatous ar-
atypia and large amounts of pale eosino- RT, there is loss of nuclear expression of
eas, or poorly differentiated ribbons and
philic cytoplasm. The cytoplasm of these SMARCB1 {1192}. Paediatric CNS em-
cords. A myxoid matrix occurs uncom-
cells has a finely granular, homogene- bryonal tumours without rhabdoid fea-
monly; in cases where this is the predomi-
ous character or may contain a poorly tures, but with loss of SMARCB1 expres-
nant histopathological pattern, distinction
defined, dense, pink body resembling sion in tumour cells, qualify as AT/RTs
from choroid plexus carcinoma can be
an inclusion. Ultrastructurally, rhabdoid as well {918}. Rare SMARCBI-deficient
challenging. Mitotic figures are usually
cells typically contain whorled bundles of non-rhabdoid tumours forming cribriform
abundant. Broad areas of geographical
intermediate filaments filling much of the strands, trabeculae, and well-defined
Fig. 8.39 Atypical teratoid/rhabdoid tumour. A Gland-like component. B Spindle cell morphology. C Mucopolysaccharide-rich background.
Definition
A benign, typically encapsulated nerve
sheath tumour composed entirely of
well-differentiated Schwann cells, with
loss of merlin (the NF2 gene product) ex-
pression in conventional forms.
Schwannomas are solitary and sporadic
in the vast majority of cases, can affect
patients of any age, and follow a benign
clinical course. Multiple schwannomas
are associated with neurofibromatosis
type 2 (NF2) and schwannomatosis.
ICD-0 code 9560/0
Grading
Conventional, non-melanotic schwanno- Fig. 9.02 A Vestibular schwannoma. Postcontrast T1 -weighted MRI showing the typical ice-cream-cone shape of a
mas and their variants correspond histo- vestibular schwannoma, with the cone representing the portion within the internal auditory canal and the scoop of ice
logically to WHO grade I. cream the portion in the cerebellopontine angle. B Paraspinal schwannoma. Postcontrast T1-weighted MRI showing
both intraspinal extramedullary and extraspinal components, with a point of constriction at the nerve exit.
Synonyms
Neurilemoma; neurinoma
Epidemiology
Schwannomas account for 8% of all intra-
cranial tumours, 85% of cerebellopontine
angle tumours, and 29% of spinal nerve
root tumours {2204}. Approximately 90%
of cases are solitary and sporadic and
4% arise in the setting of NF2. Of the 5%
of schwannomas that are multiple but not
associated with NF2 {375}, some may be
Fig. 9.03 Schwannoma. A External surface showing the parent nerve of origin and a variably translucent capsule.
associated with schwannomatosis {1558}.
B On cut surface, schwannomas often show a glistening to mucoid appearance, variable cystic degeneration, and
Patients of any age can be affected, yellow spots reflecting collections of xanthomatous macrophages.
but paediatric cases are rare. The peak
incidence is in the fourth to sixth dec-
ades of life. Most studies show no sex predilection, but some series have shown show a strong predilection for the eighth
a female predominance among intracra- cranial nerve in the cerebellopontine an-
nial tumours {526,1613,2204}. Cerebral gle, particularly in NF2 {1893}. They arise
intraparenchymal schwannomas are as- at the transition zone between central
sociated with a younger patient age and and peripheral myelination and affect the
a male predominance {375}. Schwan- vestibular division. The adjacent coch-
nomas of spinal cord parenchyma are lear division is almost never the site of
too rare for their epidemiology to be as- origin. This characteristic location, which
sessed {996}. is not shared by neurofibromas or malig-
nant peripheral nerve sheath tumours,
Localization
results in diagnostically helpful enlarge-
The vast majority of schwannomas occur
ment of the internal auditory meatus on
outside the CNS. Peripheral nerves in the
neuroimaging. Intralabyrinthine schwan-
skin and subcutaneous tissue are most
Fig. 9.01 Age and sex distribution of schwannomas, based nomas are uncommon {1763}. Intraspinal
often affected. Intracranial schwannomas
on 582 patients treated at the University Hospital Zurich. schwannomas show a strong predilection
Fig. 9.05 Schwannoma. A Compact Antoni A (left) and loose Antoni B (right) areas. B A capsule (upper left) surrounds a compact Antoni A region with nuclear palisades, consistent
with Verocay bodies.
Schwannoma 215
Fig. 9.06 Ancient schwannoma. A Marked degenerative atypia may induce concern for malignant transformation, but other features of malignancy are lacking. B Diffuse S100
expression. C The markedly atypical tumour cells are negative for Ki-67, providing further support that they are degenerative in nature.
Fig. 9.08 Cellular schwannoma. A An increased mitotic index is often seen in cellular schwannoma and should not be
taken as evidence of malignant peripheral nerve sheath tumour (MPNST) when other classic features of schwannoma
are also found. B Diffuse expression of S100 protein helps to distinguish cellular schwannoma from MPNST.
Fig. 9.07 Cellular schwannoma composed entirely of C Extensive nuclear positivity for SOX10 helps distinguish this cellular schwannoma from MPNST. D A moderate Ki-67
compact Antoni A tissue, but with other common features of proliferation index is not uncommon in cellular schwannoma, but the proliferation index is usually still lower than that
conventional schwannoma, such as hyalinized blood vessels. encountered in most MPNSTs.
nerve sheath tumour) {1924}. In one se- The tumour has a rare association with NF2 gene as a tumour suppressor inte-
ries, cellular schwannomas were found NF2 (but not with NF1) and has also been gral to the formation of sporadic schwan-
to differ from malignant peripheral nerve noted to occur in patients with schwanno- nomas {1117,2314}. The NF2 gene and
sheath tumours in that the schwannomas matosis {1108}. Cranial and spinal nerves the merlin protein (also called schwan-
had Schwannian whorls, a peritumoural are usually spared. nomin) that it encodes are discussed in
capsule, subcapsular lymphocytes, detail in the chapter on neurofibroma-
macrophage-rich infiltrates, and an ab- Electron microscopy
tosis type 2. Inactivating mutations of
sence of fascicles, as well as strong, Ultrastructural features are diagnostic. the NF2 gene have been detected in
widespread expression of S100, SOX10, The cells have convoluted, thin cytoplas- approximately 60% of all schwanno-
neurofibromin, and CDKN2A (p16), with mic processes that are nearly devoid of mas {204,1116,1117,2190,2575}. These
a Ki-67 proliferation index < 20% in most pinocytotic vesicles but are lined by a genetic events are predominantly small
examples {1924}. Cellular schwanno- continuous basal lamina. Stromal long- frameshift mutations that result in truncat-
mas are benign. Although recurrences spaced collagen (called Luse bodies) ed protein products {1536}. Although not
are seen, notably in intracranial, spinal, is a common finding in conventional described for exons 16 or 17, mutations
and sacral examples {376}, no cellular schwannoma but less so in the cellular occur throughout the coding sequence
schwannoma is known to have metasta- variant. of the gene and at intronic sites. In most
sized or to have followed a clinically ma- cases, such mutations are accompanied
lignant, fatal course. Only two examples Immunophenotype by loss of the remaining wildtype allele
of cellular schwannoma, one associated The tumour cells strongly and diffusely on chromosome 22q. Other cases dem-
with NF2, have been reported to have un- express S100 protein {2724}; often ex- onstrate loss of chromosome 22q in the
dergone malignant transformation {82}. press SOX10, LEU7, and calretinin {707, absence of detectable NF2 gene muta-
1924}; and may focally express GFAP tions. Nevertheless, loss of merlin ex-
{1635}. All schwannoma cells have sur- pression, shown by western blotting or
Plexiform schwannoma face basal lamina, so membrane staining immunohistochemistry, appears to be a
for collagen IV and laminin is extensive universal finding in schwannomas, re-
ICD-0 code 9560/0 and most commonly pericellular. Low- gardless of their mutation or allelic status
The plexiform schwannoma variant is level p53 protein immunoreactivity may {1014,1074,2222}. This suggests that ab-
defined as a schwannoma growing in a be seen, particularly in cellular schwan- rogation of merlin function is an essential
plexiform or multinodular manner and can nomas {376}. NFP-positive axons are step in schwannoma tumorigenesis. Loss
be of either conventional or cellular type generally absent, but small numbers may of chromosome 22 has also been noted
{20,2787}. Presumably involving multiple be encountered in schwannomas, par- in cellular schwannoma {1522}. Other ge-
nerve fascicles or a nerve plexus, the vast ticularly in tumours associated with NF2 netic changes are rare in schwannomas,
majority arise in skin or subcutaneous tis- or schwannomatosis {2714}. A mosaic although small numbers of cases with
sue of an extremity, the head and neck, pattern of SMARCB1 (INI1) expression loss of chromosome 1p, gain of 9q34,
or the trunk, with deep-seated examples is seen in 93% of tumours from patients and gain of 17q have been reported
also documented {20}. These tumours with familial schwannomatosis, 55% of {1471,2699}.
have been described both in childhood tumours from patients with sporadic
and at birth {2788}. Despite an often rap- schwannomatosis, 83% of NF2-associat- Genetic susceptibility
id growth, hypercellularity, and increased ed tumours, and only 5% of solitary, spo- Although most schwannomas are spo-
mitotic activity, the behaviour is that of a radic schwannomas {1909}. radic in occurrence, multiple schwan-
benign tumour, prone to local recurrence nomas may occur in the setting of two
Genetic profile tumour syndromes. Bilateral vestibular
but with no metastatic potential {2788}. Extensive analyses have implicated the schwannomas are pathognomonic of
Schwannoma 217
deposition. Similarly, melanotic schwanno-
mas feature true melanosomes and less-
uniform envelopment of individual cells by
basal lamina on electron microscopy.
The peak age incidence of melanotic
schwannoma is a decade younger than
that of conventional schwannoma. Mel-
anotic schwannomas occur in both non-
psammomatous {720} and psammoma-
tous {368,624} varieties. The vast majority
of non-psammomatous tumours affect
spinal nerves and paraspinal ganglia,
whereas psammomatous lesions also in-
volve autonomic nerves of viscera, such
as the intestinal tract and heart. Cranial
Fig. 9.10 Melanotic schwannoma with clusters of plump, spindled, and epithelioid, heavily pigmented tumour cells.
nerves may also be affected. Distinguish-
ing between the two varieties of melanot-
ic schwannoma is important, because
NF2, whereas multiple, mostly non-ves- Prognosis and predictive factors about 50% of patients with psammoma-
tibular schwannomas in the absence of Schwannomas are benign, slow-growing tous tumours have Carney complex, an
other NF2 features are characteristic of tumours that infrequently recur and only autosomal dominant disorder {367} char-
schwannomatosis (see Schwannomato- very rarely undergo malignant change acterized by lentiginous facial pigmen-
sis, p. 301). Patients with schwannoma- {2789}. Recurrences are more common tation, cardiac myxoma, and endocrine
tosis present with multiple, often painful (occurring in 30-40% of cases) for cel- hyperactivity. Endocrine hyperactivity
schwannomas, which in some cases lular schwannomas of the intracranial, includes Cushing syndrome associated
are segmental in distribution. Germline spinal, and sacral regions {376} and for with adrenal hyperplasia and acromegaly
SMARCB1 mutations at 22q11.23 have plexiform schwannoma {2788}. due to pituitary adenoma {368}. Slightly
been found in half of all familial and more than 10% of all melanotic schwan-
< 10% of all sporadic schwannomatosis nomas follow a malignant course {367}.
cases {1064,2325,2381}. Somatic NF2
inactivation has been shown in tumours, Melanotic schwannoma ICD-0 code 9560/1
but germline NF2 mutations are absent Genetic susceptibility
{1115,1557}. Germline loss-of-function Definition
A rare, circumscribed but unencapsu- Allelic loss of the PRKAR1A region on 17q
mutations in LZTR1 predispose individu- has been reported in tumours from pa-
als to an autosomal dominant inherited lated, grossly pigmented tumour com-
posed of cells with the ultrastructure and tients with Carney complex, but has not
disorder of multiple schwannomas, and been documented in non-psammoma-
are identified in approximately 80% of Immunophenotype of Schwann cells but
that contain melanosomes and are reac- tous melanotic schwannomas {2435}.
22q-related schwannomatosis cases Psammomatous melanotic schwannoma
that lack mutations in SMARCB1 {1980}. tive for melanocytic markers.
In melanotic schwannoma, cytological is a component of Carney complex, in
The presence of LZTR1 mutations also which patients have loss-of-function
confers an increased risk of vestibular atypia (including hyperchromasia and
macronucleoli) is common. Unlike in germline mutations of the PRKAR1A
schwannoma, constituting further over- gene on chromosome 17q, encoding the
lap with NF2 {2377}. conventional schwannomas, collagen IV
and laminin usually envelop cell nests cAMP-dependent protein kinase type I-
rather than showing extensive pericellular alpha regulatory subunit {2435}.
Fig. 9.11 Melanotic schwannoma. A Psammomatous calcification is a diagnostically useful feature of psammomatous melanotic schwannomas. B This dual stain reveals diffuse
Immunoreactivity for melan-A (in red) and a low Ki-67 proliferation index, with positive nuclei (in brown). The low proliferation index helps distinguish this lesion from melanoma.
C Psammomatous melanotic schwannoma. The extensive pericellular collagen-IV expression in this case supports its Schwannian nature, given that melanocytic tumours are not
associated with basement membrane deposition.
Definition
A benign, well-demarcated, intraneural
or diffusely infiltrative extraneural nerve
sheath tumour consisting of neoplastic,
well-differentiated Schwann cells inter-
mixed with non-neoplastic elements in-
cluding perineurial-like cells, fibroblasts,
mast cells, a variably myxoid to collage-
nous matrix, and residual axons or gan-
glion cells.
Multiple and plexiform neurofibromas are Fig. 9.12 Total spine MRI in a patient with neurofibromatosis type 1 with extensive bilateral paraspinal disease burden.
typically associated with neurofibromato- Neurofibromas involve nearly every nerve root; also note the thoracic spine curvature defect.
sis type 1 (NF1), whereas sporadic neu-
rofibromas are common, mostly cutane-
ous tumours that can affect patients of Clinical features nerve are affected. On cut surface, they
any age and any area of the body. Rarely painful, neurofibroma presents as are firm, glistening, and greyish tan.
a mass. Deeper tumours, including par-
ICD-0 code 9540/0 Microscopy
aspinal forms, present with motor and
Neurofibromas are composed in large
Grading sensory deficits attributable to the nerve
part of neoplastic Schwann cells with thin,
Neurofibroma corresponds histologically of origin. The presence of multiple neu-
curved to elongated nuclei and scant cy-
to WHO grade I. rofibromas is the hallmark of NF1, in as-
toplasm, as well as fibroblasts in a matrix
sociation with many other characteristic
Epidemiology of collagen fibres and Alcian blue-posi-
manifestations (see Neurofibromatosis
Neurofibromas are common and occur tive myxoid material. These cells have
type 1, p. 294).
either as sporadic solitary nodules un- considerably smaller nuclei than those
related to any apparent syndrome or (far Macroscopy of schwannomas. The cell processes
less frequently) as solitary, multiple, or Cutaneous neurofibromas are nodular to are thin and often not visible on routine
numerous lesions in individuals with NF1. polypoid and circumscribed, or are dif- light microscopy. Residual axons are
Patients of any race, age, or sex can be fuse, and involve skin and subcutaneous often present within neurofibromas, and
affected. tissue. Neurofibromas confined to nerves can be highlighted with neurofilament
are fusiform and (in all but their proximal immunohistochemistry or Bodian silver
Localization and distal margins) well circumscribed. impregnations. Large diffuse neurofi-
Neurofibroma presents most commonly Plexiform neurofibromas consist either of bromas often contain highly character-
as a cutaneous nodule (localized cuta- multinodular tangles (resembling a bag istic tactile-like structures (specifically
neous neurofibroma), less often as a cir- of worms), when involving multiple trunks pseudo-Meissner corpuscles) and may
cumscribed mass in a peripheral nerve of a neural plexus, or of rope-like le- also contain melanotic cells. Stromal col-
(localized intraneural neurofibroma), or sions, when multiple fascicles of a large, lagen formation varies greatly in abun-
as a plexiform mass within a major nerve non-branching nerve such as the sciatic dance and sometimes takes the form of
trunk or plexus. Least frequent is diffuse dense, refractile bundles with a so-called
but localized involvement of skin and shredded-carrot appearance. Intraneural
subcutaneous tissue (diffuse cutaneous neurofibromas often remain confined to
neurofibroma) or extensive to massive in- the nerve, encompassed by its thickened
volvement of soft tissue of a body area epineurium. In contrast, tumours arising
(localized gigantism and elephantiasis in small cutaneous nerves commonly
neuromatosa). Neurofibromas rarely in- spread diffusely into surrounding der-
volve spinal roots sporadically, but com- mis and soft tissues. Unlike in schwan-
monly do so in patients with NF1, in which nomas, blood vessels in neurofibromas
multiple bilateral tumours are often asso- generally lack hyalinization, and although
ciated with scoliosis and risks of malig- neurofibromas sometimes resemble the
nant transformation {1778}; in contrast, Antoni B regions of a schwannoma, they
they almost never involve cranial nerves. generally lack Antoni A-like regions and
Fig. 9.13 Neurofibroma of a spinal root, with a firm
Verocay bodies.
consistency and homogeneous cut surface.
Neurofibroma 219
Fig. 9.14 Plexiform neurofibroma. A Multinodular pattern from involvement of multiple fascicles. Note the associated diffuse neurofibroma in the background, with pseudo-Meissner
corpuscles (upper left). B EMA immunostaining highlights the perineurium surrounding multiple involved fascicles, whereas the tumour cells are mostly negative.
Fig. 9.15 Neurofibroma. A Strong, but patchy S100 positivity is seen, the stain generally labelling a smaller proportion of cells than in schwannoma. B In pseudo-Meissner
corpuscles, S100 staining is diffuse.
Neurofibroma 221
Antonescu C.R.
Perineurioma Perry A.
Reuss D.E.
Fig. 9.17 Intraneural perineurioma. A On a toluidine blue-stained plastic section, myelinated axons are surrounded by concentric rings of perineurial cell processes (pseudo-onion
bulbs). B EMA staining highlights concentric layers of perineurial cells in pseudo-onion bulbs.
Perineurioma 223
cells stain for NFP and S100 protein, re- which often have a low mitotic index, studies of malignant soft tissue perineu-
spectively. Staining for p53 protein has malignant soft tissue perineuriomas are riomas have been reported.
also been reported {637}. Soft tissue more proliferative, with mitotic counts of
Prognosis and predictive factors
perineurioma features the same basic 1-85 mitoses (median: 16} per 10 high-
Intraneural perineuriomas are benign.
immunophenotype. Claudin-1 {719,2070} power fields in the largest reported series
Long-term follow-up indicates that they
and GLUT1 {1012} are also diagnostically {1011}.
useful markers. Unlike various other soft do not have a tendency to recur or me-
Genetic profile tastasize. Biopsy alone is sufficient for
tissue tumours, perineuriomas generally
Both intraneural and soft tissue perineu- diagnosis. Conventional soft tissue peri-
lack reactivity for CD34, MUC4, and in
riomas feature the same cytogenetic ab- neuriomas are usually amenable to gross
particular, S100 protein. Malignant soft
normality: monosomy of chromosome 22 total removal. Recurrences are very in-
tissue perineuriomas usually show at
{637,827}. Loss of chromosome 13, an frequent, even in cases with histological
least some EMA staining and lack S100
abnormality found in several soft tissue atypia, and none have been reported
protein reactivity.
tumours, has also been described in soft to metastasize. Neither sclerotic nor re-
Proliferation tissue perineurioma {1717}. Loss of chro- ticular tumours are prone to recurrence
Intraneural perineuriomas, despite a pau- mosome 10 and a small chromosome {695,879}. Malignant perineuriomas are
city of mitoses, may show a Ki-67 prolif- 22q deletion involving NF2 have also far less prone to metastasize {756,1011,
eration index of 5-15% {637}. In contrast been reported {281,2311}. No genetic 1221} than are conventional malignant
to benign soft tissue perineuriomas, peripheral nerve sheath tumours {1011}.
Definition 1040}. They are rarely associated with eosinophilic cytoplasm with indistinct
Benign peripheral nerve sheath tumours cranial or spinal nerves. Most tumours cell borders, arranged in a storiform,
(PNSTs) with combined features of more showing biphasic schwannoma and re- whorled, and/or lamellar architecture
than one conventional type (i.e. neurofi- ticular perineurioma have been reported {1040}. The tumours may exhibit myx-
broma, schwannoma, and perineurioma). on the digits {1661}. oid stromal changes (seen in half of all
Two of the more common types of hybrid cases) and often display degenerative
nerve sheath tumours are schwannoma/ Clinical features
cytological atypia similar to the ancient
The clinical features of peripheral nerve
perineurioma, which typically occurs changes seen in schwannoma.
sheath hybrid tumours are similar to or
sporadically, and neurofibroma/schwan- Hybrid neurofibromas/schwannomas are
indistinguishable from those of other be-
noma, which is typically associated with tumours in which two distinct compo-
nign PNSTs and largely depend on the
schwannomatosis, neurofibromatosis nents are recognized: a schwannoma-
site of origin. Hybrid nerve sheath tu-
type 1 (NF1) or neurofibromatosis type 2 like component with nodular Schwann
(NF2). Rare cases of neurofibroma/peri- mours (including spinal examples) may
cell proliferation (which may contain
cause neurological deficit or pain when
neurioma have also been described, Verocay bodies) and a neurofibroma-like
they involve a large peripheral nerve.
usually associated with NF1. component with a mixed cellular popula-
Macroscopy tion, myxoid change, and collagen {681,
Etiology
The gross appearance and radiological 945}. Plexiform architecture is common.
Hybrid schwannoma/perineurioma oc-
findings of hybrid tumours are indistin- The schwannoma-like component is
curs sporadically {1040}, whereas neu-
guishable from those of other PNSTs (i.e. mainly composed of cellular Antoni A
rofibroma/schwannoma can occur in
schwannomas and neurofibromas). areas, often containing Verocay bodies
the setting of either schwannomatosis or
with Schwann cells demonstrating nu-
neurofibromatosis {945}. Similarly, hybrid Microscopy clear palisading. In contrast, the neurofi-
neurofibroma/perineurioma tumours are Hybrid schwannoma/perineurioma tu- broma-like component may demonstrate
more commonly reported in association mours show predominantly Schwannian abundant fibroblasts, collagen, and
with NF1 {1091,1199}. cytomorphology but have a perineurio- myxoid changes, with Schwannian cells
Localization ma-like architecture. These tumours are having a distinctive elongated and wavy
usually well circumscribed but unencap- appearance.
Hybrid nerve sheath tumours show a
sulated, and composed of spindle cells The few examples of hybrid neurofibroma/
wide anatomical distribution and often
with plump, tapering nuclei and palely perineurioma that have been described
involve the dermis and subcutis {681,
consisted of plexiform neurofibromas
Fig. 9.21 Hybrid neurofibroma/schwannoma. A,B Schwann cell micronodules. C S100-positive Schwann cell micronodules.
with considerable areas of perineuri- The most helpful stains for the work-up of lesions within the spectrum of PNSTs in
omatous differentiation, in patients with a neurofibroma/schwannoma are those NF1 {17}.
NF1 {1199}. In these lesions, biphasic that highlight the presence of a mono-
Genetic susceptibility
(Schwannian and perineuriomatous) dif- morphic Schwann cell population in the
More than half of all patients with hybrid
ferentiation was apparent mainly on im- schwannoma component (i.e. S100 and
PNSTs have multiple PNSTs, suggesting
munohistochemistry, with rare cases in SOX10) or a polymorphic cell population
a tumour syndrome. Hybrid neurofibro-
which the neurofibromatous and perineu- in the neurofibroma component, includ-
ma/schwannoma is a common tumour
riomatous areas were recognizable on ing Schwann cells (S100 and SOX10),
type in schwannomatosis, occurring in
routine H&E stains {1199}. perineurial cells (EMA and GLUT1), and
71% of patients. There is also a striking
fibroblasts. Entrapped axons may be
Immunophenotype association with neurofibromatosis {945}
seen in neurofibromatosis-associated
Schwannoma/perineurioma hybrid tu- where this hybrid lesion is more common
schwannomas, but the presence of en-
mours show dual differentiation by im- in NF2 (occurring in 26% of cases) than
trapped large bundles of axons is more
munohistochemistry, with the Schwann- in NF1 (occurring in 9% of cases). Within
common in neurofibromas {681}.
ian cells (plump-spindled) being positive patients with schwannomatosis, 61% of
In neurofibroma/perineurioma, the bipha-
for S100 protein whereas the perineurial the developed tumours had the appear-
sic Schwannian and perineuriomatous
cells (slender-spindled) show variable ance of schwannoma-like nodules within
differentiation is apparent by immunohis-
immunoreactivity for EMA, claudin-1, and a neurofibroma-like tumour, correspond-
tochemistry, with the perineuriomatous
GLUT1 {2816}. Using double staining for ing to hybrid neurofibroma/schwannoma
areas staining positively for EMA, GLUT1,
EMA and S100 protein, parallel layers of {945}. The presence of hybrid morphol-
and claudin-1 and negatively for S100
alternating S100-positive and EMA-posi- ogy and/or mosaic SMARCB1 (INI1)
protein {1199}. In fact, intraneural perineu-
tive cells can be seen, with no coexpres- expression on immunohistochemistry
rial proliferations have been documented
sion of antigens by the same cells {1040}. suggests that a schwannoma may be
by screening neurofibromatous lesions
On the basis of these dual-labelling re- associated with a form of neurofibroma-
and normal nerves in patients with NF1
sults, most tumours were found to be tosis, in particular NF2 and schwanno-
using a battery of perineurial markers,
composed of about two thirds Schwann matosis {1909,1990}. Similarly, hybrid
supporting the existence of both pure
cells and one third perineurial cells. neurofibroma/perineurioma occurs most-
and hybrid perineuriomatous
ly in association with NF1 {1199}.
Fig. 9.25 Malignant peripheral nerve sheath tumour (MPNST). A Patchy S100 expression. B E6FR Immunoreactivity. C Glandular MPNST, containing neuroendocrine cells
immunoreactive to chromogranin.
some as focal transformations, the pro- tightly packed spindle cells with variable Malignant peripheral nerve sheath
cess may be minimally apparent on gross quantities of eosinophilic cytoplasm. Nu- tumour with divergent differentiation
examination. In contrast, larger, typically clei are typically elongated and wavy
Synonyms
high-grade tumours originating in or un- and (unlike those of smooth muscle) have
Malignant triton tumour; glandular malig-
associated with a nerve produce either tapered ends. The tumours show either
nant peripheral nerve sheath tumour
fusiform, expansile masses or globular, alternating loose and densely cellular ar-
entirely unencapsulated soft tissue tu- eas or a diffuse growth pattern. Perivas- A variety of mesenchymal tissues such
mours. Both types infiltrate surrounding cular hypercellularity and tumour aggre- as cartilage, bone, skeletal muscle,
structures. The vast majority of tumours gates appearing to herniate into vascular smooth muscle, and angiosarcoma-like
are > 5 cm, and examples > 10 cm are lumina are also common {1924}. Unusual areas can be present in MPNSTs. MP-
common. Their consistency ranges from growth patterns may be seen, includ- NSTs showing rhabdomyosarcomatous
soft to hard, and the cut surface is typi- ing haemangiopericytoma-like areas or differentiation are called malignant triton
cally cream-coloured or grey. Foci of rarely, nuclear palisading. MPNSTs grow tumours. Nearly 60% of patients with ma-
necrosis and haemorrhage are common within nerve fascicles but commonly in- lignant triton tumour have NF1. Glandular
and may be extensive. vade adjacent soft tissues. A pseudo- MPNST is a variant containing glandular
capsule of variable thickness is often epithelium that resembles that of intes-
Microscopy
present. Three quarters of these tumours tine. Neuroendocrine differentiation is fre-
MPNSTs vary greatly in appearance.
have geographical necrosis and mi- quently seen, whereas squamous epithe-
Many exhibit a herringbone (fibrosarco- totic activity, often showing > 4 mitoses lium is far less often encountered. Three
ma-like) or interwoven fasciculated pat-
per high-power field (high-grade). quarters of the patients have NF1 {2785}.
tern of cell growth. Both patterns feature
Fig. 9.27 Epithelioid malignant peripheral nerve sheath tumour. A Some tumours include rhabdoid cells with eosinophilic paranuclear globular to fibrillar inclusions (arrows).
B Extensive S100 positivity. C Marked nuclear immunoreactivity for SOX10.
The common association with NF1 and a MPNST with perineurial differentiation conventional MPNSTs, but unlike MP-
spindle-cell background indistinguisha- (malignant perineurioma) NSTs, they carry an SS18-SSX2o\ SS18-
ble from that of ordinary MPNST suggest SSX1 fusion gene {2259}.
ICD-0 code 9540/3
a close relationship between high-grade
Immunophenotype
MPNST with divergent differentiation and Rare MPNSTs show histological and Only 50-70% of MPNSTs exhibit S100
conventional high-grade MPNST. ultrastructural features of perineurial dif- protein staining. Reactivity is grade-re-
The following two variants are likely to ferentiation. Like benign perineuriomas, lated. In high-grade tumours reactivity is
be different not only in their histological these tumours are EMA-positive and either patchy or found only in individual
characteristics but also in their genetics, S100-negative, but show hypercellular- cells, whereas in low-grade examples
lack of syndromic association, and/or bi- ity, nuclear atypia, and increased mitotic it may be extensive {2724}. However, in
ological behaviour, and should therefore activity. Perineurial MPNSTs have the po- epithelioid MPNST, diffuse S100 protein
be strictly distinguished from convention- tential to metastasize, but appear to be expression is common and SMARCB1
al MPNST: epithelioid MPNST and peri- less aggressive than conventional MP- (INI1) is lost in 50% of cases {718}. Lack
neurial MPNST (malignant perineurioma). NSTs {1011,2176}. of immunostaining for HMB45 and mel-
Differential diagnosis of MPNSTs an-A, taken together with origin from
The distinction of MPNSTs from other a peripheral nerve or a benign nerve
high-grade sarcomas relies mainly on sheath tumour may help distinguish
Epithelioid malignant peripheral
demonstration of tumour origin from ei- epithelioid MPNST from malignant mela-
nerve sheath tumour
ther a peripheral nerve or a benign pre- noma. Immunostaining for p53 protein is
ICD-0 code 9540/3 cursor, or on immunohistochemical or positive in 75% of all MPNSTs, in contrast
genetic features. Until proven otherwise, to the infrequent staining in neurofibro-
Less than 5% of MPNSTs are either
malignant spindle cell tumours in patients mas {931}, although cellular schwanno-
partially or purely epithelioid {718,1162,
with NF1 should be considered to be MP- mas can also be positive {1924}. Most
1435}. This variant shows no association
NSTs. One particular entity to consider MPNSTs are also negative for CDKN2A
with NF1 and can arise from malignant (p16), in contrast to the consistent but of-
transformation of a schwannoma {1628, in the differential diagnosis of MPNST
is synovial sarcoma of nerve. Synovial ten patchy expression in cellular schwan-
2789}. Both superficial (above the fascia)
sarcomas are common soft tissue sar- nomas {1785,1924}. However, some atyp-
and deep-seated examples have been
comas but can also occur as distinct ical neurofibromas also show CDKN2A
reported. The risks of recurrence, metas-
rare primary tumours of nerve. These tu- (p16) loss {2862}. EGFR is expressed in
tasis, and disease-related death seem to
mours show considerable morphological about one third of MPNSTs but is absent
be lower than those associated with con- in cellular schwannomas. Diffuse loss of
ventional MPNST {1162}. and immunohistochemical overlap with
SOX10 occurs in 75% of MPNSTs, but
estly more sensitive than S100 protein vesicles, and patchy basement membrane support perineurial differentiation.
232 Meningiomas
Table 10.01 Meningioma variants grouped by WHO grade and biological behaviour
ICD-0 code
Meningothelial meningioma WHO grade I
9531/0
bral convexities (with tumours often locat- bral oedema is occasionally prominent,
ed parasagittally, in association with the in particular with certain histological vari-
falx and venous sinus), olfactory grooves, ants and high-grade examples {1856}.
sphenoid ridges, para-/suprasellar re- Cyst formation may occur within or at
gions, optic nerve sheath, petrous ridg- the periphery of a meningioma. Neuro-
es, tentorium, and posterior fossa. Most imaging features are not entirely specific
spinal meningiomas occur in the thoracic for identifying meningiomas, predicting
region. Atypical and anaplastic menin- tumour behaviour, or excluding other
giomas most commonly affect the con- diagnoses.
vexities and other non-skull base sites
Spread
{1214}. Metastases of malignant menin-
Even benign meningiomas commonly
giomas most often involve lung, pleura,
invade adjacent anatomical structures
bone, or liver.
(especially dura), although the rate and
Clinical features extent of local spread are often greater
Meningiomas are generally slow-grow- in the more aggressive subtypes. Thus,
ing and produce neurological signs and depending on location and grade, some
symptoms due to compression of adja- meningiomas produce considerable pa-
cent structures; the specific deficits de- tient morbidity and mortality. Extracra-
pend on tumour location. Headache and nial metastases are extremely rare, oc-
seizures are common (but non-specific) curring in about 1 in 1000 meningiomas
presentations. and most often in association with WHO
grade III tumours. The rare metastases of
Imaging histologically benign meningiomas typi- Fig. 10.03 Large meningioma originating from the
On MRI, meningiomas typically present as cally occur after surgery, but can arise olfactory groove. Note the smooth, slightly lobulated
isodense, uniformly contrast-enhancing de novo as well. surface. MCA, middle cerebral artery; ON, optic nerve;
PG, pituitary gland.
Meningioma 233
Fig. 10.04 Macroscopy of meningioma. A Meningioma of the left parasagittal region of the parietal lobe. The tumour compresses the cerebral cortex, but does not infiltrate.
B Large lateral meningioma compressing the left frontal cortex. Note the attachment to the dura mater and the sharp delineation from brain structures. In this location, meningiomas
are often flat rather than round. C Meningioma of the medial sphenoid wing encasing the carotid artery. D Large meningioma of the lateral ventricles and the third ventricle causing
a hydrocephalus. E Large meningioma originating from the clivus. Note the compression of the brain stem with residual haemorrhage. The basilar artery (arrowhead) is entrapped
by the tumour but not occluded. F Spinal meningioma compressing the spinal cord.
Macroscopy attachment. Invasion of dura or dural si- sections and Table 10.01). The criteria
Most meningiomas are rubbery or firm, nuses is fairly common. Occasional men- used to diagnose atypical and anaplastic
well-demarcated, sometimes lobulated, ingiomas invade into the adjacent skull, meningiomas are applied independent of
rounded masses that feature broad dural where they may induce characteristic specific meningioma subtype.
hyperostosis, which is highly indicative of
Immunophenotype
bone invasion. Meningiomas may attach
The vast majority of meningiomas stain
to or encase cerebral arteries, but only
for EMA, although this immunoreactivity
rarely infiltrate arterial walls. They may
is less consistent in atypical and malig-
also infiltrate the skin and extracranial
nant lesions. Vimentin positivity is found
compartments, such as the orbit. Adja-
in all meningiomas, but is relatively non-
cent brain is often compressed but rarely
specific. Somatostatin receptor 2A is ex-
frankly invaded. In certain sites, particu-
pressed strongly and diffusely in almost
larly along the sphenoid wing, menin-
all cases (including anaplastic menin-
giomas may grow as a flat, carpet-like
giomas), but can also be encountered
mass, a pattern called en plaque menin-
in neuroendocrine neoplasms {1641}.
gioma. Some meningiomas appear gritty
S100 protein positivity is most common
on gross inspection, implying the pres-
in fibrous meningiomas, but is not usually
ence of numerous psammoma bodies.
diffuse, as it is in schwannomas. Other
Bone formation is far less common. Atyp-
potentially useful immunohistochemical
ical and anaplastic meningiomas tend to
markers in selected cases include Ki-67
be larger and often feature necrosis.
and progesterone receptor (see Progno-
Microscopy sis and predictive factors).
Meningiomas exhibit a wide range of his- Diagnostic ultrastructural features of
tological appearances. Of the subtypes meningiomas include abundance of
in the WHO classification, the most com- intermediate filaments (vimentin), com-
mon are meningothelial, fibrous, and plex interdigitating cellular processes
transitional meningiomas. Most of the (particularly in meningothelial variants),
Fig. 10.05 Dura mater showing multiple meningiomas subtypes behave in a benign fashion, but and desmosomal intercellular junctions.
that differ greatly in size. They are located unilaterally, four distinct variants, which are catego- These cell surface specializations, as
without extending beyond the falx cerebri (FC) to the rized as WHO grade II and III, are more well as intermediate filaments, are few
contralateral side. Multiple dural meningiomas have been likely to recur and to follow a more ag- in fibrous meningiomas, the cells be-
shown to be of clonal origin and probably result from
gressive clinical course (see the following ing separated by collagen. Secretory
spread through the dura {2413}.
234 Meningiomas
meningiomas feature single or multiple sites, create stop codons, or result in rare alterations {1615,2291}. Additional
epithelial-like lumina within single cells. frameshifts occurring mainly in the 5'- altered genes have been identified us-
These cell surfaces show short apical most two thirds of the gene {1536}. The ing genomic and targeted sequencing
microvilli and surround electron-dense common, predictable effect of these mu- strategies in a subset of NF2-wildtype
secretions {1393}. Microcystic meningi- tations is a truncated and presumably meningiomas {262,467,2217}. These
omas feature long cytoplasmic process- non-functional merlin protein (also called alterations preferentially affect WHO
es enclosing intercellular electron-lucent schwannomin). The frequency of NF2 grade I meningiomas at the skull base. A
matrix, with cells joined by desmosomes. mutations varies among meningioma hotspot mutation in the AKT1 gene (AKT1
variants. Fibroblastic and transitional E17K) is found in about 13% of meningi-
Proliferation omas, mostly of meningothelial or transi-
meningiomas, which are preferentially
In general, cellular proliferation increases tional subtype. Another mutation affects
located at the convexity, often carry NF2
in proportion to grade. The mitotic index the TRAF7 gene (mutated in 8-24% of
mutations {954,1367,2727}. In contrast,
and Ki-67 proliferation index correlate meningothelial, secretory, and microcyst- cases), almost always occurring in com-
approximately with volume growth rate. bination with KLF4 mutations, which are
ic meningiomas located at the skull base
Studies have suggested that meningi- also found in 93-100% of secretory men-
only rarely harbour NF2 mutations, but
omas with an index of > 4% have an in- ingiomas {2104}. Mutations in the SMO
are driven by other genetic alterations
creased risk of recurrence similar to that gene are found in 4-5% of WHO grade I
(see Other genes). In line with this, most
of atypical meningioma, whereas those meningiomas, mostly those located in
non-NF2 meningioma families develop
with an index of > 20% are associated meningothelial tumours {1536}. Further- the medial anterior skull base. Addition-
with death rates analogous to those as- ally, SMARCE1 mutations have recently
more, reduced expression of merlin has
sociated with anaplastic meningioma been identified in clear cell meningiomas
been observed in various histopathologi-
{1953}. However, significant differences {2375}.
cal variants of meningiomas, but seems to
in technique and interpretation make Deletions of the 9p21 region, including
be rare in meningothelial tumours {1455}.
it difficult to establish definitive cut-off the CDKN2A gene, are particularly com-
In atypical and anaplastic meningiomas,
points that would translate accurately NF2 mutations occur in approximately mon in anaplastic meningiomas and are
from one laboratory to another. associated with shortened survival {246,
70% of cases, matching the frequency
Cell of origin of NF2 mutations in benign fibroblastic 1938}. Mouse models have also shown
Meningiomas are thought to be derived and transitional meningiomas. This in- that adding CDKN2A/B loss to NF2 loss
from meningothelial (arachnoid) cells. dicates that NF2 inactivation is an early enhances the rate of formation of men-
tumorigenic event, a theory supported by ingiomas, including high-grade forms
Genetic profile findings in mouse models {1204}. Mouse {960}. Additionally, higher-grade men-
The current model of meningioma genet- models have also indicated an origin ingiomas escape senescence due to
ics in WHO grades l-lll is summarized in from prostaglandin-D synthase-positive overexpression of telomerase, which in
Fig. 10.06. meningeal precursor cells with inactivat- a subset of cases occurs due to TERT
Meningiomas were among the first solid ed NF2 {1205}. NF2-driven meningiomas promoter mutations {876}. The poten-
tumours recognized as having cytoge- with malignant progression show more tial prognostic value of this marker was
netic alterations, the most consistent genetic instability than do NF2-intact shown in a study of 252 meningiomas re-
change being monosomy 22 {2846}. In meningiomas {877}. In radiation-induced vealing hotspot C228T and C250T muta-
general, karyotypic abnormalities are meningiomas, the frequencies of NF2 tions in 1.7%, 5.7%, and 20.0% of WHO
more extensive in atypical and anaplastic mutations and loss of chromosome 22 grade I, II, and III meningiomas respec-
meningiomas {1615}. Other cytogenetic are lower, whereas structural abnormali- tively, with median progression free sur-
changes associated with meningioma in- ties of chromosome 1p are more com- vival times of 10.1 versus 179 months in
clude deletion of chromosome 1p (which mon, suggesting a different molecular mutant versus wildtype tumours {2220A}.
is associated with poor outcome) {1132} pathogenesis {1164,1501}. Other molecular alterations associated
and losses of chromosomes 6q, 9p, 10, with high tumour grade and aggressive
14q, and 18q (which occur in higher- Other genes clinical behaviour include losses of the
grade tumours) {2846}. Chromosomal The close association of NF2 mutations NDRG2 gene on 14q11.2 and the MEG3
gains reported in higher-grade meningi- in meningiomas with allelic loss on chro- gene on 14q32, gains of the RPS6KB1
omas include gains of chromosomes 1q, mosome 22 and mouse modelling of gene and other loci on the 17q23 am-
9q, 12q, 15q, 17q, and 20q. meningioma development clearly sug- plicon, loss of various NF2 homologues
gest that NF2 is the major meningioma within the erythrocyte membrane protein
The NF2 gene tumour suppressor gene on that chromo-
Mutations in the NF2 gene are detected band 4.1 family (e.g. the EPB41L3 gene
some {2727}. However, deletion studies on chromosome 18p11.3), and loss of
in most meningiomas associated with of chromosome 22 have also detected
neurofibromatosis type 2 (NF2) and as the protein 4.1 B binding partner, CADM1
losses and translocations of genetic ma- {116,333,343,1548,1615}.
many as 60% of sporadic meningiomas terial outside the NF2 region, raising the
{1466,2727}. In most cases, such muta- possibility that other tumour-associated Clonality of solitary, recurrent, and
tions are small insertions or deletions or genes are located there. Candidate multiple meningiomas
are nonsense mutations that affect splice genes include LARGE, MN1, AP1B1, and Studies of X chromosome inactivation us-
SMARCB1, although these show only ing Southern blot analysis indicate that
Meningioma 235
controls to report a first-degree family
history of meningioma {469}. In the Inter-
phone Study, the largest study of genetic
polymorphisms and meningioma risk,
investigators found a significant associa-
tion with meningioma for 12 SNPs drawn
from DNA repair genes {181}. The group
reported a novel and biologically intrigu-
ing association between meningioma risk
and three variants in BRIP1 {17q22}, the
gene encoding the FACJ protein, which
interacts with BRCA1. A genome-wide
association study identified a single sus-
ceptibility locus at 10p12.31 (MLLT10)
{593}. MLLT10 is implicated in various
leukaemias and activates the WNT path-
way. A rare association with naevoid ba-
sal cell carcinoma syndrome (also called
Gorlin syndrome) has also been suggest-
ed, based on germline SUFU or PTCH1
mutations {1265,2202}. The relationship
between meningioma and other inher-
ited tumour syndromes, such as Werner
syndrome and Cowden syndrome, is less
defined.
236 Meningiomas
presence of some atypical features (but Progesterone receptor status because a significant subset of histologi-
not enough for WHO grade II designa- Progesterone receptor expression is cally and clinically benign meningiomas
tion) increases the risk of subsequent inversely associated with meningioma also lack the receptor, the significance of
progression/recurrence over those with grade. Its absence negatively impacts this finding in the absence of other prog-
no atypical features at all {1581 A}. Malig- disease-free intervals in some series, nostic features should not be overstated.
nant histological features are associated but in most, it is not independent of other
with shorter survival times: 2-5 years de- known prognostic factors, such as grade
pending largely on the extent of resection {1940,2181}. Almost all WHO grade III
{30A,483A,1951}. meningiomas are receptor negative, but
Fibrous meningioma
Meningothelial meningioma lobules should not be confused with the
sheeting or loss of architectural pattern Definition
Definition seen in atypical meningioma. This sub- A variant of meningioma that consists of
A classic and common variant of me- type is encountered most often in the an- spindled cells forming parallel, storiform,
ningioma, with medium-sized epithelioid terior skull base and is less likely to be and interlacing bundles in a collagen-rich
tumour cells forming lobules, some of driven by NF2 mutations {942,1367}. matrix.
which are partly demarcated by thin col- Because the tumour cells so closely re- In fibrous meningioma, whorl formation
lagenous septa. semble those of the normal arachnoid and psammoma bodies are infrequent.
Like normal arachnoid cap cells, the tu- cap, reactive meningothelial hyperplasia Nuclear features characteristic of menin-
mour cells of meningothelial meningioma occasionally resembles this meningi- gothelial meningioma are often found fo-
are largely uniform, with oval nuclei with oma variant. The most florid examples of cally. The tumour cells form fascicles with
delicate chromatin and variable nuclear meningothelial hyperplasia are typically various amounts of intercellular collagen,
holes (i.e. empty-looking clear spaces) found adjacent to optic nerve gliomas, which are striking in some cases. These
and nuclear pseudoinclusions (i.e. cyto- other tumour types, or haemorrhage; fascicles may raise the differential diag-
plasmic invaginations). Eosinophilic cyto- meningothelial hyperplasia is also com- nosis of solitary fibrous tumour / haeman-
plasm is abundant, and the delicate, intri- monly found in the setting of chronic giopericytoma (SFT/HPC), but only SFT/
cately interwoven tumour cell processes renal disease, advanced patient age, HPC expresses nuclear STAT6 {2308}.
seen ultrastructurally cannot be dis- arachnoiditis ossificans, spontaneous Rare fibrous meningiomas also include
cerned on light microscopy, explaining intracranial haemorrhage, and occasion- nuclear palisades resembling Verocay
the outdated synonym “syncytial menin- ally in patients with diffuse dural thicken- bodies, a diagnostic pitfall exacerbated
gioma’’. Whorls and psammoma bodies ing and contrast enhancement on neuro- by frequent S100 expression in this sub-
are infrequent in meningothelial men- imaging {1945}. type, albeit not as diffusely staining as
ingioma; when present, they tend to be most schwannomas. Like other subtypes,
less formed than in transitional, fibrous, ICD-O code 9531/0 most fibrous meningiomas express EMA.
or psammomatous subtypes. Larger
Fig. 10.07 Meningothelial meningioma with lobular Fig. 10.08 Fibrous meningioma. A A distinctive feature of this variant is the development of abundant reticulin and
growth pattern, syncytium-like appearance due to poorly collagen fibres between the individual cells. B Most fibrous meningiomas express EMA.
defined cell borders, scattered clear nuclear holes, and
occasional intranuclear pseudoinclusions (arrows).
Fig. 10.10 Psammomatous meningioma. A CT showing bone-like density of a psammomatous meningioma (arrowhead) involving the cervicomedullary junction. B Almost complete
replacement of the meningioma by psammomatous calcifications (postdecalcif cation specimen). C EMA immunostaining reveals meningioma cells between psammoma bodies.
238 Meningiomas
Fig. 10.12 Angiomatous meningioma. A Blood vessels constitute most of the mass. The intervening tumour cells are difficult to recognize as meningothelial. B Tumour cells showing
positivity for EMA. C Strong immunoreactivity for somatostatin receptor type 2A.
Fig. 10.13 Microcystic meningioma on T2-weighted MRI, Fig. 10.14 Microcystic meningioma. A Cobweb-like background with numerous delicate processes. B Thin processes
with macrocysts and adjacent brain oedema. are often evident on EMA immunostaining.
Fig. 10.15 Small secretory meningioma (T) on T2- Fig. 10.16 Secretory meningioma. A The pseudopsammoma bodies are periodic acid—Schiff—positive. B Evidence of
weighted MRI, showing extensive peritumoural brain epithelial metaplasia includes cytokeratin positivity in tumour cells forming gland-like spaces.
oedema.
Grading
Secretory meningioma corresponds his-
tologically to WHO grade I.
Lymphoplasmacyte-rich
meningioma
Definition
A rare variant of meningioma that features
extensive chronic inflammatory infiltrates,
often overshadowing the inconspicuous
meningothelial component.
Some previously reported cases of lym-
phoplasmacyte-rich meningioma likely
constitute inflammatory processes with
associated meningothelial hyperpla-
sia, although cases behaving similarly
to conventional meningioma have also Fig. 10.20 Chordoid meningioma. A On cut surface, the mucoid matrix is grossly evident. B Eosinophilic tumour
been described {1421}. Neuroimaging cells in a mucous-rich matrix. C Trabeculae of eosinophilic and vacuolated epithelioid cells associated with a basophilic
mucin-rich stroma. D Vimentin immunohistochemistry highlights the ribbon-like architecture.
features vary widely, with frequent peri-
tumoural oedema and occasional multi-
focality or diffuse carpet-like meningeal often predominate and plasma cells are These alterations have no known clinical
involvement resembling pachymeningi- not always conspicuous, the alternative significance, and many probably do not
tis. Systemic haematological abnormali- term “inflammation-rich meningioma” has constitute true metaplasia (e.g. lipid ac-
ties, including hyperglobulinaemia and also been proposed {1421}. cumulation rather than true lipomatous
iron-refractory anaemia have also been metaplasia {483}). Clinical correlation is
reported {2866}. Because macrophages ICD-0 code 9530/0 occasionally needed to distinguish os-
sified meningiomas from meningiomas
Grading
exhibiting bone invasion.
Lymphoplasmacyte-rich meningioma
corresponds histologically to WHO ICD-0 code 9530/0
grade I.
Grading
Metaplastic meningioma corresponds
Metaplastic meningioma histologically to WHO grade I.
Definition
A variant of meningioma with striking fo- Chordoid meningioma
cal or widespread mesenchymal compo-
nents including osseous, cartilaginous, Definition
Fig. 10.19 Lipoma-like metaplastic meningioma. lipomatous, myxoid, and xanthomatous A rare variant of meningioma that histo-
Positivity for EMA in lipoma-like cells suggests fat
tissue, either singly or in combinations. logically resembles chordoma, featuring
accumulation in meningioma cells rather than true
adipocyte metaplasia.
240 Meningiomas
patternless (commonly) or sheeting ar-
chitecture and round to polygonal cells
with clear, glycogen-rich cytoplasm and
prominent blocky perivascular and inter-
stitial collagen.
The perivascular and interstitial collagen
occasionally coalesces into large acel-
lular zones of collagen or forms brightly
eosinophilic amianthoid-like collagen. It
shows prominent periodic acid-Schiff-
positive and diastase-sensitive cytoplas-
mic glycogen. Whorl formation is vague
at most and psammoma bodies are in-
conspicuous. Clear cell meningioma has
a proclivity for the cerebellopontine angle
and spine, especially the cauda equina
region. It also tends to affect younger
patients, including children and young
adults. Clear cell meningiomas are asso-
ciated with more aggressive behaviour,
including frequent recurrence and occa-
sional cerebrospinal fluid seeding {2873}.
Familial examples have been reported in
association with SMARCE1 mutations
{2379}. The more aggressive behaviour
of these tumours, corresponding to WHO
Fig. 10.21 Clear cell meningioma. A Sheets of rounded clear cells and perivascular interstitial collagenization. grade II, has been most clearly demon-
B Abundant periodic acid-Schiff-positive intracytoplasmic glycogen. C Immunoreactivity for EMA. strated when the clear-cell pattern is pre-
dominant and well developed.
cords or trabeculae of eosinophilic, often of these tumours, corresponding to WHO
vacuolated cells set in an abundant mu- grade II, has been most clearly demon- ICD-0 code 9538/1
coid matrix. strated when the Chordoid pattern is pre-
Grading
In Chordoid meningioma, Chordoid areas dominant and well developed.
Clear cell meningioma corresponds his-
are often interspersed with more typical ICD-0 code 9538/1 tologically to WHO grade II.
meningioma tissue; pure examples are
uncommon. Chronic inflammatory infil- Grading
trates are often patchy when present, Chordoid meningioma corresponds his- Atypical meningioma
but may be prominent. Chordoid men- tologically to WHO grade II.
ingiomas are typically large, supraten- Definition
torial tumours. They have a very high A meningioma of intermediate grade be-
rate of recurrence after subtotal resec- tween benign and malignant forms, with
tion {501}. Infrequently, patients have Clear cell meningioma increased mitotic activity, brain invasion
associated haematological conditions, on histology, or at least three of the follow-
such as anaemia or Castleman disease Definition ing features: increased cellularity, small
{1249}. The more aggressive behaviour A rare variant of meningioma with a
Fig. 10.22 Brain-invasive meningioma. A Tongue-like protrusions into adjacent brain parenchyma. B Leptomeningeal meningioma in a child, with extensive perivascular spread
along Virchow-Robin spaces and hyalinization mimicking meningioangiomatosis. This unusual pattern of spread should not be misinterpreted as true brain invasion. C Entrapped
GFAP-positive islands of gliotic brain parenchyma at periphery of the tumour.
Fig. 10.25 Papillary meningioma. A At low magnification, the pseudopapillary pattern is evident, with loss of cellular cohesion away from central vascular cores. B This meningioma
combines a papillary growth pattern with rhabdoid cytology, including globular paranuclear inclusions (inset).
242 Meningiomas
Fig. 10.26 Rhabdoid meningioma. A Eccentrically placed vesicular nuclei, prominent nucleoli, and eosinophilic globular/fibrillar paranuclear inclusions. B Vimentin-positive
paranuclear inclusions. C Rhabdoid meningioma cell showing a paranuclear whorled bundle of intermediate filaments with entrapped organelles.
zone resembling the pseudorosettes of demonstrated when the papillary pattern prominent eosinophilic paranuclear in-
ependymoma. This feature frequently in- is predominant and well developed. clusions, appearing either as discernible
creases in extent with recurrences, and whorled fibrils or compact and waxy.
other high-grade histological features are ICD-0 code 9538/3 These rhabdoid cells resemble those de-
almost always found. Papillary meningi- scribed in other tumours, including atypi-
Grading
omas tend to occur in young patients, in- cal teratoid/rhabdoid tumour of the brain;
Papillary meningioma corresponds histo-
cluding children {1545}. An invasive ten- however, unlike in atypical teratoid/rhab-
logically to WHO grade III {1545}.
dency, including brain invasion, has been doid tumour, SMARCB1 expression is
noted in 75% of cases, recurrence in retained in rhabdoid meningioma {1941}.
55%, metastasis (mostly to lung) in 20%, Rhabdoid meningioma Rhabdoid cells may become increas-
and death of disease in about half {1368, ingly evident with tumour recurrences.
1901}. Some meningiomas combine a Definition Most rhabdoid meningiomas have a high
papillary architecture with rhabdoid cy- An uncommon variant of meningioma proliferation index and other histological
tology {2796}. The more aggressive be- that consists primarily of rhabdoid cells: features of malignancy. Some combine
haviour of these tumours, corresponding plump cells with eccentric nuclei, open a papillary architecture with rhabdoid
to WHO grade III, has been most clearly chromatin, a prominent nucleolus, and cytology (see Papillary meningioma,
p. 242). When the rhabdoid features are
Fig. 10.27 Anaplastic (malignant) meningioma (common, albeit non-specific macroscopic features). A Note the soft, gelatinous consistency on cut surface, as well as the large yellow
zone of necrosis on the right. B The superior sagittal sinus is occluded by tumour. C The inner surface of the skull is moth-eaten due to extensive bone invasion by an adjacent
meningioma.
Fig. 10.28 Bilateral parasagittal anaplastic (malignant) Fig. 10.29 Anaplastic (malignant) meningioma. A An atypical mitotic figure and prominent nucleoli. B Sarcoma-
meningioma. Irregular borders and highly invasive like anaplastic (malignant) meningioma. Spindled morphology, increased matrix deposition, and poorly differentiated
growth pattern on postcontrast T1-weighted MRI. cytology.
Fig. 10.31 Anaplastic (malignant) meningioma. A Although vimentin positivity is not very specific, even the most poorly differentiated meningiomas are typically strongly and diffusely
positive. This can be helpful in the differential diagnosis with metastatic carcinomas, most of which are negative or only focally positive for vimentin. B Positivity for EMA is typically
patchy in meningiomas of all grades. Because 10-20% are negative, a lack of EMA staining does not exclude the diagnosis of meningioma. C Strong positivity for CK7 (and other
cytokeratins) in this example represented a diagnostic pitfall for metastatic carcinoma; however, other morphological, immunohistochemical, and genetic features were characteristic
of meningothelial origin. D Ki-67 proliferation index > 20%. E Rare nuclei are positive for progesterone receptor. F Most tumour nuclei display two green centromere 9 signals, but
only one red 9p21 (CDKN2A) signal, consistent with deletion.
fully developed and combined with other ICD-0 code 9538/3 account for 1-3% of meningiomas over-
malignant features, these meningiomas all. In addition to high mitotic counts,
often have an aggressive clinical course Grading most also show extensive necrosis and
consistent with WHO grade III {1252, Rhabdoid meningioma corresponds his- a Ki-67 proliferation index > 20%. Rare
1950}. However, some meningiomas tologically to WHO grade III. cases show true epithelial or mesenchy-
show rhabdoid features only focally and/ mal metaplasia {1910}. Confirmation of
or lack other histological features of ma- the meningothelial origin of cases with
lignancy; such cases are less aggres- Anaplastic (malignant) diffuse anaplasia often requires either a
sive as a group {2639A}. Therefore, it is meningioma history of meningioma at the same site
suggested that they be graded as nor- Definition or immunohistochemical, ultrastructural,
mally, but with the added descriptor of A meningioma that exhibits overtly malig- and/or genetic support.
“with rhabdoid features” and a comment nant cytology (resembling that of carcino- Anaplastic meningiomas are often fa-
that closer follow-up may be warranted ma, melanoma, or high-grade sarcoma) tal, with average survival times ranging
{2639A}. Rare forms appear rhabdoid on and/or markedly elevated mitotic activity. from < 2 years to > 5 years, depending
histology, but ultrastructurally show inter- In one study, markedly elevated mitotic greatly on the extent of resection {1951,
digitating processes rather than the typi- activity was defined as > 20 mitoses per 2448}. Clinical risk factors for anaplastic
cal paranuclear aggregates of intermedi- 10 high-power (0.16 mm2) fields {1951}. meningioma include a non-skull base or-
ate filaments {823}. Anaplastic (malignant) meningiomas igin, male sex, and prior surgery {1214}.
Because malignant progression in
244 Meningiomas
meningiomas, as in gliomas, is a contin- Other morphologicalvariants encountered secondarily in a variety
uum of increasing anaplasia, determining of meningiomas is that of meningothe-
the cut-off point between atypical and Due to the wide morphological spec- lial rosettes, which are composed mostly
anaplastic meningioma is sometimes trum that can be encountered in men- of cell processes and collagen, with or
challenging. ingiomas, rare examples are difficult without a central gland-like lumen {1520}.
to classify as any of the well-accepted Most tumours once called pigmented
variants. These include meningiomas meningiomas are now known to be mel-
ICD-0 code 9530/3 with oncocytic, mucinous, sclerosing, anocytomas. However, the recruitment of
whorling-sclerosing, GFAP-expressing, melanocytes from the adjacent meninges
Grading and granulofilamentous inclusion-bear- into the substance of a true meningioma
Anaplastic (malignant) meningioma corre- ing features {46,173,781,917,1039,2168}. accounts for dark pigmentation in rare
sponds histologically to WHO grade III. However, there is currently insufficient cases {1768}.
evidence that these tumours constitute
distinct variants. Another rare pattern
Fig. 10.32 Rosette-forming meningioma. A Meningioma with rosette formation composed mostly of cell processes. B Vimentin immunostaining emphasizes the cell processes in
meningothelial rosettes. C Trichrome staining highlights the dense collagen in the centre of some meningothelial rosettes.
Fig. 10.33 Meningioma with oncocytic features. A Marked degenerative nuclear atypia. B EMA expression. C Immunostain for antimitochondrial antigen confirms the oncocytic
changes.
Definition and the other benign mesenchymal tu- terminale and also occur at the thoracic
Benign and malignant mesenchymal tu- mours are even rarer. In two series, of level. Intraventricular and tuber cinereum
mours originating in the CNS, with ter- 19 and 17 cases, sarcomas accounted lipomas are rare {233}. Occasional CNS
minology and histological features cor- for < 0.1-0.2% of the intracranial tumours lipomas have a fibrous connection with
responding to their soft tissue and bone {1838.1919} . The higher values that have surrounding soft or subcutaneous tis-
counterparts. been reported in the past are a reflection sue. Osteolipomas have predilection for
Mesenchymal tumours arise more com- of overdiagnosis related to historical clas- the suprasellar/interpeduncular regions
monly in the meninges than in the CNS sification schemes. The most common {233,2367}. Most spinal lipomas (in par-
parenchyma or choroid plexus. In prin- tumour types include fibrosarcoma and ticular angiolipomas) arise in the epidural
ciple, any mesenchymal tumour may undifferentiated pleomorphic sarcoma / space.
arise within or secondarily impact on the malignant fibrous histiocytoma (MFH)
nervous system, but the primary mesen- Clinical features
{1838.1919} .
chymal CNS tumours are very rare. They The clinical symptoms and signs are
Mesenchymal tumours can occur in pa-
can occur in patients of any age and variable and non-specific, and depend
tients of any age. Rhabdomyosarcoma
arise more commonly in supratentorial largely on tumour location. Spontaneous
occurs preferentially in children, whereas
than in infratentorial or spinal locations. regression is rare {1390}. Whereas the
undifferentiated pleomorphic sarcoma /
The clinical symptoms and neuroradio- neuroradiological appearance of most
MFH and chondrosarcoma usually mani-
logical appearance of most tumours are mesenchymal tumours is non-specific,
fest in adults. As a whole, sarcomas show
non-specific. the neuroimaging characteristics of li-
no obvious sex predilection.
The histological features of mesenchy- poma are virtually diagnostic; on MRI,
Etiology T1-weighted images show the high sig-
mal tumours affecting the CNS are similar
Intracranial fibrosarcoma, undifferenti- nal intensity of fat, which then disappears
to those of the corresponding extracra-
ated pleomorphic sarcoma / MFH, chon- with fat-suppression techniques. Speck-
nial soft tissue and bone tumours {714}.
drosarcoma, and osteosarcoma can oc- led calcifications are typical of chondroid
Solitary fibrous tumour / haemangioperi-
cytoma (by far the most common mesen- cur several years after irradiation {453, and osseous tumours.
1791}. Isolated cases of intracranial and
chymal, non-meningothelial neoplasm) Spread
spinal fibrosarcoma, undifferentiated
and peripheral nerve sheath tumours (the Primary meningeal sarcomatosis is a dif-
pleomorphic sarcoma / MFH, and angio-
most common neoplasms of cranial and fuse leptomeningeal sarcoma lacking
sarcoma have also been related to previ-
paraspinal nerves) are described sepa- circumscribed masses {2598}. Although
ous trauma or surgery {1020}, an etiology
rately. Antiquated nosological terms, this entity is strictly defined as a non-
such as “spindle cell sarcoma”, “pleo- that may be more common to desmoid-
meningothelial mesenchymal tumour,
type fibromatosis {1684}. EBV is associ-
morphic sarcoma,” and “myxosarcoma” most published cases have not been
ated with the development of intracranial
have been replaced by designations diagnosed according to modern nomen-
smooth muscle tumours in immunocom-
indicating more specific differentiation clature. Re-examination of published
promised patients {287}.
or updated terminology {714}. The non- cases using immunohistochemistry has
specific diagnostic term “meningeal sar- Localization revealed that most cases actually con-
coma” is also to be avoided, because it Tumours arising in meninges are more stitute carcinoma, lymphoma, glioma, or
has been used in the past to denote both common than those originating within embryonal tumour.
sarcomatoid anaplastic meningiomas CNS parenchyma or in choroid plexus.
and various types of sarcomas. Macroscopy
Most mesenchymal tumours are su-
The macroscopic appearance of mesen-
pratentorial, but rhabdomyosarcomas
Grading chymal tumours depends entirely on their
are more often infratentorial. Chondrosar-
Mesenchymal, non-meningothelial tu- differentiation and is similar to that of the
mours range from benign neoplasms comas involving the CNS arise most often
corresponding extracraniospinal soft tis-
in the skull base. Among benign mesen-
(corresponding histologically to WHO sue tumours. Lipomas are bright yellow,
chymal lesions, intracranial lipomas have
grade I) to highly malignant sarcomas lobulated lesions. Epidural lipomas are
a characteristic location and typically oc-
(corresponding histologically to WHO delicately encapsulated and discrete,
cur at midline sites, such as the anterior
grade IV). whereas intradural examples are often
corpus callosum, quadrigeminal plate,
Epidemiology intimately attached to leptomeninges
suprasellar and hypothalamic regions,
The various forms of lipoma account and CNS parenchyma. Chondromas are
and auditory canal. Spinal cord exam-
for only 0.4% of all intracranial tumours, demarcated, bosselated, greyish-white,
ples involve the conus medullaris-filum
Fig. 11.02 Solitary fibrous tumour / haemangiopericytoma. A The falcine tumour in a 51 -year-old man shows postgadolinium enhancement to a variable extent. B The tumour of the
posterior fossa / cerebellopontine angle in a 55-year-old man shows postgadolinium enhancement. C Tumour of the upper thoracic spine in a 45-year-old man (a T1 mass, 1.6 cm in
length) shows postgadolinium enhancement and a dural tail, mimicking meningioma.
A negative result should prompt consid- by high cellularity and a delicate, rich with the solitary fibrous tumour pheno-
eration of alternative diagnoses (see Dif- network of reticulin fibres typically invest- type is generally benign, provided gross
ferential diagnosis). When STAT6 immu- ing individual cells. Thin-walled branch- total resection can be achieved, whereas
nohistochemistry or NAB2-STAT6 fusion ing haemangiopericytoma-like (staghorn) tumours with the haemangiopericytoma
testing are not or cannot be performed, vessels are a feature shared by both phenotype have a high rate of recur-
this should be indicated in the report. phenotypes. rence (> 75% at 10 years) and may de-
The histological spectrum encompasses Solitary fibrous tumour / haemangioperi- velop extracranial metastases, especially
two main morphological variants: the cytoma (SFT/HPC) is rare (accounting in bones, lungs, and liver (in -20% of
solitary fibrous tumour phenotype char- for < 1% of all primary CNS tumours) cases).
acterized by a patternless architecture or and most commonly affects adults (in
ICD-0 codes
short fascicular pattern, with alternating the fourth to sixth decade of life). The tu-
Solitary fibrous tumour /
hypocellular and hypercellular areas with mours are typically dural-based and of-
thick bands of collagen, and the haeman- haemangiopericytoma
ten supratentorial, with about 10% being
Grade 1 8815/0
giopericytoma phenotype characterized spinal. The clinical behaviour of tumours
Grade 2 8815/1
Grade 3 8815/3
Grading
Outside the CNS (e.g. in the soft tissue,
pleura, and other visceral sites), the term
“haemangiopericytoma” has long been
subsumed into the designation “solitary
fibrous tumour”, with unified criteria for
malignancy. These criteria include hy-
percellularity and necrosis in addition to
elevated mitotic count (which remains
Fig. 11.04 Solitary fibrous tumour. A Strong and diffuse positivity for CD34 is typical of this phenotype. B Nuclear the best indicator of poor outcome) {714,
localization of STAT6 protein detected by immunohistochemistry. 861}. A mitotic count of > 4 mitoses per
10 high-power fields is required for the One study proposed a three/four-tiered solitary fibrous tumours / haemangioperi-
designation of solitary fibrous tumour grading scheme (grades I, lla, lib, and cytomas has significant therapeutic im-
as malignant, irrespective of solitary fi- III) after combining the solitary fibrous plications, the current consensus is that it
brous tumour or haemangiopericytoma tumour and haemangiopericytoma des- is still premature to consider replacing the
histopathological phenotype {714}. In the ignations and applying common (but current three-tiered with another grading
CNS, the classification and grading of slightly different) criteria based on hy- system. Larger studies are needed to de-
these tumours has been somewhat dif- percellularity, necrosis, and mitotic count termine whether the malignancy defini-
ferent, resulting in a three-tiered system, (< 5 vs > 5 mitoses per 10 high-power tion (i.e. > 4 mitoses per 10 high-power
with grade I tumours considered benign fields). In that study, mitotic count was fields), which is applied to non-CNS sites
and typically treated by surgical resec- found to be the only independent prog- irrespective of solitary fibrous tumour or
tion alone, and grade II and III tumours nostic factor for progression-free and haemangiopericytoma histopathologi-
considered malignant and treated with overall survival in multivariate analysis cal phenotype, is relevant to meningeal
adjuvant therapy, typically radiotherapy. {256}. Because the distinction between locations.
A hypocellular, collagenized tumour with grade I versus grades II and III meningeal
a classic solitary fibrous tumour pheno-
type is considered to correspond histo-
logically to grade I, whereas more dense-
ly cellular tumours mostly corresponding
to the haemangiopericytoma phenotype
are considered malignant. Tumours with
a haemangiopericytoma phenotype are
subclassified as grade II or grade III
(anaplastic) depending on mitotic count
(< 5 vs > 5 mitoses per 10 high-power
fields) {1533,1637}. Patients diagnosed
with grade II or III haemangiopericytoma
benefit from adjuvant radiotherapy {813, Fig. 11.06 Haemangiopericytoma. A Only focal positivity for CD34 is present in this malignant tumour. B Nuclear
814}. localization of STAT6 protein is detected by immunohistochemistry.
Clinical features
In most cases, the symptoms and signs
are consistent with their localization,
accompanied by mass effect, with in-
creased intracranial pressure due to
tumour size {859,1637}. Massive intra-
cranial haemorrhage {1602} and hypo-
glycaemia from tumours that release
insulin-like growth factor {2391} are rare
complications.
Fig. 11.07 Intradural extramedullary solitary fibrous tumour / haemangiopericytoma. A T1-weighted MRI. Isointense
Imaging
tumour {15 mm x 15 mm x 15 mm) located at T10-T11. B T2-weighted MRI. C Postcontrast T1-weighted MRI. The Plain CT images show solitary, irregularly
lesion is homogeneously and diffusely enhanced after gadolinium injection. contoured masses without calcifications
or hyperostosis of the adjacent skull.
On MRI, the tumours are isointense on
T1-weighted images, with high or mixed
intensity on T2-weighted images, along
with variable contrast enhancement. Du-
ral contrast enhancement at the periph-
ery of the lesion (dural tail) and flow voids
may be observed {2693}. Arteriography
reveals a hypervascular mass with promi-
nent draining veins.
Macroscopy
Solitary fibrous tumours / haemangioperi-
cytomas are usually well-circumscribed,
firm white to reddish-brown masses, de-
pending on the degree of collagenous
stroma and cellularity. Occasionally, they
show infiltrative growth or lack dural at-
tachment {365,377,1656}. Variable myxoid
or haemorrhagic changes may be present.
Microscopy
Solitary fibrous tumour / haemangioperi-
Fig. 11.08 Solitary fibrous tumour / haemangiopericytoma. A Patternless architecture with alternating hypocellular and
cytoma shows two main distinct histo-
hypercellular areas. B Highly cellular area. C Hypocellular areas with thick bands of collagen. D STAT6 is strongly logical phenotypes, although cases with
expressed in all tumour nuclei. intermediate/hybrid morphology are also
seen. The classic solitary fibrous tumour
Epidemiology Age and sex distribution phenotype shows a patternless archi-
The true incidence and prevalence of tecture characterized by a combination
Peak incidence occurs in the fourth to of hypocellular and hypercellular areas
this entity are difficult to ascertain, due
fifth decade of life, and males are affect- separated by thick bands of hyalinized,
to inconsistent nomenclature. In the 2014
ed slightly more frequently than females sometimes keloidal or amianthoid-like
statistical report published by the Central
{522,1637,2269}. Primary CNS solitary collagen and thin-walled branching
Brain Tumor Registry of the United States
(CBTRUS), because of their rarity, soli- fibrous tumours / haemangiopericyto- haemangiopericytoma-like (staghorn)
mas have been reported in the paediatric vessels. The tumour cells have a mono-
tary fibrous tumour / haemangiopericyto-
population, although they are exceed- morphic ovoid to spindle-shaped cy-
mas are grouped with other mesenchy-
ingly rare {1623,2550}. tomorphology, with scant eosinophilic
mal tumours of the meninges, which as
a group have an average annual age-ad- cytoplasm. The nuclei are round or
Localization
justed incidence rate of 0.08 cases per oval, with moderately dense chromatin
Most solitary fibrous tumours / haeman-
100 000 population {1863}. Data from and inconspicuous nucleoli lacking the
giopericytomas are dural-based (often
large series suggest that solitary fibrous pseudoinclusions characteristic of men-
supratentorial), and about 10% are spi-
tumour / haemangiopericytomas consti- ingiomas. Mitoses are generally scarce,
nal. Skull base, parasagittal, and falcine
tute < 1% of all CNS tumours {522,859, rarely exceeding 3 per 10 high-power
locations are especially common {1637,
1637,2269}. fields {365,714}. In contrast, the classic
2269}. Uncommon locations include the
cerebellopontine angle {2516}, pineal
rearrangement support this diagnosis domain 1; NCD2, NAB-conserved domain 2; N-ter, N-terminus; PID, protein interaction domain; SH2, SRC homology
domain; TAD, transcriptional activator domain; wt, wildtype.
{1507}. Mesenchymal chondrosarcoma,
a rare malignant tumour with a bimorphic
pattern, is composed of sheets and nests proximity ligation assay {1317,2308}. Other
The individual tumour cells are sur-
of poorly differentiated small round cells markers, such as desmin, SMA, cytokera-
rounded by electron-dense, extracellular
interrupted by islands of well-differentiat- tin, EMA, and progesterone receptor, may
basement membrane-like material - the
ed hyaline cartilage and a branching vas- be rarely encountered as a focal finding
ultrastructural equivalent of the reticulin
culature. Because the cartilage islands {1656,1949,2066,2764}. ALDH1A1 gene
network visible on light microscopy. True
can be extremely focal, this entity may overexpression, which was initially detect-
desmosomes and gap junctions (as seen
be mistaken for malignant solitary fibrous ed by microarray analysis, can be demon-
in meningiomas) are absent {524}.
tumour / haemangiopericytoma if insuffi- strated by immunohistochemistry showing
ciently sampled {714}. Malignant periph- Immunophenotype ALDH1 positivity in 84% of cases, com-
eral nerve sheath tumour rarely occurs Solitary fibrous tumours / haemangioperi- pared to only 1% of meningiomas {255}.
in the meninges and may resemble the cytomas are typically diffusely positive for
haemangiopericytoma phenotype. How- vimentin and CD34 {1949}, although loss of Proliferation
ever, malignant peripheral nerve sheath CD34 expression is common in malignant The median Ki-67 proliferation index
tumour is usually negative for CD34 and tumours. The NAB2-STAT6 fusion leads to was 10% (range: 0.6-36%) in a series of
STAT6 and may show focal expression of nuclear relocalization of STAT6 protein and 31 haemangiopericytomas {2039}. An-
S100 protein and SOX10. can be detected with very high specific- other study reported a median Ki-67 pro-
ity and sensitivity by immunohistochemis- liferation index of 5% in a series of 29 sol-
Electron microscopy
try {1317,1866,2308}. Meningiomas show itary fibrous tumours and 10% in a series
Solitary fibrous tumours / haemangio-
faint nuclear and/or cytoplasmic positiv- of 43 cellular solitary fibrous tumours /
pericytomas are composed of closely
ity, but no strong isolated nuclear STAT6 haemangiopericytomas {256}.
apposed elongated cells with short pro-
immunostaining {2308}. The NAB2-STAT6
cesses that contain small bundles of in- Cell of origin
fusion can also be detected at the protein
tracytoplasmic intermediate filaments. The histogenesis of CNS solitary fibrous
level with high specificity and sensitivity by
tumour/haemangiopericytoma remains a is traditionally considered to be benign, considered to be grade I and the hae-
matter of debate. Their fibroblastic nature provided that gross total resection can mangiopericytoma phenotype grade II or
and the presence of a common NAB2- be achieved and atypical histological III) may need to be adapted to improve
STAT6 gene fusion {444,2141,2308} are features are absent {365}. The prognostic the prognostic significance.
strong arguments for grouping CNS soli- significance of focal (rather than general-
tary fibrous tumour and haemangioperi- ized) atypia in these tumours and of inva- Haemangioblastoma
cytoma together under the term “solitary sion in bone and dural sinuses is unclear
fibrous tumour / haemangiopericytoma”. {209,669}. In contrast, even after gross to- Plate K.H.
tal resection, tumours with the haemangi- Aldape K.D.
Genetic profile Vortmeyer A.O.
opericytoma phenotype have a high rate
The central (and to date specific) genetic Zagzag D.
of recurrence (> 75% in patients followed
abnormality in solitary fibrous tumour / Neumann H.P.H.
for > 10 years). In addition, about 20% of
haemangiopericytoma is a genomic in-
patients with tumours of the haemangio-
version at the 12q13 locus, fusing the Definition
pericytoma phenotype develop extracra- A tumour histologically characterized by
NAB2 and STAT6 genes in a common
nial metastases, especially to bone, lung, neoplastic stromal cells and abundant
direction of transcription {444,2141}. This
and liver {209,815,903,2673}. Gross total small vessels.
gene fusion is present in most cases, re-
resection favourably affects recurrence Haemangioblastoma is a benign slow-
gardless of histological grade or anatom-
and survival, and patients benefit from growing tumour of adults, typically oc-
ical location (meningeal, pleural, or soft
adjuvant radiotherapy {813,814,815,903}.
tissue). The recent discovery of NAB2- curring in the brain stem, cerebellum,
As discussed previously, the historical and spinal cord. Haemangioblastomas
STAT6 fusion in the majority of solitary
three-tiered grading system (in which
fibrous tumours / haemangiopericytomas
the solitary fibrous tumour phenotype is
has provided strong evidence for a mor-
phological continuum. The presence of
the NAB2-STAT6 fusion protein results in
nuclear localization of STAT6 and strong
nuclear positivity for STAT6 by immuno-
histochemistry {2308}.
In contrast, the rare sinonasal haemangi-
opericytoma does not exhibit the NAB2-
STAT6 fusion, but instead harbours CTN-
NB1 mutations {18,929}.
Genetic susceptibility
There is no evidence of familial cluster-
ing of meningeal solitary fibrous tumour /
haemangiopericytoma.
Prognosis and predictive factors
The clinical behaviour of tumours with
the solitary fibrous tumour phenotype
Fig. 11.11 Haemangioblastoma. A,B The tumour is multicystic (white arrow) and well demarcated from the surrounding
cerebellum (black arrows).
Fig. 11.14 Haemangioblastoma. A Stromal cells with clear, vacuolated cytoplasm due to accumulation of lipid droplets. B The cellular variant is a closer mimic of metastatic renal
cell carcinoma and is characterized by cohesive nests of epithelioid stromal cells, with less-vacuolated cytoplasm and fewer intervening capillaries.
Haemangioblastoma 255
surrounding neural tissues rarely occurs.
Mitotic figures are rare. Stromal cells ac-
count for only 10-20% of the cells and
constitute the neoplastic component of
the tumour. Their nuclei can vary in size,
with occasional atypical and hyperchro-
matic nuclei. However, haemangioblasto-
ma’s most characteristic and distinguish-
ing morphological feature is numerous
lipid-containing vacuoles, resulting in the
typical clear-cell morphology of haeman-
gioblastoma, which may resemble meta-
static renal cell carcinoma (RCC). The
fact that patients with VHL are also prone
to RCC adds to the complexity of this
differential diagnosis. Cases of tumour-
to-tumour metastasis (RCC metastatic
to haemangioblastoma) have also been
reported in this setting {934}.
Immunophenotype
Fig. 11.15 Haemangioblastoma. A Nuclear expression of HIF1A in stromal cells. B Immunostaining for inhibin highlights
The stromal and capillary endothelial cells
the stromal cells. C Unlike in metastatic renal cell carcinoma, the tumour cells of this cellular haemangioblastoma are differ significantly in their expression pat-
inhibin-positive. D CD34 immunostaining highlights the rich vascular network, whereas intervening stromal cells are terns. Stromal cells lack endothelial cell
negative. markers, such as von Willebrand factor
and CD34, and do not express endotheli-
um-associated adhesion molecules such
Microscopy Numerous thin-walled vessels are ap-
as CD31 {336,2769}. Unlike endothe-
Haemangioblastomas are character- parent and are readily outlined by a reti-
lial cells, stromal cells variably express
ized by two main components: (1) stro- culin stain. In accordance with the highly
neuron-specific enolase, NCAM1, S100,
mal cells that are characteristically large vascular nature of haemangioblastoma,
and ezrin {336,337,1100}. Vimentin is the
and vacuolated but can show consider- intratumoural haemorrhage may occur.
major intermediate filament expressed by
able cytological variation and (2) abun- In adjacent reactive tissues, particularly
stromal cells. Stromal cells also express
dant vascular cells. Cellular and reticular in cyst and syrinx walls, astrocytic glio-
a variety of other proteins, including
variants of haemangioblastoma are dis- sis and Rosenthal fibres are frequently
CXCR4 {1498,2839}, aquaporin-1 {1524},
tinguished by the abundance and mor- observed. The tumour edge is gener-
brachyury, several carbonic anhydrase
phology of the stromal cell component. ally well demarcated, and infiltration into
isozymes {2040}, and EGFR {335}, but
they do not usually express GFAP {2769}.
Table 11.01 Common immunohistochemical profiles of haemangioblastoma and renal cell carcinoma Both HIF1A {2841} and HIF2A {712} have
Molecule Haemangioblastoma Renal cell carcinoma been detected in stromal cells, and they
may drive the expression of VEGF, which
Aquaporin-1 + {428,2720} +/- {2720}
is also abundant in stromal cells {1363}.
Brachyury + {133} - {133} The corresponding receptors VEGFR1
CD10 - {1999,2720}; +/- {2132} + {1999,2132,2720} and VEGFR2 {2768}, are expressed on
AE1/AE3 - {577,2720} + {577,2720}
endothelial cells, suggesting a paracrine
mode of angiogenesis activation {971,
CAM5.2 - {1999} + {1999}
2437}. The endothelial cells of haeman-
02-40 +/- {2132}; + {2193} +/- {2132}; - {2193} gioblastomas also express receptors for
EMA +/- {2720} + {2720} other angiogenic growth factors, includ-
- {366,577,1021,1999};
ing platelet-derived growth factors {335}.
Inhibin alpha + {366,577,1021,1999,2132,2720}
+/- {2132,2720}
Immunohistochemistry is useful for distin-
guishing haemangioblastoma from RCC.
LEU7 +/- {1061}; + {1999} - {1061}; +/- {1999}
RCCs are positive for epithelial markers
NCAM1 (also called CD56) + {1999} - {1999} such as EMA, whereas haemangioblas-
Neuron-specific enolase +/- {1061} +/- {1061} tomas are negative. Additional potentially
PAX2 - {366,2132} + {366,2132} useful markers include D2-40 {2193} and
inhibin alpha {1021}, which are both posi-
PAX8 - {366} + {366}
tive in haemangioblastoma but generally
Renal cell carcinoma marker - {1093,2132} + {1093}; +/- {2132} negative in RCC. CD10 staining shows
S100 +/- {1061} +/- {1061} the opposite results {1193}.
Haemangioblastoma 257
Antonescu C.R. Epithelioid
Other Paulus W.
Bouvier C.
Figarella-Branger D. haemangioendothelioma
Perry A.
mesenchymal Rushing E.J.
von Deimling A.
Wesseling P. Definition
Hainfellner J.A. A low-grade malignant vascular neo-
tumours plasm characterized by the presence of
epithelioid endothelial cells, arranged in
Haemangioma cords and single cells embedded in a
Definition distinctive chondromyxoid or hyalinized
A benign vascular neoplasm greatly vary- stroma.
ing in size. Most haemangiomas affecting Epithelioid haemangioendothelioma is
the CNS are primary lesions of bone that rarely located in the skull base, dura, or
impinge on the CNS secondarily. Dural {1, brain parenchyma {106,1802}. Its cells
1244} and parenchymal {2361} haeman- contain relatively abundant eosinophilic
giomas are less common. cytoplasm, which may be vacuolated.
Histologically, haemangiomas have pre- In general, the nuclei are round or occa-
dominantly capillary-type growth and oc- sionally indented or vesicular, and show
cur mostly in the paediatrics age group. only minor atypia. Mitoses and limited
Infantile haemangiomas are consistently Fig. 11.17 Capillary haemangioma. Reddish-brown necrosis may be seen. Small intracyto-
positive for GLUT1, a marker that is typi- sponge-like appearance of an intraosseous capillary plasmic lumina (blister cells) are seen,
cally used to distinguish haemangioma haemangioma on cut surface of a skull resection but well-formed vascular channels are
from arteriovenous malformation in ex- specimen. typically absent. Immunohistochemical
tracranial locations {409}. However, in studies (e.g. for CD31 and ERG) confirm
a recent study, both cerebral cavern- fibrotic walls. Cerebral cavernous mal- these tumours’ endothelial nature. Ap-
ous malformations and cerebral arterio- formations can be inherited as an auto- proximately 90% of epithelioid haeman-
venous malformations showed endotheli- somal dominant disorder (accounting for gioendotheliomas harbour the recurrent
al immunoexpression of GLUT1 and thus 20% of cases), but most are sporadic. t(1;3)(p36;q25) translocation, which re-
seemed to differ from most other arterio- Biallelic somatic and germline mutations sults in a WWTR1-CAMTA1 fusion {651,
venous malformations {1632}. in one of the cerebral cavernous malfor- 2510}. A smaller subset of epithelioid
mation genes have been implicated as a haemangioendotheliomas have a t(x;11)
Malformative vascular lesions
Most vascular lesions of the CNS are two-hit mechanism of inherited cerebral
malformative in nature, including cerebral cavernous malformation pathogenesis
cavernous malformation (also called cav- {33}. Another tumefactive vascular lesion
ernous angioma or cavernoma), arterio- that can occur in the brain or meninges
venous malformation, venous angioma, is intravascular papillary endothelial hy-
and capillary telangiectasia. Cerebral perplasia, a papillary proliferation of en-
cavernous malformations typically occur dothelium associated with thrombosis
in the brain, but the spinal cord and the {1366}.
eye may also be involved. Histologically, ICD-0 code 9120/0
cerebral cavernous malformations are
composed of an admixture of capillary-
Fig. 11.18 Epithelioid haemangioendothelioma.
type and large saccular vessels with Intracytoplasmic lumina and a basophilic stroma are
prominent features of this example.
Fig. 11.19 Capillary haemangioma. A Lobular proliferation of small thin-walled blood vessels. B The lobular growth pattern is visualized on this Immunostain for CD31.
(p11;q22) translocation, which results in a Kaposi sarcoma A wide patient age range has been re-
YAP1-TFE3 fusion {80}. ported, although peak incidence occurs
Definition
in the second decade of life. The histol-
ICD-0 code 9133/3 A malignant neoplasm characterized by
ogy, immunophenotype, and biology are
spindle-shaped cells forming slit-like
essentially identical to those of tumours
blood vessels, which is only rarely en-
encountered in bone or soft tissue {714}.
countered as a parenchymal or meninge-
Angiosarcoma al tumour, typically in the setting of HIV
The tumour is composed of sheets of
small, round, primitive-appearing cells
Definition type 1 infection or AIDS {115,334}.
with scant clear cytoplasm and uniform
A high-grade malignant neoplasm with In this setting, it is often difficult to deter-
nuclei with fine chromatin and smooth
evidence of endothelial differentiation. mine whether a Kaposi sarcoma lesion
nuclear contours. Homer Wright rosettes
The rare examples of angiosarcoma that is primary or metastatic. The tumour is
are occasionally seen, but are usually not
originate in brain or meninges {1636} almost always immunopositive for HHV8
prominent. Most tumours stain at least
vary in differentiation from patently vas- {2140}.
focally with synaptophysin and neuron-
cular tumours with anastomosing vascu- ICD-0 code 9140/3 specific enolase, whereas cytokeratin
lar channels lined by mitotically active, is only focally seen (in as many as 20%
cytologically atypical endothelial cells of cases). CD99 shows strong and dif-
to poorly differentiated, often epithelioid Ewing sarcoma / peripheral fuse membranous immunoreactivity in
solid lesions, in which immunoreactivity primitive neuroectodermal the vast majority. CD99 can also be ex-
for vascular markers (e.g. CD31, CD34, tumour pressed (although this expression is usu-
ERG, and FLI1) is required for definitive Definition ally more patchy and cytoplasmic) in oth-
diagnosis. Occasional cytokeratin reac- A small round blue cell tumour of neuro- er tumour types, including solitary fibrous
tivity complicates the distinction of poorly ectodermal origin that involves the CNS tumour / haemangiopericytoma and (less
differentiated angiosarcoma from meta- either as a primary dural neoplasm {565, commonly), medulloblastoma or other
static carcinoma {2131}. No genetic ab- 1617,1696,2358} or by direct extension embryonal CNS neoplasms. Therefore,
normalities have been described for CNS from contiguous bone or soft tissue (e.g. most Ewing sarcoma / peripheral primi-
angiosarcomas. skull, vertebra, or paraspinal soft tissue). tive neuroectodermal tumours must be
ICD-0 code 9120/3 Radiologically, primary CNS Ewing sar- confirmed at the molecular level either by
coma / peripheral primitive neuroecto- RT-PCR for the presence of an EWSR1-
dermal tumour can mimic meningioma. FLI1 or EWSR1-ERG fusion transcript or
by FISH for EWSR1 gene rearrangement
{279}. Alternative gene fusions in the
Fig. 11.21 Ewing sarcoma / peripheral primitive neuroectodermal tumour. A Invasion of nerve roots. B Diffuse membrane immunoreactivity for CD99. C FISH results positive for
EWSR1 (EW S) gene rearrangement, with split of paired red and green signals (white lines).
Angiosarcoma 259
site, may incorporate intradural portions Liposarcoma
of cranial nerve roots and their ganglia.
Many also feature striated muscle or oth- Definition
er mesenchymal tissues. Some of these A malignant tumour composed entirely or
lesions have been referred to as choristo- partly of neoplastic adipocytes.
mas. It has even been suggested that Intracranial liposarcoma is extremely
intracranial lipomas containing various rare. An example associated with sub-
other tissue types represent a transition dural haematoma has been described
between lipoma and teratoma {2572}. {461}, and an example of gliosarcoma
Whether these various lesions are neo- with a liposarcomatous element has
plasms or malformative overgrowths is been reported {242}.
Fig. 11.22 Postcontrast T1 -weighted MRI of a
dural-based Ewing sarcoma / peripheral primitive yet to be determined.
ICD-0 code 8850/3
neuroectodermal tumour mimicking meningioma.
Epidural lipomatosis
Epidural lipomatosis is a rare lesion that
Ewing sarcoma-like family of tumours
consists of diffuse hypertrophy of spinal
have also been described, including Desmoid-type fibromatosis
epidural adipose tissue. As such, it is not
CIC-DUX4 {1104} and the BCOR-CCNB3
a neoplasm but a metabolic response, Definition
intrachromosomal inversion {1971}.
often to chronic administration of steroids A locally infiltrative but cytologically be-
ICD-0 code 9364/3 {919}. nign lesion composed of uniform my-
ofibroblastic-type cells in an abundant
Angiolipoma collagenous stroma, arranged in inter-
Lipoma secting fascicles {1684}.
Definition Desmoid-type fibromatosis must be dis-
Definition A lipoma variant with prominent vascular- tinguished from cranial fasciitis of child-
A benign lesion that microscopically re- ity; by definition, the vessels are of cap- hood, a process histologically related to
sembles normal adipose tissue {306}. illary type and are generally most prom- nodular fasciitis, featuring rapid growth
Intracranial lipomas are believed to be inent in the periphery, often containing within the deep scalp, lacking an intra-
congenital malformations rather than true dispersed fibrin thrombi. dural component, and having no ma-
neoplasms, resulting from abnormal dif- The proportions of adipose cells and lignant potential {1438}. Cranial infantile
ferentiation of the meninx primitiva (the vasculature in angiolipoma vary {1982, myofibromatosis also enters into the dif-
undifferentiated mesenchyme) {1203}. 2367}. With time, interstitial fibrosis may ferential diagnosis but often displays a
ensue. Angiolipomas may be overdiag- biphasic pattern, with alternating hae-
ICD-0 code 8850/0 nosed because ordinary haemangiomas mangiopericytoma-like areas and myoid
Microscopy are often accompanied by fat; however, components {2479}.
ordinary haemangiomas have a more
Lipoma heterogeneous spectrum of vascular ICD-0 code 8821/1
Most lipomas show lobulation at low mag- channels, including thick-walled venous-
nification. Lipomas have an inconspicu- type vascular channels and cavernous
ous capillary network. Patchy fibrosis is spaces. Myofibroblastoma
a common feature, and calcification and
ICD-0 code 8861/0
myxoid change are occasionally seen. Definition
Osteolipomas are exceedingly rare and A benign mesenchymal neoplasm com-
may show zonation, with central adipose posed of spindle-shaped cells with fea-
tissue and peripheral bone {2367}. tures of myofibroblasts embedded in a
Hibernoma stroma that contains coarse bands of hy-
Complex lipomatous lesions
alinized collagen and conspicuous mast
Complex lipomatous lesions vary con- Definition cells, admixed with a variable amount of
siderably in terms of their histological A very rare lipoma variant within the CNS, adipose tissue {714}.
composition. For example, lumbosacral composed of uniform granular or multi- Myofibroblastomas of the CNS are simi-
lipomas (leptomyelolipomas) that occur vacuolated cells with small, centrally lo- lar to their mammary-type counterparts,
in the context of tethered spinal cord syn- cated nuclei, resembling brown fat {1442}. being part of a larger spectrum of CD34-
drome are likely malformative and may
positive lesions (including spindle cell
consist of subcutaneous and intradural ICD-0 code 8880/0
lipoma and cellular angiofibroma) that
components linked by a fibrolipomatous
show common 13q14 losses by FISH or
stalk that may attach to the dorsum of the
loss of RB immunoexpression {420,742}.
cord or to the filum terminate {998}. Lipo-
Myofibroblastomas are also strongly pos-
mas of the cerebellopontine angle {201},
itive for desmin {2348}.
an uncommonly affected off-midline
ICD-O code 8825/0
Fibrosarcoma
Definition
A rare sarcoma type showing monomor-
phic spindle cells arranged In intersect-
ing fascicles (a so-called herringbone
pattern).
Fibrosarcomas are markedly cellular, ex-
hibit brisk mitotic activity, and often fea-
ture necrosis {789}. Similar histological
features are seen in adult-type fibrosar-
coma; congenital/infantile fibrosarcoma;
and fibrosarcomatous transformation in
the setting of a solitary fibrous tumour /
haemangiopericytoma or dermatofibro-
sarcoma protuberans. Sclerosing epithe-
Fig. 11.23 Fibrosarcoma. A This hypercellular radiation-induced neoplasm shows features of fibrosarcoma with
lioid fibrosarcoma affecting the CNS has
intersecting fascicles of spindled cells; note the entrapped island of gliotic brain tissue. B Immunostain for GFAP
highlights entrapped islands of gliotic brain, whereas tumour cells are negative. C Increased mitotic activity.
also been reported {205}.
been implicated in the pathogenesis of immunoreactivity for vimentin, but no expression of more
specific lineage markers.
numerous mitoses as well as necrosis. the paraspinal region or epidural space) exceptionally rare. Most tumours consist
Only isolated cases of the inflammatory {1595,2851}. Parenchymal examples primarily of undifferentiated small cells,
variant of this entity have been reported are rare {623}. An association with EBV whereas strap cells with cross striations
to involve brain {1598}. and immunosuppression has been es- are only occasionally observed. Immu-
tablished {2851}, but leiomyosarcomas nostaining for desmin and myogenin
ICD-0 code 8802/3 arising in these settings are less clearly usually confirms the diagnosis. Rhab-
malignant and may respond to immune domyosarcomas must be differentiated
reconstitution. Most leiomyosarcomas from other brain tumours that occasion-
Leiomyoma diffusely express desmin and SMA. ally show skeletal muscle differentiation,
such as medullomyoblastomas, gliosar-
Definition ICD-0 code 8890/3
comas, MPNSTs, germ cell tumours, and
A benign smooth muscle tumour that can even rare meningiomas {1120}. Malignant
typically be readily recognized by its pat- ectomesenchymoma, a mixed tumour
tern of intersecting fascicles, being com- Rhabdomyoma composed of ganglion cells or neuro-
posed of eosinophilic spindle cells with blasts and one or more mesenchymal
blunt-ended nuclei {1506}. Definition
elements (usually rhabdomyosarcoma)
As a rule, leiomyomas lack mitotic activ- A benign lesion consisting of mature stri-
may also occur in the brain {1919}.
ity and cytological atypia. Occasional ated muscle.
examples feature nuclear palisading and One reported case of rhabdomyoma as- ICD-0 code 8900/3
should not be mistaken for schwannoma. sociated with a cranial nerve also fea-
Diffuse leptomeningeal leiomyoma {1195} tured a minor adipose tissue component
and an angioleiomyomatous variant {2630}. However, most reported intra-
Chondroma
{1410} have been described. EBV- and neural examples are in fact neuromuscu-
AIDS-associated cases have also been lar choristoma (also called benign triton Definition
reported {1225}. tumour). This is an important diagnostic A benign, well-circumscribed neoplasm
distinction given the high risk of postop- composed of low-cellularity hyaline
ICD-0 code 8890/0 erative fibromatosis associated with neu- cartilage.
romuscular choristoma {979}. CNS rhab- Isolated cases of intracranial chon-
domyomas must also be distinguished droma (usually dural-based) have been
from skeletal muscle heterotopia, most of reported {500,1397}. Outside the CNS,
Leiomyosarcoma
which occur within prepontine leptome- chondromas often develop in the skull
Definition ninges {710}. and only secondarily displace dura and
A malignant neoplasm with predominant- brain. Malignant transformation of a large
ICD-0 code 8900/0
ly smooth muscle differentiation.
The morphological variants of leiomyo-
sarcoma include epithelioid leiomyosar-
coma, myxoid leiomyosarcoma, granular Rhabdomyosarcoma
cell leiomyosarcoma, and inflammatory
leiomyosarcoma {715}. Definition
Intracranial leiomyosarcomas {555, A malignant neoplasm with predominant-
1537}, like their soft tissue counterparts, ly skeletal muscle differentiation.
retain the intersecting fascicles at 90° Whether meningeal or parenchymal,
angles and eosinophilic cytoplasm, but nearly all primary CNS rhabdomyo-
show marked nuclear pleomorphism, sarcomas are of the embryonal type
increased mitotic activity, and necro- {2069,2513}; alveolar rhabdomyosar-
sis. Most intracranial leiomyosarcomas coma {1259} and a rhabdomyosarcoma-
Fig. 11.26 Dural chondroma, a meningeal tumour
arise in or adjacent to the dura (e.g. in tous element in gliosarcoma {2465} are
composed of mature hyaline cartilage.
Chondrosarcoma
Definition
A malignant mesenchymal tumour with
Fig. 11.27 Chondrosarcoma. A MRI of a low-grade chondrosarcoma arising from the vertebral column. Note the
cartilaginous differentiation.
lobulated contours and invasion into adjacent soft tissues. B Meningeal low-grade chondrosarcoma showing glistening
Most chondrosarcomas arise de novo,
nodules of hyaline cartilage with focal softening and liquefaction.
but some develop in a pre-existing be-
nign cartilaginous lesion.
Microscopy
Conventional chondrosarcoma
Intracranial, extraosseous chondrosar-
comas of the classic type are rare {407,
1352,1855,1919}. The same is true for
extraskeletal myxoid chondrosarcoma,
which has been reported to arise within
the brain {416} as well as in the leptome-
ninges of the brain. Chondrosarcomas
arising in the skull base, in particular in
the midline, should be distinguished from
(chondroid) chordoma. Unlike chordo-
mas, chondrosarcomas are non-reactive
for keratin, EMA {1685}, and brachyury
{2672}.
Mesenchymal chondrosarcoma
Mesenchymal chondrosarcoma also
Fig. 11.28 Chondrosarcoma. A Low-grade chondrosarcoma may show small stellate to epithelioid cells set within
arises more often in bones of the skull
a myxoid background, overlapping morphologically with chordoma. B S100 immunoreactivity is typically strong in
or spine than within dura or brain paren-
low-grade chondrosarcomas, but is not very specific, because it may also be seen in other diagnostic considerations,
chyma {2200,2262,2820}. Some tumours such as chordoma. C Lack of nuclear brachyury expression helps distinguish chondrosarcoma from chordoma.
consist primarily of the small-cell com- D The combination of a small blue cell tumour with well-formed hyaline cartilage is characteristic of mesenchymal
ponent, punctuated by scant islands of chondrosarcoma.
Chondrosarcoma 263
Osteochondroma is characterized by the
presence of a cartilaginous cap and a fi-
brous perichondrium that extends to the
periosteum of the bone.
ICD-0 code 9210/0
Osteosarcoma
Definition
Fig. 11.30 Dural osteoma. A Bosselated dural-based osseous tumour. B On microscopy, gliotic brain parenchyma is
A malignant bone-forming mesenchymal
seen adjacent to the dense bone of the dural osteoma.
tumour.
confirmed by the presence of NCOA2 from asymptomatic dural calcification, Osteosarcoma predominantly affects
gene rearrangements {2688}. ossification related to metabolic disease adolescents and young adults. The pre-
or trauma, and rare examples of astro- ferred sites are the skull and the spine
cytoma and gliosarcoma with osseous and more rarely the meninges and the
Osteoma differentiation. brain {144,352,2214,2227,2326}. Bone
matrix or osteoid deposition by the pro-
Definition
ICD-0 code 9180/0 liferating tumour cells is required for the
A benign bone-forming tumour with limit-
diagnosis. Osteosarcomatous elements
ed growth potential.
may exceptionally be encountered as
Isolated cases of intracranial osteoma
Osteochondroma components of germ cell tumour and
(usually dural-based) have been reported
gliosarcoma {132}.
{427}. Outside the CNS, osteomas often
Definition
develop in the skull and only secondarily ICD-0 code 9180/3
A benign cartilaginous neoplasm, which
displace dura and brain. Histologically,
may be pedunculated or sessile, arising
they correspond to similar tumours aris-
on the surface of the bone.
ing in bone and must be distinguished
Definition
Primary melanocytic neoplasms of the
CNS are diffuse or localized tumours that
presumably arise from leptomeningeal
melanocytes.
Benign lesions that are diffuse without
forming macroscopic masses are termed
melanocytosis, whereas malignant dif-
fuse or multifocal lesions are termed
melanomatosis. Benign or intermediate-
grade tumoural lesions are termed mel- Fig. 12.01 A Meningeal melanocytosis involving the subarachnoid space of the cerebral hemispheres. B Meningeal
anocytomas. Malignant lesions that are melanomatosis infiltrating the meninges around the brain stem and cerebellum.
Meningeal melanocytosis and decade, with an equal sex distribution radiological evidence of CNS involve-
meningeal melanomatosis and no racial predisposition {1201}. ment has been reported in as many as
23% of asymptomatic children with giant
Localization
congenital naevi {726}. As part of a com-
Meningeal melanocytosis Melanocytosis and melanomatosis in-
pletely distinct clinical entity, melanocy-
volve the supratentorial leptomeninges,
tosis may also be associated with con-
Definition the infratentorial leptomeninges, and may
genital naevus of Ota {117}.
Meningeal melanocytosis is a diffuse or involve the superficial brain parenchyma
multifocal proliferation of cytologically by extending into perivascular Virchow- Imaging
bland melanocytic cells that arises from Robin spaces. They generally involve CT and MRI of melanocytosis and mela-
the leptomeninges and involves the sub- large expanses of the subarachnoid nomatosis show diffuse thickening and
arachnoid space. space with focal or multifocal nodularity enhancement of the leptomeninges,
Meningeal melanocytosis cells can occasionally seen. The sites of highest often with focal or multifocal nodularity
spread into the perivascular spaces with- frequency include the cerebellum, pons, {1981}. Depending on melanin content,
out frank invasion of the brain {1533}. medulla, and temporal lobes. diffuse and circumscribed melanocytic
tumours of the CNS may have a char-
Clinical features
ICD-0 code 8728/0 acteristic appearance on MRI due to
Neurological symptoms associated with
the paramagnetic properties of melanin,
Meningeal melanomatosis melanocytosis or melanomatosis arise
resulting in an isodense or hyperintense
secondarily to either hydrocephalus or
Definition signal on T1 -weighted images and a hy-
local effects on the CNS parenchyma.
A primary CNS melanoma that arises pointense signal on T2-weighted images
Neuropsychiatric symptoms, bowel and
from leptomeningeal melanocytes and {2372}.
bladder dysfunction, and sensory and
displays a diffuse pattern of spread motor disturbances are common. Once Macroscopy
throughout the subarachnoid space and malignant transformation occurs, symp- Diffuse melanocytic neoplasms present
Virchow-Robin spaces, often with CNS toms progress rapidly, with increasing as dense black replacement of the suba-
invasion. intracranial pressure resulting in irritabil- rachnoid space or as dusky clouding of
ity, vomiting, lethargy, and seizures. the meninges.
ICD-0 code 8728/3 Neurocutaneous melanosis is a combi-
Microscopy
nation of melanocytosis or melanoma-
The pathological proliferation of lepto-
Epidemiology tosis with giant or numerous congenital
meningeal melanocytes and their pro-
Diffuse meningeal melanocytic neo- melanocytic naevi of the skin, usually in-
duction of melanin account for the main
plasms are rare, and population-based volving the trunk or head and neck, and
microscopic findings in these diseases
incidence is not available {1201}. Menin- with various other malformative lesions,
{583}. Tumour cells diffusely involving
geal melanocytosis and melanomatosis such as Dandy-Walker syndrome, sy-
the leptomeninges assume a variety of
are strongly linked with neurocutaneous ringomyelia, and lipomas {563,564,
shapes, including spindled, round, oval,
melanosis, a rare phacomatosis that is 1574}. Approximately 25% of patients
and cuboidal. In melanocytosis, indivi-
typically associated with giant congenital with meningeal melanocytosis have sig-
dual cells are cytologically bland and ac-
naevi and presents before the age of 2 nificant concomitant cutaneous lesions.
cumulate within the subarachnoid space
years. In one series of 39 such cases, the Conversely, about 10-15% of patients
and Virchow-Robin spaces without dem-
age at presentation for CNS manifesta- with large congenital melanocytic naevi
onstrating overt CNS invasion {2372}.
tions ranged from stillbirth to the second of the skin develop clinical symptoms re-
Unequivocal CNS parenchymal invasion
lated to CNS melanocytosis {564}, and
Meningeal melanocytoma
Definition
A well-differentiated, solid, and non-infil-
trative melanocytic neoplasm that arises
from leptomeningeal melanocytes.
Meningeal melanocytoma is charac-
terized by the presence of epithelioid,
fusiform, polyhedral, or spindled mel-
anocytes, without evidence of anaplasia,
necrosis, or elevated mitotic activity.
ICD-0 code 8728/1
Epidemiology
Melanocytomas account for 0.06-0.1%
of brain tumours, and the annual inci-
dence has been estimated at 1 case per
10 million population {1149}. Melanocy-
Fig. 12.04 Meningeal melanocytoma. A Loose or tight nests of low-grade, pigmented spindle cells with intervening tomas can occur in patients of any age
stroma containing higher levels of melanin pigment. Note the vague, loosely formed whorls and fascicles. (range: 9-73 years), but are most fre-
B Accumulation of large, melanin-containing macrophages (melanophages) is seen between tumour cells with a more quent in the fifth decade of life (mean
spindled phenotype. The nuclei of tumour cells are bean-shaped and have micronucleoli. Melanin within the cytoplasm
of melanophages is typical in larger aggregates. C Melanin-containing macrophages (melanophages).
Diffuse large B-cell lymphoma polyomaviruses SV40 and BK virus {1702, fluid (CSF) analysis is limited {1340}.
of the CNS 1725}) do not play a role. Meningeal dissemination is diagnosed
in 15.7% of cases {12.2% by CSF cyto-
Definition Localization
morphology, 10.5% by PCR, and 4.1%
A diffuse large B-cell lymphoma (DLBCL) About 60% of all PCNSLs involve the su-
by MRI) {1341}. Pleocytosis is found in
confined to the CNS at presentation. pratentorial space, including the frontal
35-60% of PCNSL cases and correlates
Excluded from this entity are lymphomas lobe (in 15% of cases), temporal lobe (in with meningeal dissemination {1341}. Cell
arising in the dura, intravascular large 13- 8%), parietal lobe (in 7%), and occipital
counts may even be normal. The CSF
cell lymphoma, and lymphomas of T-cell lobe (in 3%), basal ganglia and periven-
harbours neoplastic cells in a minority
or NK-cell lineage (which may also pres- tricular brain parenchyma (in 10%), and
of patients with leptomeningeal involve-
ent in the CNS), as well as lymphomas corpus callosum (in 5%). The posterior
ment, and their detection may require
with systemic involvement or with sec- fossa and spinal cord are less frequently
repeated lumbar puncture. The combi-
ondary involvement of the CNS, Immuno- affected (in 13% and 1% of cases, re- nation of cytological and immunohisto-
deficiency-associated primary CNS lym- spectively) {562}. A single tumour is en-
chemical analysis with multiparameter
phomas are discussed separately. countered in 60-70% of patients, with
flow cytometry may enhance detection
the remainder presenting with multiple
ICD-0 code 9680/3 of CSF lymphoma cells {2299}. PCR
tumours {562}. The leptomeninges may
analysis of the CDR3 region of the IGH
Epidemiology be involved, but exclusive meningeal
gene region followed by sequencing of
Primary CNS lymphomas (PCNSLs) ac- manifestation is unusual. Ocular manifes- the PCR products may identify a clonal
count for 2.4-3% of all brain tumours tation (i.e. in the vitreous, retina, or op-
B-cell population in the CSF, but does
and 4-6% of all extranodal lympho- tic nerve) occurs in 20% of patients and
not enable lymphoma classification. El-
mas {2286}. The overall annual inci- may antedate intracranial disease {1123}.
evated CSF levels of miR-21, miR-19,
dence rate of PCNSL is 0.47 cases per Extraneural dissemination is very rare. In
and miR-92a have been reported to dif-
100 000 population {2652}. In the past cases with systemic spread, PCNSL has
ferentiate PCNSL from inflammatory and
two decades, an increased incidence a propensity to home to the testis, an- other CNS disorders {124}; however, the
has been reported in patients aged > 60 other immunoprivileged organ {237,1124}.
diagnostic usefulness of this parame-
years {2652}. PCNSL can affect patients
Clinical features ter and its potential as a marker during
of any age, with a peak incidence dur-
Patients present with cognitive dysfunc- follow-up {125} are yet to be definitively
ing the fifth to seventh decade of life. The
tion, psychomotor slowing, and focal established.
median patient age is 56 years, and the
male-to-female ratio is 3:2. neurological symptoms more frequently
Macroscopy
than with headache, seizures, and cra- As observed on postmortem examina-
Etiology nial nerve palsies. Blurred vision and eye
tion, PCNSLs occur as single or multiple
In immunocompetent individuals, etio- floaters are symptoms of ocular involve-
masses in the brain parenchyma, most
logical factors are unknown. Viruses (e.g. ment {140,1340,1926}.
frequently in the cerebral hemispheres.
EBV, HHV6 {1915}, HHV8 {1704}, and the
Imaging Often, they are deep-seated and ad-
MRI is the most sensitive technique to jacent to the ventricular system. The
detect PCNSL, which is hypointense on tumours can be firm, friable, granular,
T1-weighted images, isointense to hy- haemorrhagic, and greyish tan or yellow,
perintense on T2-weighted images, and with central necrosis. Or they can be vir-
densely enhancing on postcontrast im- tually indistinguishable from the adjacent
ages. Peritumoural oedema is relatively neuropil. Demarcation from surrounding
limited and is less severe than in malig- parenchyma is variable. Some tumours
nant gliomas and metastases {1340}. appear well delineated, like metastases.
Meningeal involvement may present as When diffuse borders and architectural
hyperintense enhancement {1403}. With effacement are present, the lesions re-
steroid therapy, lesions may vanish within semble gliomas. Like malignant gliomas,
hours {562}. these tumours may diffusely infiltrate
large areas of the hemispheres without
Spread forming any distinct mass, a manifesta-
The diagnostic value of cerebrospinal tion which has been referred to as ‘lym-
Fig. 13.01 Age and sex distribution of primary CNS lymphomas in
phomatosis cerebri’. However, this term
immunocompetent patients.
272 Lymphomas
pattern is frequent. Infiltration of cerebral 2128}. BCL2 expression is common; 82%
blood vessels causes fragmentation of PCNSLs have a BCL2-high, MYC-high
of the argyrophilic fibre network. From phenotype {296}. Mitotic activity is brisk;
these perivascular cuffs, tumour cells in- accordingly, the Ki-67 proliferation index
vade the neural parenchyma, either with usually exceeds 70% or even 90% {296}.
a well-delineated invasion front with small Apoptotic cells may be frequent. With the
clusters or with single tumour cells dif- exception of isolated cases, there is no
fusely infiltrating the tissue, which shows evidence of EBV infection {1705}, and the
a prominent astrocytic and microglial presence of EBV should prompt evalua-
activation and harbours reactive inflam- tion for underlying immunodeficiency.
matory infiltrates consisting of mature
Fig. 13.02 Primary CNS lymphoma. Postcontrast Genetic profile
T1-weighted MRI showing multifocal disease with T and B cells. Morphologically, PCNSLs
PCNSLs are mature B-cell lymphomas.
homogeneous contrast enhancement and relatively little consist of large atypical cells with large
The tumour cells correspond to late ger-
surrounding oedema. Periventricular disease is evident round, oval, irregular, or pleomorphic nu-
minal centre exit B cells with blocked
in both the frontoparietal region and the brain stem. clei and distinct nucleoli, corresponding
terminal B-cell differentiation. Thus, they
to centroblasts or immunoblasts. Some
carry rearranged and somatically mutat-
does not define a distinct disease entity, cases show a relatively monomorphic
ed immunoglobulin (IG) genes with evi-
so it should not replace the specific diag- cell population, with intermingled mac-
dence of ongoing somatic hypermutation
nosis (i.e. DLBCL of the CNS). Meningeal rophages mimicking the appearance of
{1705,1925,2548}. Consistent with the on-
involvement may resemble meningitis or Burkitt lymphoma.
going germinal centre programme, they
meningioma, or can even be inconspicu-
Immunophenotype show persistent BCL6 activity {296}. The
ous macroscopically.
The tumour cells are mature B cells with process of somatic hypermutation is not
Microscopy a PAX5-positive, CD19-positive, CD20- confined to its physiological targets (IG
positive, CD22-positive, CD79a-positive and BCL6 genes), but extends to other
Stereotactic biopsy genes that have been implicated in tum-
phenotype. IgM and IgD, but not IgG,
Stereotactic biopsy is the gold standard origenesis, including BCL2, MYC, PIM1,
are expressed on the surface {1707},
for establishing the diagnosis and classi- PAX5, RHOH, KLHL14, OSBPL10, and
with either kappa or lambda light chain
fication of CNS lymphoma. It is important SUSD2 {297,1709,2639}. These data indi-
restriction. Most express BCL6 {60-80%)
to withhold corticosteroids before biopsy, cate that aberrant somatic hypermutation
and MUM1/IRF4 {90%), whereas plasma
because they induce rapid tumour wan- has a major impact on the pathogenesis
cell markers (e.g. CD38 and CD138) are
ing. Corticosteroids have been shown to of PCNSL. The fixed IgM/lgD phenotype
usually negative. Less than 10% of all
prevent diagnosis in as many as 50% of of the tumour cells is in part due to mis-
PCNSLs express CD10 {561}. CD10 ex-
cases {298}. carried IG class switch rearrangements
pression is more frequent in systemic
Histopathology DLBCL; therefore, CD10 positivity in a during which the Smu region is deleted
PCNSLs are highly cellular, diffusely CNS lymphoma with DLBCL characteris- {1707}. PRDM1 mutations also contribute
growing, patternless tumours. Centrally, tics should prompt a thorough investiga- to impaired IG class switch recombina-
large areas of geographical necrosis tion for systemic DLBCL that might have tion {502}.
are common, and may harbour viable metastasized to the CNS. HLA-A/B/C Translocations affect the IG genes (in
perivascular lymphoma islands. At the and HLA-DR are variably expressed, with 38% of cases) and BCL6 (in 17-47%)
periphery, an angiocentric infiltration approximately 50% of PCNSLs having recurrently, whereas MYC translocations
lost HLA class I and/or II expression {237, are rare and translocations of the BCL2
Fig. 13.06 Primary CNS lymphoma. Microarray-based comparative genomic hybridization demonstrating copy number and allelic profile of a sample with a gain in 18q. The log2
ratio is displayed from the p arm to the g arm of the chromosome, showing a gain of two copies of the same allele in 18q12.3qter (shaded region: log2 ratio = 1; four allele states).
276 Lymphomas
is associated with a very poor prognosis
{1893,1817,2017}
Anaplastic large cell lymphoma
Juvenile xanthogranuloma
Definition
Juvenile xanthogranuloma arising in the
brain or the meninges, either with or with-
out cutaneous lesions.
Juvenile xanthogranuloma of the CNS
corresponds histologically and im-
munohistochemically to its cutaneous
Fig. 14.04 Rosai-Dorfman disease. A Multinodular mass composed of a mixed inflammatory infiltrate, including
large pale histiocytes, numerous lymphocytes, and plasma cells. B Emperipolesis with histiocytic engulfment of
counterpart.
intact lymphocytes, plasma cells, neutrophils, and eosinophils. C CD45 expression by phagocytosed haematopoietic
cells.
282 Histiocytic tumours
Epidemiology
The mean patient age is 22 months
{1134}.
Localization
Juvenile xanthogranuloma of the CNS
localizes to the brain {53%), intradural ex-
tramedullary spine {13%), or nerve roots
{15%), with meningeal involvement also
being common {568}.
Clinical features
The signs and symptoms of juvenile
xanthogranuloma depend on the sites
of involvement, but often include sei-
zures, diabetes insipidus, and visual
disturbances. Fig. 14.05 Juvenile xanthogranuloma. Note numerous histiocytic cells and two large multinucleated Touton cells.
Macroscopy
Juvenile xanthogranuloma lesions are of-
ten received as fragmented, soft, yellow
to tan-pink biopsy specimens.
Microscopy
Juvenile xanthogranuloma is composed
of rounded to spindled, variably vacuolat-
ed histiocytes, scattered Touton and for-
eign body-type giant cells, lymphocytes,
and occasional eosinophils {1411}.
Immunophenotype Fig. 14.06 Histiocytic sarcoma. A Large, highly pleomorphic histiocytic tumour cells with irregular nuclei and prominent
The neoplastic histiocytes of juvenile nucleoli. B The lineage-specific marker CD163 was diagnostic in this high-grade neoplasm.
xanthogranuloma are CD1a-negative,
CD11c-positive, CD68-positive, fac- Localization Immunophenotype
tor XII la-positive, negative or positive Reported cases of histiocytic sarcoma in The tumour cells are typically positive for
for MAC387, lysozyme-negative, and the CNS have involved the brain paren- histiocytic markers (e.g. CD68, CD163,
S100-negative. chyma, meninges, and cavernous sinus lysozyme, CD11c, and CD14), variably
{421}. positive for CD34, and negative for my-
eloid antigens, dendritic antigens, CD30,
Clinical features
ALK, and other lymphoid markers, as
Patients with histiocytic sarcoma present
well as for glial, epithelial, and melano-
with variable initial signs and symptoms,
cytic antigens. The tumour cells are
Histiocytic sarcoma which tend to progress rapidly due to dis-
negative for the follicular dendritic cell
seminated disease {421}.
antigens CD23 and CD35. However, fol-
Definition licular dendritic cell sarcoma expressing
Macroscopy
A rare, aggressive, malignant neoplasm Histiocytic sarcomas are destructive, these antigens may primarily arise in the
with the histological and immunopheno- soft, fleshy white masses with occasional brain and must be differentiated from his-
typic characteristics of mature histiocytes. yellow necrotic foci. tiocytic sarcoma {966}.
Most cases of histiocytic sarcoma occur
in adults. Microscopy Genetic profile
Histiocytic sarcoma is characterized by Histiocytic sarcoma is not defined by a
highly cellular, non-cohesive infiltrates certain genetic profile, although a sin-
ICD-0 code 9755/3 gle case with BR4F V600E mutation has
of large, moderately pleomorphic, mitoti-
cally active histiocytes with abundant eo- been described {1085}. They usually
Epidemiology lack IGH or T-cell receptor gene Clonal-
sinophilic cytoplasm, variably indented
The mean reported patient age in case to irregular nuclei, and often prominent ity {497}. Cases with evidence of clonal
series is 52 years {1043}. nucleoli. Occasional multinucleated or rearrangement are attributed to transdif-
spindled forms are also common, as is ferentiation from neoplastic T- or B-cell
Etiology
background reactive inflammation {421}. precursor lesions {2493}.
Isolated cases of radiation-associated
histiocytic sarcoma of the CNS have
been reported {399,2795}.
Definition Peak incidence occurs in patients aged most common site) {1025,2251,2278}.
In the CNS, the morphological, Immuno- 10-14 years, and a clear majority of cas- Suprasellar examples originate in the
phenotypic, and (in some respects) ge- es of all histological types involve males neurohypophyseal / infundibular stalk.
netic homologues of gonadal and other {210,485,1017,2251}. Analysis of a regis- Intraventricular, diffuse periventricular,
extraneuraxial germ cell neoplasms. try containing 1463 Japanese patients thalamostriate, cerebral hemispheric,
The major germ cell tumour types are found that 70% were aged 10-24 years cerebellar, bulbar, intramedullary, and
germinoma, teratoma, yolk sac tumour, and 73% were male {485}. Congenital intrasellar variants can be encountered,
embryonal carcinoma, and choriocarci- examples (typically teratomas) are well as can congenital holocranial examples
noma. Neoplasms harbouring multiple recognized, but only 2.9% of patients in (usually teratomas). Germinomas prevail
types are called mixed germ cell tumours. this series were aged < 5 years, and only in the suprasellar compartment and ba-
Otherwise pure germinomas containing 6.2% were aged > 35 years. The great sal ganglionic / thalamic regions, and
syncytiotrophoblastic giant cells are rec- majority of pineal region cases affect non-germinomatous subtypes predomi-
ognized as a distinct variant. Teratomas boys, whereas an excess of suprasellar nate at other sites. Multifocal CNS germ
are subclassified as mature, immature, or lesions occur in girls. In the Japanese cell tumours usually involve the pineal re-
exhibiting malignant transformation. registry cited above, 89% of teratomas, gion and suprasellar compartment, either
78% of germinomas, and 75% of other simultaneously or sequentially. Bilateral
Epidemiology germ cell tumour types arose in males. basal ganglionic and thalamic lesions
CNS germ cell tumours principally affect Pure germinomas outnumber other types, are also well recognized.
children and adolescents and seem to be followed by mixed lesions and teratomas.
more prevalent in eastern Asia than in the Clinical features
In a series of 153 histologically verified
Europe and the USA. These tumours ac- The clinical manifestations and their du-
cases {1612}, 41.1% were germinomas
count for 2-3% of all primary intracranial ration vary with histological type and
(including examples with syncytiotropho-
neoplasms and for 8-15% of paediatric location. Germinomas are generally as-
blastic elements, which accounted for
examples in series from Japan; Taiwan, sociated with a more protracted symp-
5.2% of all cases), 32% were mixed germ
China; and the Republic of Korea |485A, tomatic interval than are other types. Le-
cell tumours, 19.6% were teratomas (of
1017,1192A,1612,2452}, but for only 0.3- sions in the pineal region compress and
which 63.3% were mature, 23.3% were
0.6% of primary intracranial tumours and obstruct the cerebral aqueduct, resulting
immature, and 13.3% exhibited malig-
3-4% of those affecting children in se- in progressive hydrocephalus with intra-
nant elements), 3.3% were embryonal
ries in Europe and North America {210, cranial hypertension. These lesions are
carcinomas, 2% were yolk sac tumours,
506A,558,596,1025,1154,1862A,1863}. also prone to compressing and invading
and 2% were choriocarcinomas. How-
The highest reported incidence statis- the tectal plate, producing a paralysis of
ever, the relative incidence rates of the
tics come from Japan, where a recent upwards gaze and convergence called
specific tumour types vary according to
survey of Kumamoto Prefecture revealed Parinaud syndrome. Neurohypophyseal/
location.
an annual age-adjusted incidence rate suprasellar germ cell tumours impinge
of 0.45 cases per 100 000 population Etiology on the optic chiasm, causing visual field
aged < 15 years, more than double the CNS germ cell tumours’ predilection to defects, and often disrupt the hypo-
rates in the USA and Germany {1573}. occur in peripubertal patients, their local- thalamohypophyseal axis, precipitating
ization in diencephalic centres regulating diabetes insipidus and manifestations of
gonadal activity, and their increased inci- pituitary failure such as delayed growth
dence in Klinefelter syndrome have been and sexual maturation. The secretion by
regarded as evidence that elevated cir- neoplastic syncytiotrophoblasts of hCG,
culating gonadotropin levels play a role in a stimulant of testosterone production,
their pathogenesis. The association with can cause precocious puberty (isosex-
Klinefelter syndrome could also reflect ual pseudoprecocity) in boys. The ad-
X chromosome overdosage, a common ditional expression of cytochrome P450
genetic feature of these neoplasms. aromatase, which catalyses the conver-
sion of C19 steroids to estrogen, may
Localization explain the rare instances of precocious
Number of cases Number of cases
About 80% of CNS germ cell tumours puberty in girls with hCG-producing tu-
Fig. 15.01 Age and sex distribution of CNS germ cell arise along a midline axis extending from mours {1814}. In this setting, hCG may
tumours, based on 1463 cases; data from a report the pineal gland (their most common site) also have some intrinsic follicle stimulat-
published by the Brain Tumor Registry of Japan (1969— to the suprasellar compartment (their next ing hormone-like activity {2415}.
1996).
Overview 287
pure germinoma {2495}. The most viru- germ cell tumour, and it can also occur
lent CNS germ cell tumours are yolk sac as a component of a mixed germ cell tu-
tumours, embryonal carcinomas, chorio- mour, in combination with other germ cell
carcinomas, and mixed lesions in which tumours. Germinoma is extremely sensi-
these types are prominent. In contrast, tive to radiotherapy, and cure rates are
immature teratomas and mixed tumours high.
dominated by teratoma or germinoma
with only minor high-grade, non-germino- ICD-0 code 9064/3
matous components seem to occupy an
intermediate position in terms of biologi- Macroscopy
cal behaviour {1611,2251}. Survival rates
Germinomas are composed of soft and
as high as 60-70% have been achieved
through treatment of these more aggres- friable tan-white tissue. They are gener-
ally solid, but may exhibit focal cystic
sive tumours with combined chemo-
change. Haemorrhage and necrosis are
therapy and irradiation {1665}. Local re-
rare.
Fig. 15.02 MRI of a solid, contrast-enhancing germinoma currence and cerebrospinal fluid-borne
of the pineal region, with a smaller cerebrospinal fluid- dissemination are the usual patterns of Microscopy
borne metastasis in the suprachiasmatic cistern. progression, but abdominal contamina- Germinomas contain large, undifferenti-
tion via ventriculoperitoneal shunts and ated cells that resemble primordial ger-
haematogenous spread (principally to minal elements. These are arranged in
lung and bone) can also occur. sheets, lobules, or (in examples mani-
festing stromal desmoplasia) regimented
Germinoma cords and trabeculae. The cytological
features include round, vesicular, and
Definition centrally positioned nuclei; prominent
A malignant germ cell tumour histologi- nucleoli; discrete cell membranes; and
cally characterized by the presence of relatively abundant cytoplasm, which is
large primordial germ cells with promi- often clear due to glycogen accumula-
nent nucleoli and variable cytoplasmic tion. Mitotic activity is apparent and may
Fig. 15.03 Germinoma of the suprasellar region in a
clearing. be conspicuous, but necrosis is uncom-
7-year-old girl. Nearly all germinomas contain a substan- mon. Delicate fibrovascular septa (varia-
tial population of reactive lymphoid cells. bly infiltrated by small lymphocytes) are a
been suggested that germline variants of Germinoma is the most common CNS typical feature; some germinomas show
a chromatin-modifying gene, JMJD1C, a lymphoplasmacellular reaction so florid
may be associated with an increased risk
of intracranial germ cell tumours in Japa-
nese {2689}.
Prognosis and predictive factors
The factor that bears most heavily on
outcome is histological subtype {1025,
1611,1612,2278}. Mature teratomas are
potentially curable by surgical excision.
Pure germinomas are remarkably radio-
sensitive, with long-term survival rates of
> 90% after craniospinal irradiation alone
{1665}. The addition of chemotherapy to
treatment regimens may provide compa-
rable germinoma control at lower radia-
tion doses and field volumes {1210,1449,
1611,1665,2251}. Whether germinomas
harbouring syncytiotrophoblastic cells
or associated with elevated beta-hCG
levels carry an increased risk of recur-
rence and require intensified therapy
has been controversial {1665}. A recent
study demonstrating beta-hCG mRNA
Fig. 15.04 Germinoma. A Tumour cells with abundant clear cytoplasm, round nuclei, and prominent nucleoli; note the
expression across CNS germ cell tumour
lymphocytic infiltrates along fibrovascular septa. B Large tumour cells with round vesicular nuclei, prominent nucleoli,
types did not find that mRNA levels cor- and clear cytoplasm. C Syncytiotrophoblastic giant cell in an otherwise typical germinoma. D Immunostaining for hCG.
related with recurrence in the setting of
Definition
An aggressive non-germinomatous ma-
lignant germ cell tumour characterized
by large epithelioid cells resembling
those of the embryonic germ disc.
Other common features of embryonal
carcinoma are geographical necrosis, a
high mitotic count, and pseudoglandular
or pseudopapillary structures. Embryonal
carcinoma can also occur as a compo-
nent of a mixed germ cell tumour, in com-
bination with other germ cell tumours.
ICD-0 code 9070/3
Macroscopy
Embryonal carcinomas are solid lesions
composed of friable greyish-white tissue
that may exhibit focal haemorrhage and
necrosis.
Fig. 15.05 Germinoma. A Membranous and Golgi region immunolabelling for KIT. B Immunoreactivity for OCT4.
C Cytoplasmic and membranous reactivity for PLAP. D Expression of KIT protein in tumour cells. Microscopy
Embryonal carcinomas are composed
Their biological significance has been of large cells that proliferate in nests and
that it obscures the neoplastic elements.
controversial {1665}, but the presence of sheets, form abortive papillae, or line
Germinomas that provoke an intense
such cells should not prompt a diagnosis gland-like spaces. Tumour cells excep-
granulomatous response can resemble
of choriocarcinoma. tionally form so-called embryoid bodies
sarcoidosis or tuberculosis {1331}.
The reactive lymphoid elements within replete with germ discs and miniature
Immunophenotype amniotic cavities. Other typical histo-
germinomas are usually dominated by
Consistent cell membrane and Golgi T cells, including both CD4-expressing logical features include macronucleoli,
region immunoreactivity for KIT and helper/inducer and CD8-expressing abundant clear to violet-hued cytoplasm,
membranous D2-40 labelling distin- cytotoxic/suppressor elements {2250, a high mitotic count, and zones of coagu-
guish germinomas from solid variants 2719}, but CD20-labelling B cells and lative necrosis.
of embryonal carcinoma and yolk sac CD138-labelling plasma cells may be Immunophenotype
tumour {1080}. Less consistent (and conspicuous, and constitute evidence Cytoplasmic immunoreactivity for CD30,
non-specific) is cytoplasmic or membra- of humoral immune responses to tumour although potentially shared by the epi-
nous PLAP expression {210,1017,2196}. {2759}. thelial and mesenchymal components
Germinomas regularly display immuno-
of teratomas, distinguishes embryonal
reactivity for the RNA-binding LIN28A
carcinomas from other germ cell tumours
protein {353} and nuclear expression of
{1080}. Uniformly and strongly reactive
the transcription factors NANOG {2239},
for cytokeratins and often positive for
OCT4 {1080}, ESRG {2695}, UTF1 {1885},
PLAP {210,684,1017,2196}, these tu-
and SALL4 {1631}, but are typically non-
mours also display labelling for LIN28A
reactive for CD30 and alpha-fetoprotein
{353} and nuclear expression of OCT4
{210,684,1017,2196}. A minority display
{1080}, ESRG {2695}, UTF1 {1885},
cytoplasmic labelling by the CAM5.2
SALL4 {1080}, and SOX2 {2240}. KIT
and AE1/AE3 cytokeratin antibodies,
expression may be seen and is gener-
a phenomenon which may, along with
ally focal and non-membranous {1080},
ultrastructural evidence of intercellular
but embryonal carcinomas are typically
junction and lumen formation {1672}, in-
negative for alpha-fetoprotein, beta-hCG,
dicate a capacity to differentiate along
and human placental lactogen {210,684,
epithelial lines or towards embryonal
1017,2196}.
carcinoma, but one that is without dem-
onstrated clinical importance. Otherwise
pure germinomas may harbour syncytio-
Fig. 15.06 Embryonal carcinoma composed of large
trophoblastic elements that express be-
epithelial cells forming abortive papillae and glandular
ta-hCG and human placental lactogen.
structures with macronuclei.
Definition
An aggressive non-germinomatous ma-
lignant germ cell tumour composed
of syncytiotrophoblasts, cytotropho-
blasts, and occasionally intermediate
trophoblasts.
Necrosis and haemorrhage are often
present in choriocarcinoma. There is
usually a marked elevation of hCG in the
blood or cerebrospinal fluid. Choriocarci-
noma can also occur as a component of
a mixed germ cell tumour, in combination
with other germ cell tumours.
ICD-0 code 9100/3
Macroscopy
Choriocarcinomas are solid, typically
haemorrhagic, and often extensively
necrotic.
Fig. 15.07 Yolk sac tumour. A Typical sinusoidal growth pattern. B Schiller—Duval body and numerous mitoses.
C Reticular growth pattern with numerous hyaline globules. D Alpha-fetoprotein immunolabelling. Microscopy
Histological diagnosis requires the pres-
ence of both cytotrophoblastic elements
Yolk sac tumour projections to form papillae called Schil-
ler—Duval bodies. Yolk sac tumours can and syncytiotrophoblastic giant cells.
Definition The giant cells typically contain multiple
also contain eccentrically constricted
An aggressive non-germinomatous ma- hyperchromatic or vesicular nuclei, often
cysts delimited by flattened epithelial
lignant germ cell tumour composed of clustered in a knot-like fashion, within
elements (termed ‘polyvesicular vitelline
primitive germ cells arranged in various a large expanse of basophilic or vio-
pattern’), enteric-type glands with goblet
patterns, which can recapitulate the yolk laceous cytoplasm. Neoplastic syncytio-
cells, and foci of hepatocellular differenti-
sac, allantois, and extra-embryonic mes- trophoblast surrounds or partially drapes
ation (termed ‘hepatoid variant’). Brightly
enchyme and produce alpha-fetoprotein. cytotrophoblastic components, which
eosinophilic, periodic acid-Schiff-posi-
Yolk sac tumour can also occur as a consist of cohesive masses of large
tive, and diastase-resistant hyaline glob-
component of a mixed germ cell tu- mononucleated cells with vesicular nu-
ules are characteristic, although variable;
mour, in combination with other germ cell clei and clear or acidophilic cytoplasm.
they may occupy the cytoplasm of epi-
tumours. Ectatic vascular channels, blood lakes,
thelial cells or lie in extracellular spaces.
Mitotic activity varies considerably, and and extensive haemorrhagic necrosis are
ICD-0 code 9071/3 necrosis is uncommon. characteristic.
Immunophenotype
Macroscopy Immunophenotype Syncytiotrophoblasts are characterized
Yolk sac tumours are typically solid and Cytoplasmic immunoreactivity of epi- by diffuse cytoplasmic immunoreactivity
greyish tan. They are usually friable or thelial elements for alpha-fetoprotein, al- for beta-hCG and human placental lac-
(due to extensive myxoid change) gelati- though potentially shared by the enteric togen {210,684,1017,2196}. Cytokeratin
nous in consistency. Focal haemorrhage glandular components of teratomas, dis-
may be apparent. tinguishes yolk sac tumours from other
germ cell neoplasms {210,684,1017,
Microscopy 2196}. Hyaline globules are also reactive.
This neoplasm is composed of primitive- Epithelial components consistently label
looking epithelial cells (which putatively for cytokeratins, are frequently positive
differentiate towards yolk sac endoderm) for glypican-3 {1631}, and may also be
set in a loose, variably cellular, and often positive for PLAP. Yolk sac tumours ex-
myxoid matrix resembling extraembry- hibit labelling for LIN28A {353} and nu-
onic mesoblast. The epithelial elements clear expression of SALL4 {1631}. OCT4
may form solid sheets, but are more com- expression is exceptional. KIT reactivity
monly arranged in a loose network of ir- is also rare; when present, it is typically
regular tissue spaces (termed ‘reticular focal, cytoplasmic rather than membra-
pattern’) or around anastomosing sinu- nous, and without Golgi area accentua-
soidal channels as a cuboidal epithelium, tion {1080}. Human placental lactogen Fig. 15.08 Choriocarcinoma with syncytiotrophoblastic
in some cases draped over fibrovascular and beta-hCG are not expressed. giant cells and cytotrophoblasts.
Microscopy
Mature teratomas consist entirely of fully
differentiated, adult-type tissue elements
that exhibit little or no mitotic activity. Ec-
todermal components commonly include
Fig. 15.09 Sagittal T1-weighted MRI of a teratoma in the epidermis and skin appendages, cen- Fig. 15.10 Large immature teratoma of the cerebellum
pineal region, occupying the dorsal aspect of the third tral nervous tissue, and choroid plexus. in a 4-week-old infant, with characteristic cysts and
ventricle. Smooth and striated muscle, bone, car- chondroid nodules.
tilage, and adipose tissue are typical
mesodermal components. Glands, often
labelling is also demonstrable, with some cystically dilated and lined by respiratory encountered are rhabdomyosarcomas
choriocarcinomas also expressing PLAP, or enteric-type epithelia, are the usual and undifferentiated sarcomas {210,
but KIT and OCT4 labelling are not seen endodermal components, but hepatic 1612,2196}, followed by enteric-type
{1080}. and pancreatic tissue may also be en- adenocarcinomas {737,1275}, squa-
countered. Gut- and bronchus-like struc- mous carcinomas {1612}, and primitive
tures replete with muscular coats or car- neuroectodermal tumours {2595}. Eryth-
Teratoma tilaginous rings, respectively, as well as roleukaemia {987} and leiomyosarcoma
Definition mucosa may also be formed. {2369} have also been reported to arise
A germ cell tumour composed of somatic in this setting, as has a carcinoid tumour
tissues derived from two or three of the Immature teratoma associated with an intradural spinal tera-
germ layers (i.e. the ectoderm, endo- toma {1096}. The pathogenesis of an in-
derm, and mesoderm). ICD-0 code 9080/3 trasellar tumour containing elements of
Teratomas can be further subclassified germinoma and Burkitt-like B-cell lym-
as mature teratomas, which are com- Microscopy phoma is unclear {2609}. Yolk sac tumour
posed exclusively of mature, adult-type components (rather than teratomatous
Immature teratomas consist of incom- components) have been speculated to
tissues (e.g. mature skin, skin appendag- pletely differentiated elements resem-
es, adipose tissue, neural tissue, smooth be the progenitors of select enteric-type
bling fetal tissues. When admixed with adenocarcinomas originating in intracra-
muscle, cartilage, bone, minor salivary mature tissues, the presence of any im-
glands, respiratory epithelium, and gas- nial germ cell tumours {737}.
mature teratoma component mandates
trointestinal epithelium) and immature classification of the tumour as immature
teratomas, which contain immature, em- teratoma, even if the incompletely differ- Mixed germ cell tumour
bryonic, or fetal tissues either exclusively entiated elements constitute only a small
or in addition to mature tissues. Rare part of the neoplastic process. Common ICD-0 code 9085/3
teratomas contain a component result- features are compact and mitotically ac-
ing from the malignant transformation of tive stroma reminiscent of embryonic Macroscopy
a somatic tissue, usually a carcinoma or mesenchyme, as well as primitive neuro-
sarcoma, but embryonal tumours with the The appearance of a mixed germ cell tu-
ectodermal elements that may form neu-
features of a primitive neuroectodermal mour reflects the macroscopic features
roepithelial multilayered rosettes with a
tumour can also arise in this setting in the of the constituent germ cell tumour com-
central lumen or canalicular arrays that
CNS, a fact prompting careful evaluation ponents, as have been described for the
resemble developing neural tube. Clefts
in certain clinicopathological settings, pure forms.
lined by melanotic neuroepithelium are
such as a pineal tumour of childhood. often seen; these result from abortive Microscopy
Pathologists should specify the type of differentiation of the retinal pigment Any combination of germ cell tumour var-
secondary cancer present and avoid epithelium. iants can be encountered. Pathologists
the non-specific designation “malignant reporting such lesions must specify the
teratoma’’. Teratoma with malignant
subtypes present and state the relative
transformation proportions of each.
ICD-0 code 9080/1
ICD-0 code 9084/3 Immunophenotype
Individual components have the same
Microscopy antigenic profiles described for the pure
Teratoma-containing intracranial germ forms of these tumour variants.
cell tumours can include a variety of so-
matic-type cancers; the most commonly
Teratoma 291
Reuss D.E.
Neurofibromatosis type 1 von Deimling A.
Perry A.
Definition Neurofibromas
An autosomal dominant disorder char- Among the major subtypes of neurofibro-
acterized by neurofibromas, multiple ma, the dermal and plexiform variants are
cafe-au-lait spots, axillary and inguinal characteristic of NF1. Deep-seated local-
freckling, optic gliomas, osseous lesions ized intraneural neurofibromas arise less
and iris hamartomas (Lisch nodules). Pa- commonly, and may cause neurological
tients with neurofibromatosis type 1 (NF1) symptoms. Plexiform neurofibromas pro-
have an increased risk for malignant pe- duce diffuse enlargement of major nerve
ripheral nerve sheath tumour (MPNST), trunks and their branches, sometimes
gastrointestinal stromal tumour, rhabdo- yielding a rope-like mass, and are almost
myosarcoma, juvenile chronic myeloid pathognomonic of NF1. Plexiform neu-
leukaemia, duodenal carcinoids, C-cell rofibromas may develop during the first
hyperplasia / medullary thyroid carcino- 1-2 years of life, as single subcutaneous Fig. 16.01 Pilocytic astrocytoma of the optic nerve
(optic nerve glioma; arrowhead) in a patient with
mas, other carcinomas, and phaeochro- swellings with poorly defined margins.
neurofibromatosis type 1.
mocytoma. The disorder is caused by They may also cause severe disfigure-
mutations of the NF1 gene on chromo- ment later in life, affecting large areas
some 17q11.2. of the body. If these tumours arise in the
head or neck region, they can impair vital
OMIM number {1624} 162200 functions. Plexiform neurofibromas have
Incidence/epidemiology a lifetime risk of malignant progression to
The birth frequency of NF1 has been esti- MPNST of about 10% {1006}.
mated to be about 1 case per 3000 births
Malignant peripheral nerve sheath
{658,2680}.
tumours
Sites of involvement The MPNSTs that arise in patients with
Multiple sites and organ systems may be NF1 usually occur at a younger age, may
involved. The most commonly involved be multiple, and may include divergent
are the central and peripheral nervous differentiations with rhabdomyoblastic
system, the skin, the eyes, and the bones elements (malignant triton tumour) or
(see Table 16.01}. glandular elements (glandular MPNST).
MPNSTs reduce life expectancy signifi-
cantly {663}.
Gliomas
Most gliomas in patients with NF1 are Fig. 16.02 Macroscopic preparation of a bilateral optic
Table 16.01 National Institutes of Health (NIH) diagnostic
pilocytic astrocytomas within the optic nerve glioma in a patient with neurofibromatosis type 1.
criteria for neurofibromatosis type 1 (NF1) {739A}
nerve. Bilateral growth is characteristic of
The presence of > 2 of the following features is
NF1. Optic nerve gliomas in patients with
diagnostic:
NF1 may remain static for many years,
Six or more cafe-au-lait macules more than 5 mm
and some may regress {1516}. Other glio-
in greatest diameter in prepubertal individuals
and more than 15 mm in greatest diameter in
mas observed at an increased frequency
postpubertal individuals in NF1 include diffuse astrocytomas and
Two or more neurofibromas of any type or one glioblastomas {908,1470}.
plexiform neurofibroma
Other CNS manifestations
Freckling in the axillary or inguinal regions
The following features are more frequent
Optic glioma in NF1: macrocephaly {2476}, learning
Two or more Lisch nodules (iris hamartomas) disabilities and attention deficit hyper-
A distinctive osseous lesion such as sphenoid activity disorder {1075}, epilepsy {1859},
aqueductal stenosis, hydrocephalus Fig. 16.03 Bilateral optic nerve glioma in a patient
dysplasia ortibial pseudarthrosis
with neurofibromatosis type 1. Note the enlargement
A first-degree relative (parent, sib, or offspring) with {587}, and symmetrical axonal neuropa-
of the compartments of the optic nerves and collar-like
NF1 as defined by the above criteria thy {691}.
extension into the subarachnoid space. Masson stain.
Definition
An autosomal dominant disorder char-
acterized by neoplastic and dysplastic
lesions that primarily affect the nervous
system, with bilateral vestibular schwan-
nomas as a diagnostic hallmark. Other
manifestations include schwannomas of
other cranial nerves, spinal and periph-
eral nerves, and the skin; intracranial
and spinal meningiomas; gliomas, in
particular spinal ependymomas; and a
variety of non-tumoural and dysplastic/
developmental lesions, including menin- Fig. 16.05 T1 -weighted, contrast-enhanced MRI from a patient with neurofibromatosis type 2. A Bilateral vestibular
gioangiomatosis, glial hamartomas, ocu- schwannomas (arrowheads), the diagnostic hallmark of neurofibromatosis type 2. B Multiple meningiomas presenting
lar abnormalities (e.g. posterior subcap- as contrast-enhanced masses.
sular cataracts, retinal hamartomas, and
epiretinal membranes), and neuropa- Diagnostic criteria Confirmatory testing for NF2 mutations
thies. NF2 is caused by mutations of the The diagnosis of NF2 is based on clini- may be helpful when a patient does not
NF2 gene on chromosome 22q12. cal features and may be challenging be- meet the clinical criteria for a definite di-
cause of the wide variability of symptoms agnosis but the phenotype is suggestive.
OMIM number {1624} 101000 and time of onset. Particularly difficult to
Nervous system neoplasms
diagnose are genetic mosaics (account-
Incidence/epidemiology
ing for 30% of sporadic cases), in which Schwannomas
The disorder affects between 1 in 25 000
segmental involvement or milder disease Schwannomas associated with NF2
and 1 in 40 000 individuals {662}. About
may occur {1307}, and paediatric cases are WHO grade I tumours composed
half of all cases are sporadic, occurring
in which the full manifestation of the dis- of neoplastic Schwann cells, but differ-
in individuals with no family history of NF2
ease has not yet developed. The distinc- ing from sporadic schwannomas in sev-
and caused by newly acquired germline
tion from other forms of neurofibromatosis eral ways. NF2 schwannomas present
mutations. In the past, the considerable
(neurofibromatosis type 1 and schwanno- in younger patients (in the third decade
variability of the clinical manifestations
matosis) is difficult in some cases. There of life) than do sporadic tumours (in the
of NF2 resulted in underdiagnosis of the
is clinical phenotypic overlap between sixth decade), and many patients with
syndrome.
NF2 mosaic, early NF2, and schwanno- NF2 develop the diagnostic hallmark of
matosis; some cases that fulfil the clinical the disease, bilateral vestibular schwan-
Table 16.03 National Institutes of Health (NIH) / diagnostic criteria for schwannomatosis nomas, by their fourth decade of life
Manchester criteria for neurofibromatosis type 2 (NF2) have later proven to be NF2 {1990}. {659,1599}. NF2 vestibular schwanno-
{655A} The original clinical diagnostic criteria mas may entrap seventh cranial nerve
The presence of one or more of the following for NF2 were established at the National fibres {1198} and have higher proliferative
features is diagnostic: Institutes of Health (NIH) Consensus De- activity {75}, although these features do
Bilateral vestibular schwannomas velopment Conference on Neurofibroma-
tosis in 1987 {1758}. Several revisions of
A first-degree relative with NF2 AND unilateral
vestibular schwannoma OR any two of: meningioma,
these criteria have since been proposed:
schwannoma, glioma, neurofibroma, posterior
the NIH 1991 criteria, the Manchester
subcapsular lenticular opacities* criteria (see Table 16.03}, the National
Unilateral vestibular schwannoma AND any two of:
Neurofibromatosis Foundation (NNFF)
meningioma, schwannoma, glioma, neurofibroma,
criteria, and the Baser criteria. Each of
posterior subcapsular lenticular opacities* these revisions expanded the original cri-
Multiple meningiomas AND unilateral vestibular
teria, aiming to also identify patients with
schwannoma OR any two of: schwannoma, glioma,
multiple NF2 features who do not present
neurofibroma, cataract* with bilateral vestibular schwannomas
*Any two of = two individual tumours or cataracts.
and have no family history of NF2 {137,
659,905}. Fig. 16.06 Bilateral vestibular schwannomas, diagnostic
for neurofibromatosis type 2.
Fig. 16.09 A Multiple schwannomas of spinal roots. B Schwannomas in neurofibromatosis type 2 often show a distinct
nodular pattern.
Fig. 16.10 A Meningioangiomatosis associated with neurofibromatosis type 2. An intracortical lesion composed of a perivascular proliferation of cells (predominantly meningothelial)
in Virchow-Robin spaces. B Diffuse cortical meningioangiomatosis associated with neurofibromatosis type 2. Trichrome stain. C Multiple Schwann cell tumourlets arising in the
cauda equina of a patient with neurofibromatosis type 2 (Luxol fast blue, H&E).
Schwannomatosis 301
protein, resulting in G0/G1 cell cycle ar-
rest {185,2648}.
According to the tumour suppressor gene
model, both copies of the SMARCB1
gene are inactivated in these tumours. In
schwannomas of patients with schwan-
nomatosis with SMARCB1 germline mu-
tation in addition to loss of the second
SMARCB1 allele, there is also inactivation
of both copies (by mutation and deletion)
of the NF2 gene, located 6 Mb distal to
SMARCB1 on chromosome 22 {260,921,
2325}. The deletion of SMARCB1 and
NF2 is a consequence of the loss of one
copy of chromosome 22 {922}.
Fig. 16.13 Schwannomas in schwannomatosis are often myxoid, with an appearance that mimics that of neurofibromas.
Based on these observations, a four-hit,
three-step model of tumorigenesis in
schwannomatosis is proposed: (inher-
a uterine leiomyoma in a patient with to be elucidated, and other families af- ited) SMARCB1 germline mutation oc-
schwannomatosis; the tumour had a fected by schwannomatosis with COQ6 curs (hit 1), followed by loss of the other
molecular profile similar to that of the involvement have not yet been reported. chromosome 22 with the wildtype copy
schwannomas, as well as the corre- Germline mutations of the NF2 gene of SMARCB1 and one copy of NF2 (hits 2
sponding mosaic staining for SMARCB1 have been excluded in schwannomato- and 3), followed by a somatic mutation of
protein, indicating that the SMARCB1 sis {1115,1237,1557}, but the presence of the remaining copy of the NF2 gene (hit
defect in schwannomatosis may occa- other, somatically acquired mutations in 4}. This model, with somatic mutations of
sionally contribute to the oncogenesis of the NF2 gene is characteristic in schwan- the NF2 gene as the last step, explains
extraneural neoplasms {1062}. nomatosis-associated schwannomas. the observation of different NF2 muta-
One third of all patients with sporadic tions in multiple schwannomas in a sin-
Inheritance and genetic heterogeneity
schwannomatosis have segmental dis- gle patient with schwannomatosis {1990}.
The great majority of schwannomatosis
tribution of their tumours, suggesting so- This four-hit model of genetic events also
cases are sporadic, with only 15% of occurs in meningiomas in patients with
matic mosaicism for the causative gene,
patients having a positive family history.
but this has not yet been demonstrated SMARCB1 germline mutation {102,455,
In the familial form, the disease displays
for SMARCB1 or LZTR1. 2622}.
an autosomal dominant pattern of inherit-
In schwannomatosis, most germline mu-
ance, with incomplete penetrance {1557}. The SMARCB1 gene tations in SMARCB1 are non-truncating
In 2007, the SMARCB1 gene on chromo-
Gene structure and expression missense mutations, splice-site muta-
some arm 22q was identified as a famil- tions, or in-frame deletions, which are
ial schwannomatosis-predisposing gene The SMARCB1 gene is located in chro-
mosome region 22q11.23 and contains predicted to result in the synthesis of
{1064}. In subsequent studies, the gene
nine exons spanning 50 kb of genomic an altered SMARCB1 protein with modi-
proved to be involved in about 50% of
DNA {2649}. Alternative splicing of exon 2 fied activity {2380}. The mosaic staining
familial cases, but in < 10% of sporadic
results in two transcripts and two proteins pattern seen in many schwannomatosis-
cases {260,921,2191,2380}.
with lengths of 385 and 376 amino acid associated schwannomas suggests the
In 2014, the LZTR1 gene, also on 22q, absence of SMARCB1 protein in part of
was identified as a second causative residues, respectively. The so-called
SNF5 homology domain in the second the tumour cells {1909}. Truncating non-
gene in schwannomatosis {1980}. In
half of the protein harbours highly con- sense and frameshift mutations, also re-
patients with schwannomatosis without
served structural motifs through which ported in patients with schwannomatosis,
SMARCB1 germline mutations, LZTR1
SMARCB1 interacts with other proteins generate a premature termination codon
mutations were found in about 40% of fa-
{2430}. The SMARCB1 protein is a core and are predicted to result in the ab-
milial and 25% of sporadic cases {1073, sence of SMARCB1 protein expression.
1877,2377}. The fact that most schwan- subunit of mammalian SWI/SNF chroma-
tin remodelling complexes, which regu- For the truncating mutations in exon 1 of
nomatosis cases cannot be explained by
late the expression of many genes by us- SMARCB1, it was recently demonstrated
the involvement of SMARCB1 or LZTR1
ing ATP for sliding the nucleosomes along that translational reinitiation at a down-
suggests the existence of additional
the DNA helix, facilitating or repressing stream AUG codon occurs, resulting in
causative genes {1073}.
transcription {2760}. The SMARCB1 pro- the synthesis of an N-terminally truncated
Recently, a germline missense mutation SMARCB1 protein {1063}. Other mecha-
was identified in the COQ6 gene on chro- tein functions as a tumour suppressor
via repression of CCND1 gene expres- nisms, such as alternative splicing, may
mosome arm 14q, which segregated with
sion, induction of the CDKN2A gene, and operate to overcome the deleterious ef-
the disease in a large family affected by
hypophosphorylation of retinoblastoma fect of truncating mutations in the other
schwannomatosis {2856}. However, the
exons of SMARCB1.
oncogenic effect of the mutation has yet
Schwannomatosis 303
Plate K.H.
Von Hippel-Lindau disease Vortmeyer A.O.
Zagzag D.
Neumann H.P.H.
Aldape K.D.
Definition Table 16.06 Sites of involvement in von Hippel-Lindau patient age of 25 years), and thus offer
An autosomal dominant disorder charac- disease the possibility of an early diagnosis.
terized by the development of clear cell Non-
Organ/ CNS
renal cell carcinoma (RCC), capillary hae- Tumours neoplastic
tissue CNS haemangioblastomas develop
mangioblastoma of the CNS and retina, lesions
mainly in young adults (at a mean patient
phaeochromocytoma, and pancreatic CNS Haemangioblastoma
age of 29 years). They are predominantly
and inner ear tumours. Von Hippel-Lin- Eye (retina) Haemangioblastoma located in the cerebellum, followed by
dau disease (VHL) is caused by germline Clear cell renal cell the brain stem and spinal cord. Approxi-
mutations of the VHL tumour suppressor Kidney Cysts
carcinoma mately 25% of all cases are associated
gene, located on chromosome 3p25-26.
Adrenal with VHL.
The von Hippel-Lindau disease tumour gland
Phaeochromocytoma
suppressor protein (VHL protein) plays a Adrenal gland
Neuroendocrine islet
key role in cellular oxygen sensing. Pancreas Cysts Phaeochromocytomas may constitute a
cell tumours
major clinical challenge, particularly in
OMIM number {1624} 193300 Endolymphatic sac
Inner ear families affected by VHL with predisposi-
tumour
Historical annotation tion to the development of these tumours.
Lindau described capillary haemangio- Epididymis
Papillary They are often associated with pancre-
cystadenoma
blastoma and noted its association with atic cysts.
retinal vascular tumours (previously de-
scribed by von Hippel) and tumours of
the visceral organs, including the kidney. Sites of involvement Other extrarenalmanifestations
Renal lesions in carriers of VHL germline Other extrarenal manifestations include
Incidence/epidemiology mutations are either cysts or clear cell neuroendocrine tumours, endolymphatic
VHL is estimated to have an annual in- RCCs. They are typically multifocal and sac tumours of the inner ear, and epididy-
cidence rate of 1 affected individual per bilateral. The mean patient age at mani- mal and broad ligament cystadenomas.
36 000-45 500 population. festation is 37 years (vs 61 years for spo-
Gene structure
Diagnostic criteria radic clear cell RCC), with a patient age
The VHL tumour suppressor gene is lo-
The clinical diagnosis of VHL is based at onset of 16-67 years. There is a 70%
cated at chromosome 3p25-26. It has
on the presence of capillary haemangio- chance of developing clear cell RCC by
three exons and a coding sequence of
blastoma in the CNS or retina and the the age of 70 years. Metastatic RCC is
639 nucleotides. Germline mutations of
presence of one of the typical VHL-asso- the leading cause of death from VHL.
the VHL gene are spread over the three
ciated extraneural tumours or a pertinent The median life expectancy of patients
exons. Missense mutations are most
family history. Germline VHL mutations with VHL is 49 years.
common, but nonsense mutations, mi-
can virtually always be identified in VHL. Eye crodeletions/insertions, splice-site muta-
Retinal haemangioblastomas manifest tions, and large deletions also occur. In
earlier than kidney cancer (at a mean accordance with the function of VHL as
a tumour suppressor gene, VHL gene
Multiple 5% 65%
Fig. 16.15 Von Hippel-Lindau disease. A Bilateral adrenal phaeochromocytoma and (B) multiple pancreatic
neuroendocrine tumours.
neurons express neuronal-associated proteins were developed. Immunostain- cortical disorganization, and (cortical) gi-
proteins, they display cytoarchitectural ing a given tuber with antihamartin or ant cells with organellar dysfunction with-
features of immature or poorly differen- antituberin antibodies does not provide in the brains of affected animals {874}.
tiated neurons, such as reduced axonal evidence of which mutation is present in This phenotype could be rescued by
projections and spine density {1009, a given subject, and therefore is not of postnatal administration of sirolimus (also
1072}. Giant cells in cortical tubers show great diagnostic value. Both proteins are known as rapamycin), which resulted, in
a cellular and molecular heterogeneity widely expressed throughout the CNS of abrogation of both seizures and prema-
similar to that seen in SEGA, and immu- the normal developing brain {1169,2655}. ture death.
nohistochemical markers characteristic Many approaches have been taken to
Extraneuralmanifestations
of glial and neuronal phenotypes sug- studying tubers, especially surgically re-
The extraneural manifestations of tu-
gest a mixed glioneuronal origin of these sected lesions, because DNA, mRNA,
berous sclerosis and the frequencies
cells. Many giant cells in tubers express and proteins are better preserved within
at which they occur are summarized in
nestin mRNA and protein {506}. Some gi- them than in autopsy specimens, and au-
Table 16.08.
ant cells demonstrate immunoreactivity topsies of patients with tuberous sclerosis
for GFAP {1009}, but others with an iden- are rare. Cell biology approaches have Molecular genetics
tical morphological phenotype express also been taken to examining the biology Tuberous sclerosis is caused by inac-
neuronal markers, including gap junction of hamartin and tuberin and how they tivating mutations in one of two genes:
beta-2 protein and gap junction beta-1 may mediate cell adhesion through the TSC1 at 9q or TSC2 at 16p. The proteins
protein (also called connexins 26 and ERM proteins (ezrin, radixin, and moes- encoded by the TSC genes, tuberin and
32), neurofilaments, class III beta-tubulin, in) and the GTPase Rho {1423}. Deep hamartin, interact within the cell and form
MAP2, and alpha-internexin {506,1009}. sequencing of TSC1, TSC2, and KRAS a complex {486,1212,1987}. Mutation of
Flowever, formation of well-defined syn- demonstrates that small second-hit mu- either gene results in disrupted function
apses between giant cells and adjacent tations in these genes are rare events of the tuberin-hamartin complex, result-
neurons is not a consistent finding. Cor- within tubers {2048}. Insulin signalling ing in similar disease phenotypes. In
tical hamartomas morphologically indis- pathways (normally impacted through sporadic tuberous sclerosis cases, mu-
tinguishable from tubers may occur in inhibition by both tuberin and hamartin) tations are 5 times as common in TSC2
chronic focal epilepsies without clinical show subtle but definite differences in as in TSC1 {51,516,1174}, whereas in
or genetic evidence of an underlying tuberous sclerosis tubers versus foci of families with multiple affected members
tuberous sclerosis condition {223,225, severe (i.e. ILAE Type lib) cortical dys- the mutation ratio of the two genes is
2305}. The pathogenesis of these spo- plasia {1690}. Electrophysiological ap- 1:1 {2231}. TSC1 or TSC2 mutations are
radic lesions is unclear. Subependymal proaches have also shown differences in identified in about 85% of patients with
hamartomas are elevated, often calcified neurophysiological and synaptic abnor- tuberous sclerosis. The remaining 15% of
nodules. They are composed of cells in- malities in surgically resected brain tis- cases may be mosaics or have a muta-
distinguishable from those found in cor- sue samples from patients with tuberous tion in an unanalysed non-coding gene
tical tubers, but are smaller in size than sclerosis versus patients with severe cor- area. Mosaicism has been reported for
cortical tubers. tical dysplasia {390}. A mouse model of TSC1 and TSC2 mutations in some par-
Soon after the TSC2 and TSC1 genes tuberous sclerosis, in which mosaic Tsc1 ents of patients with sporadic cases and
were first cloned in the 1990s, probes for loss was induced in neural progenitor in patients with tuberous sclerosis {2229,
the gene transcripts and the translated cells, showed megalencephaly, marked
Definition Table 16.09 Frequency of tumour manifestation in various organ/tissue sites in TP53 germline mutation carriers
acterized by multiple primary neoplasms Organ/tissue Typical histological types in TP53 germline
mutation carriers
in children and young adults, with a
predominance of soft tissue sarcomas, Breast Carcinoma 31%
osteosarcomas, breast cancer, brain tu- Soft tissue Soft tissue sarcoma 14%
mours, and adrenocortical carcinoma. CNS Astrocytoma, glioblastoma, medulloblastoma, choroid plexus tumour 13%
Li-Fraumeni syndrome (LFS) is most
Adrenal gland Adrenal cortical carcinoma 12%
commonly caused by a germline muta-
tion in the TP53 tumour suppressor gene Bone Osteosarcoma 9%
Tumour counts
Fig. 16.20 Target organs for tumorigenesis in 1350 patients carrying a TP53 germline mutation.
Definition Table 16.10 International Cowden Consortium diagnostic criteria for Cowden syndrome
An autosomal dominant disorder charac- operational diagnostic criteria on the basis of the published literature
terized by multiple hamartomas involving Pathognomonic criteria and their own clinical experience {640,
tissues derived from all three germ cell Adult Lhermitte-Duclos disease (LDD) 2849}. Trichilemmomas and papilloma-
layers and a high risk of breast, epithe- Mucocutaneous lesions tous papules are particularly important
lial thyroid, endometrial, renal, and colon Trichilemmomas (facial4} to recognize. Cowden syndrome usually
cancers. Facial trichilemmomas are high- Acral keratoses presents within the third decade of life.
ly characteristic of Cowden syndrome, Papillomatous papules It has variable and broad expression
which is caused mainly by germline mu- Mucosal lesions and an age-related penetrance. By the
tations in PTEN. Adult-onset dysplastic Major criteria third decade of life, 99% of affected in-
cerebellar gangliocytoma (Lhermitte- Breast cancer dividuals have developed mucocutane-
Duclos disease) is also considered to Thyroid cancer (especially follicular) ous stigmata, although any of the other
be pathognomonic {245}. Recently, other Macrocephaly (> 97th percentile) features could already be present. The
Cowden syndrome predisposition genes Endometrial carcinoma most commonly reported manifestations
have also been identified: the SDH Minor criteria are mucocutaneous lesions, thyroid ab-
genes, PIK3CA, and KLLN. Other thyroid lesions (e.g. goitre or nodule) normalities, fibrocystic disease and car-
Mental retardation cinoma of the breast, gastrointestinal
OMIM number {16244} 158350 Hamartomatous intestinal polyps hamartomas, multiple early-onset uterine
Incidence/epidemiology Lipomas leiomyomas, macrocephaly (specifically,
Fibrocystic breast disease megalencephaly), and mental retardation
Before the identification of PTEN, the in-
Fibromas
cidence of Cowden syndrome was esti- {941,1525,2414,2849}.
Genitourinary tumours (e.g. uterine fibroids, renal cell
mated to be 1 case per 1 million popu-
Carcinoma) or malformations Dysplastic cerebellar gangliocytoma
lation {2414}. After this gene for Cowden
Requirements for diagnosis (Lhermitte-Duclos disease)
syndrome had been identified {1499}, a
Mucocutaneous lesions if: This unusual tumour of the CNS is closely
molecular-based estimate of prevalence
- Six or more facial papules (of which three or
associated with Cowden syndrome {641,
in the same population was 1 case per
more must be trichilemmoma), or 1533,1873}. Adult-onset Lhermitte-Du-
200 000 population {1764}. Due to dif-
- Cutaneous facial papules and oral mucosal clos disease, even in the absence of
ficulties in recognizing this syndrome,
papillomatosis, or other features or family history, is highly
prevalence figures are likely to be under-
- Oral mucosal papillomatosis and acral predictive of a germline mutation in PTEN
estimates. One recent study estimated keratoses, or {2864}, and Lhermitte-Duclos disease
de novo PTEN mutation frequency to be - Six or more palmoplantar keratoses is now considered pathognomonic for
about 11% at minimum and 48% at maxi- - Two or more major criteria met (one must be
Cowden syndrome. Other malignancies
mum {1653}. macrocephaly or LDD)
and benign tumours have also been
One major criteria and three minor criteria
Diagnostic criteria reported in patients or families with
Four minor criteria
The National Comprehensive Cancer Cowden syndrome. Some authors be-
Requirements for diagnosis in individuals
Network has established a set of opera- lieve that endometrial carcinoma could
with a family member with Cowden syndrome
tional clinical diagnostic criteria for iden- also be a component tumour of Cowden
A pathognomonic criterion
tifying individuals with possible Cowden syndrome. It remains to be determined
Any one major criterion with or without minor criteria
syndrome [http://www.nccn.org], A re- whether other tumours (e.g. sarcomas,
Two minor criteria
cent prospective study subsequently History of Bannayan-Riley-Ruvalcaba syndrome
lymphomas, leukaemias, and meningi-
led to the development of the Cleveland omas) are true components of the syn-
adult-onset Lhermitte-Duclos disease
Clinic score - a semiquantitative scoring drome. For details, see Dysplastic cere-
was revised from a major diagnostic cri- bellar gangliocytoma (Lhermitte-Duclos
system that has shown greater adequacy
terion to a pathognomonic criterion and disease), p. 142.
than the National Comprehensive Can-
given the highest weight (of 10) in the
cer Network criteria [http://www.lerner.
PTEN Cleveland Clinic scoring system. Intestinal hamartomatous polyps
ccf.org/gmi/ccscore] {2503}. In response
Because of the variable and broad ex- In a small but systematic study of 9 well-
to the results of a study that found PTEN
pression of Cowden syndrome and the documented cases of Cowden syndrome
mutations in 15 of 18 unselected patients
lack of uniform diagnostic criteria prior to (7 of which had a germline mutation in
with a pathological diagnosis of dys-
1996, the International Cowden Consor- PTEN), all 9 patients had hamartoma-
plastic cerebellar gangliocytoma {2864},
tium (ICC) {1765} compiled operational tous polyps {2712}. Several varieties of
Definition fused ribs, and first-degree relatives with naevoid basal cell carcinoma syndrome
An autosomal dominant disease associ- the syndrome {1284,2331}. The minor seem to be exclusively of the desmoplas-
ated with developmental disorders and criteria include medulloblastoma (mainly tic/nodular variants (see Desmoplastic/
predisposition to benign and malignant of the desmoplastic/nodular subtypes nodular medulloblastoma, p. 195, and
tumours, including basal cell carcinomas {67}), ovarian fibroma, macrocephaly, Medulloblastoma with extensive nodu-
of the skin, odontogenic keratocysts, pal- congenital facial abnormalities (e.g. cleft larity, p. 198) {67,787,2296,2376}. It has
mar and plantar dyskeratotic pits, intrac- lip or palate, frontal bossing, and hyper- therefore been proposed that desmo-
ranial calcifications, macrocephaly, and telorism), skeletal abnormalities (e.g. digit plastic medulloblastomas in children
medulloblastomas of the desmoplastic/ syndactyly), and radiological bone ab- aged < 2 years serve as a major criterion
nodular subtypes; caused by germline normalities (e.g. bridging of the sella tur- for the diagnosis of naevoid basal cell
mutations of genes encoding members cica) {67,128}. The diagnosis of naevoid carcinoma syndrome {67,787}. The prog-
of the hedgehog signalling pathway, in- basal cell carcinoma syndrome is made nosis of naevoid basal cell carcinoma
cluding the PTCH1 gene on 9q22, its when two or more major or one major and syndrome-associated medulloblastomas
homologue PTCH2 on 1p34, and the two or more minor criteria are present seems to be better than that of sporadic
SUFU gene on 10q24. {67}. The clinical features manifest at dif- cases, and it has been suggested that
ferent points in life. Macrocephaly and rib radiation therapy protocols be adjusted
OMIM number {1624} 109400 anomalies can be detected at birth, and in patients aged < 5 years with naevoid
Synonyms medulloblastoma typically develops with- basal cell carcinoma syndrome, to pre-
Naevoid basal cell carcinoma syndrome in the first 3 years of life. Jaw cysts do not vent the formation of secondary tumours
is also known as Gorlin syndrome, Gor- become evident before the age of about {67,2416}.
lin-Goltz syndrome, basal cell naevus 10 years, and basal cell carcinomas can
syndrome, and fifth phacomatosis. be detected 10 years later {746A}. Sever-
al other tumour types have also been re-
Incidence/epidemiology ported in individual patients with naevoid
A prevalence of 1 case per 57 000 pop- basal cell carcinoma syndrome, includ-
ulation has been reported {657}. About ing meningioma, melanoma, chronic
1-2% of patients with medulloblastoma lymphocytic leukaemia, non-Hodgkin
carry a PTCH1 germline mutation {657}. lymphoma, ovarian dermoid cyst, and
Of 131 children with medulloblastomas, breast and lung carcinoma. However, the
6% had germline SUFU mutations {29}. statistical significance of the association
About 2% of patients with naevoid basal between these neoplasms and naevoid
cell carcinoma syndrome with germline basal cell carcinoma syndrome has yet
PTCH1 mutations develop medulloblas- to be demonstrated {2331}. Radiation
toma, and the risk is as much as 20% treatment of patients with naevoid basal
higher in patients with germline SUFU cell carcinoma syndrome, for example,
mutations {2376}. Naevoid basal cell craniospinal irradiation for the treatment
carcinoma syndrome caused by PTCH2 of cerebellar medulloblastoma, induces
mutations is rare; only two families have multiple basal cell carcinomas of the skin
been described {667,747}. as well as various other tumour types
Diagnostic criteria within the radiation field {405,1813,2416}.
The most common manifestations of Sites of involvement
naevoid basal cell carcinoma syndrome Fig. 16.26 The SHH pathway. In normal development,
are multiple basal cell carcinomas, as Naevoid basal cell carcinoma hedgehog signaling is activated by interaction of a
well as odontogenic keratocysts of the syndrome-associated medulloblastoma secreted hedgehog ligand (Hh) with the multipass
jaw. In one study, basal cell carcinomas In a recent review of 33 reported me- transmembrane receptor PTCH. Ligand binding relieves
and odontogenic keratocysts were found dulloblastoma cases associated with the repressive effects of PTCH on SMO and permits the
naevoid basal cell carcinoma syndrome, activation and nuclear translocation of GLI transcription
together in > 90% of affected individuals
factors. GLI activation is also promoted by FU, and
by the age of 40 years {660}. Other ma- all but one tumour had developed in chil-
suppressed by SU(FU). COS2 proteins are thought to
jor criteria include calcification of the falx dren aged < 5 years, and 22 cases {66%)
serve as a scaffold for these interactions. Once in the
cerebri, palmar and plantar pits, bifid or had presented in patients aged < 2 years nucleus, GLI factors induce the transcription of various
{67}. Medulloblastomas associated with pathway targets, including feedback loops involving
PTCH1 and GUI
SUFU on 10q {2376}. The detection rate indicates the location of the sterol-sensing domain. Adapted from Lindstrom E et al. {1510}.
Fig. 17.02 Adamantinomatous craniopharyngioma. A Sagittal postcontrast T1-weighted MRI shows a large, Fig. 17.03 Papillary craniopharyngioma. This sagittal
enhancing, partially cystic suprasellar and sellar mass, characteristic of adamantinomatous craniopharyngioma. postcontrast T1-weighted MRI shows an enhancing
B Large adamantinomatous craniopharyngioma extending into the third ventricle. Postmortem X-ray showed extensive cystic mass involving the anterior third ventricle; the solid
calcification, which is typical for this craniopharyngioma variant. component shows papillary fronds.
Proliferation
Ki-67 immunoreactivity is concentrated
along the peripherally palisading cells in
the adamantinomatous type, and is more
randomly distributed in papillary lesions
{613,2058}. The reported Ki-67 prolifera-
tion index varies considerably from case
to case, and is higher than might be ex-
pected given the relative indolence of
the neoplasms {613,2058}. No consistent
Fig. 17.04 Adamantinomatous craniopharyngioma Fig. 17.05 Adamantinomatous craniopharyngioma. relationship between proliferation index
extending towards the cerebral peduncles; note the so- Fresh tumour material showing an uneven surface with and recurrence has been established.
called machine-oil appearance of the dorsal portion and small calcifications and flakes of wet keratin (white
calcifications. deposits). Ultrastructure
Electron microscopy is seldom needed,
CT shows contrast enhancement of the Spread given the relatively typical features in
solid portions and of the cyst capsule, as Dissemination in the subarachnoid space most cases. In addition to glycogen and
well as typical calcifications. On MRI, the or implantation along the surgical track or the usual organelles, the constituent epi-
cystic areas are T1-hyperintense, where- path of needle aspiration is a rare compli- thelial cells contain tonofilaments joined
as the solid components and the mural cation {190,1450,1473,2165,2287}. by desmosomes. Fenestrated capillary
nodules are T1-isointense, with a slightly endothelium, amorphous ground ma-
Immunophenotype
heterogeneous quality. On enhanced trix, and collagen fibrils characterize the
The tumour cells immunolabel with an-
MRI images, the cystic portion is isoin- connective tissue stroma. Mineral pre-
tibodies against pancytokeratin, CK5/6,
tense with ring enhancement, whereas cipitates appear to arise in membrane-
CK7, CK14, CK17, CK19, EMA, claudin-1
the solid components are hyperintense bound vesicles {2).
and beta-catenin. Only the adamantino-
{2183}. Adamantinomatous tumours may
matous variant shows aberrant nuclear Differential diagnosis
superficially infiltrate neighbouring brain
accumulation of beta-catenin, especially Xanthogranulomas of the sellar region
and adhere to adjacent blood vessels
in the whorl-like cell clusters along the are histologically composed of cholester-
and nerves.
tumour margin and in finger-like tumour ol clefts, macrophages (xanthoma cells),
Papillary craniopharyngiomas are typi-
protrusions {1028}. Papillary craniophar- multinucleated giant cells, chronic inflam-
cally non-calcified, solid lesions with a
yngiomas harbour BRAF V600E muta- mation, necrotic debris, and haemosid-
more uniform appearance on CT and
tions that can be detected by immuno- erin deposits {191). Xanthogranuloma
MRI {507,2245}.
histochemistry, with uniform staining of the sellar region is considered to be a
Craniopharyngioma 325
Fig. 17.08 Adamantinomatous craniopharyngioma. A Finger-like tumour protrusions in the surrounding brain tissue. B Cell groups of an adamantinomatous craniopharyngioma in
the surrounding brain tissue, in which a distinct piloid gliosis with abundant Rosenthal fibres is evident.
Fig. 17.09 Adamantinomatous craniopharyngioma. A Immunostaining for CK5/6 highlights foci of squamous differentiation, including foci of wet keratin. B Only focal Immunoreactivity
for daudin-1. C Finger-like protrusions in the surrounding brain tissue harbouring cell clusters with aberrant nuclear accumulation of beta-catenin.
reactive lesion, most often to remnants of Rathke cleft cysts, beta-catenin local- craniopharyngiomas and Rathke cleft
Rathke cleft cyst {6}. Foci of squamous izes to the cell membrane, whereas the cysts, as well as reports of unique con-
or cuboidal epithelium as well as small nuclear accumulation described in ada- genital craniopharyngiomas with amelo-
tubules may be encountered, whereas mantinomatous craniopharyngiomas is blastic, tooth bud, and adenohypophy-
typical areas of adamantinomatous epi- typically absent {1028}. seal primordia components {60,1721,
thelium are usually absent or amount to 2317,2807}. Additional evidence is the
< 10% of the tissue {191). Epithelial cells Cell of origin
report of a tumour arising from a Rathke
Several observations, including cytoker-
in xanthogranulomas do not exhibit nu- cleft cyst that contained cells that were
atin expression profiles, indicate that
clear accumulation of beta-catenin {329}. transitional between squamous, mucus-
craniopharyngiomas arise from neoplas-
Epidermoid and Rathke cleft cysts producing, and anterior pituitary lobe se-
tic transformation of ectodermal-derived
are sometimes raised in the differen- cretory cells {1246}.
epithelial cell remnants of Rathke pouch
tial diagnosis, especially in small tissue The hypothesis that craniopharyngiomas
fragments. Epidermoid cysts are distin- and the craniopharyngeal duct. Epithelial
are of neuroendocrine lineage is support-
cell rests have been reported to occur
guished by the presence of a uniloculat- ed by the finding that scattered tumour
between the roof of the pharynx and the
ed cavity lined by squamous epithelium cells can (rarely) express pituitary hor-
floor of the third ventricle, most frequently
and filled with flaky, dry keratin. Rathke mones {2475}, chromogranin-A {2807},
along the anterior infundibulum and the
cleft cysts enter into the differential diag- and hCG {2486}. The finding that crani-
anterior superior surface of the adenohy-
nosis in particular when they show exten- opharyngiomas share stem cell markers
sive squamous metaplasia {2307}. More pophysis - sites of the previous Rathke
(e.g. SOX2, OCT4, KLF4, and SOX9) with
pouch and involuted duct that links these
commonly, the cyst wall is lined by simple the normal pituitary gland further sup-
structures. Metaplasia of cells derived
columnar or cuboidal epithelium, which ports a common origin {70,785}.
from the tooth primordia determine the
often is ciliated, with mucinous goblet
adamantinomatous subtype, whereas Genetic profile
cells. A respiratory-type epithelium may
metaplastic changes in cells derived The WNT signalling pathway is strongly
occasionally be present, accompanied
by a xanthogranulomatous reaction af- from buccal mucosa primordia give implicated in the pathogenesis of ada-
rise to the squamous papillary variant mantinomatous craniopharyngiomas.
ter rupture of the cyst wall {932,2573,
{201). Further support for the origin of Genetic analyses have confirmed that as
2837}. Unlike papillary craniopharyngio-
craniopharyngiomas from Rathke pouch many as 95% of the tumours show muta-
mas, Rathke cleft cysts lack BRAFV600E
epithelium is the occasional occurrence tions in exon 3 of the beta-catenin gene
mutations, although cross-reactive stain-
of mixed tumours with characteristics of (CTNNB1) {263,329,1231,2316}. These
ing of cilia can be seen {1180,2307}. In
Fig. 17.10 Papillary craniopharyngioma. A At low magnification, the tumour has a cauliflower-like appearance, with surface epithelium covering central fibrovascular cores. B At
higher magnification, the lining is consistent with non-keratinizing squamous epithelium.
Craniopharyngioma 327
Fig. 17.11 Papillary craniopharyngioma. A Immunostaining for p63 confirms that the great majority of this tumour is composed of squamous epithelium. B Small component of
surface respiratory epithelium is highlighted with CK7 staining; this feature overlaps with the lining of Rathke cleft cyst, which can also show squamous metaplasia, mimicking papillary
craniopharyngioma. C Robust immunoreactivity for claudin-1. D Physiological expression of beta-catenin at the tumour cell membranes.
sinonasal carcinoma) should be carefully of cases), which can be detected by cholesterol-rich machinery oil-like fluid
excluded. immunohistochemistry. or calcifications. The surface of papil-
lary craniopharyngioma, like that of other
ICD-0 code 9352/1
papillary tumours, may appear corrugat-
Papillary craniopharyngioma Epidemiology ed or cauliflower-like.
Papillary craniopharyngiomas occur al-
Definition Microscopy
most exclusively in adults, with a mean
A papillary, mostly supratentorial or third The essential features of papillary crani-
patient age of 40-55 years {507}, and
ventricular craniopharyngioma charac- opharyngioma include compact, mono-
show no obvious sex predilection.
terized by fibrovascular cores lined by morphic sheets of well-differentiated
non-keratinizing squamous epithelium. Macroscopy squamous epithelium without surface
Papillary craniopharyngiomas occur al- Papillary craniopharyngiomas are keratinization. This variant typically lacks
most exclusively in adults and frequently solid or rarely cystic tumours, without calcifications, picket fence-like pali-
show BRAFV600E mutations (in 81-95% sades, whorl-like cell nodules, and wet
keratin. T cells, macrophages, and neu-
trophils are scattered throughout the
fibrovascular cores and tumour epithe-
lium. Rudimentary papillae may surround
the fibrovascular cores. Rarely, ciliated
epithelium and periodic acid-Schiff-
positive goblet cells are encountered.
Fig. 17.12 Papillary craniopharyngioma. A Typical non-keratinizing squamous epithelium and focal lymphocytic
infiltrate. B V600E-mutant BRAF is consistently expressed.
Definition
A circumscribed tumour that is composed
of large epithelioid to spindled cells with
distinctively granular, eosinophilic cyto-
plasm (due to an abundance of intracyto-
plasmic lysosomes) and that arises from
the neurohypophysis or infundibulum.
Granular cell tumour of the sellar region
generally exhibits slow progression and a
benign clinical course. Like pituicytomas
and spindle cell oncocytomas, granular
cell tumours show nuclear expression
of TTF1, suggesting that these three tu-
mours may constitute a spectrum of a
single nosological entity.
Fig. 17.14 Granular cell tumour of the sellar region. Postcontrast T1 -weighted MRI. The sagittal plane (A) and coronal
ICD-0 code 9582/0
plane (B) show prominent contrast enhancement. Note the characteristic sellar/suprasellar anatomical location.
imaging features, cases in which the architecture is typically nodular; sheets membranous debris. A few other orga-
tumour can be clearly seen to be sepa- and/or spindled/fascicular patterns can nelles and intracytoplasmic filaments
rated from the pituitary by the inferior end also be seen, occasionally in a whorling may be observed, but neurosecretory
of the pituitary stalk are suggestive of pattern. Periodic acid-Schiff staining granules are absent {152}.
granular cell tumour {86}. Nevertheless, of cytoplasmic granules is resistant to Immunophenotype
due to the relative rarity of the tumour, diastase digestion. Small foci of foamy Granular cell tumours are variably posi-
the diagnosis is rarely anticipated prior to cells may be observed. The tumour cell tive for CD68 (by KP1 staining), S100
surgical resection, which is also the case nuclei are small, with inconspicuous nu- protein, alpha-1-antitrypsin, alpha-1-anti-
for suprasellar pituicytomas. cleoli and evenly distributed chromatin. chymotrypsin, and cathepsin B, and are
Perivascular lymphocytic aggregates negative for NFPs, cytokeratins, chro-
Macroscopy
are common. Mitotic activity is usually mogranin-A, synaptophysin, desmin,
The tumours are usually lobulated and
inconspicuous, and proliferative activ- SMA, and the pituitary hormones. Most
well circumscribed, with a soft but rub-
ity is usually very low. Some lesions are tumours are negative for GFAP, although
bery consistency firmer than that of pitui-
characterized by nuclear pleomorphism, variable immunoreactivity has been not-
tary adenoma. The cut surface is typically
prominent nucleoli, multinucleated cells, ed in a subset of granular cell tumours.
grey to yellow. Necrosis, cystic degener-
and increased mitotic activity (with as Granular cell tumours show nuclear
ation, and haemorrhage are uncommon.
many as 5 mitoses per 10 high-power staining for TTF1 {1452}.
The tumour may infiltrate surrounding
fields and a Ki-67 proliferation index of
structures, such as the optic chiasm and Cell of origin
7%). Such tumours have been referred to
cavernous sinus; these features may pre- The finding that granular cell tumours
as atypical granular cell tumours by some
vent gross total surgical resection. strongly express the nuclear transcrip-
authors, although the clinical and biologi-
tion factor TTF1, like pituicytes of the de-
Microscopy cal significance is uncertain {1230,2659}.
veloping and mature neurohypophysis,
Granular cell tumours consist of densely By electron microscopy, the cytoplasm
suggests a pituicyte derivation {1452,
packed polygonal cells with abundant of the granular tumour cells is filled with
165}. Both pituicytomas and spindle
granular eosinophilic cytoplasm. The phagolysosomes containing unevenly
distributed electron-dense material and
Fig. 17.16 Granular cell tumour of the neurohypophysis. A Marked S100 protein expression. BTTF1 nuclear immunoreactivity.
cell oncocytomas of the hypophysis neurohypophysis {1654,2499}. Granular R132H-mutant IDH1, V600E-mutant
also express nuclear TTF1, suggesting cell tumours occasionally occur in the BRAF, or KIAA1549-BRAF fusion {1654}.
a histogenesis from pituicytes for these CNS outside the pituitary gland (e.g. in
Prognosis and predictive factors
tumours as well. It has been speculated the meninges, cerebral hemispheres,
Most granular cell tumours are clinically
that granular cell tumours and spindle third ventricle, or cranial nerves); these
benign, with slow progression and lack of
cell oncocytomas constitute pituicytomas tumours may be derived from glial cells,
invasive growth. Surgical removal is the
that are composed of tumour cells with Schwann cells, or macrophages {479,
preferred therapy for larger tumours, but
lysosome-rich and mitochondrion-rich 2118,2631}.
the firm and vascular nature of pituitary
cytoplasm, respectively, giving rise to
Genetic profile granular cell tumours, sometimes com-
distinct morphologies {1301,1452,1654}.
A unique genetic signature for granu- bined with the lack of an obvious dissec-
The derivation of three morphologically
lar cell tumour has not been defined. tion plane from the adjacent brain, may
distinct tumours from pituicytes might
The limited number of cases that have hamper gross total resection.
be explained by the existence of multi-
been tested to date have not shown
ple subtypes of pituicytes in the normal
Fig. 17.19 Pituicytoma. Elongate and plump tumours cells arranged in a fascicular pattern.
Macroscopy bodies (axonal dilatations for neuropep- supports a pituicyte derivation {1452,
Pituicytomas are solid and circumscribed tide storage in the neurohypophysis). 165}. Both granular cell tumours of the
masses that can measure up to several sellar region and spindle cell oncocy-
centimetres and have a firm, rubbery tex- Immunophenotype tomas also express nuclear TTF1, sug-
ture. Only rarely has a cystic component Pituicytomas are low-grade gliomas that gesting a histogenesis from pituicytes for
been reported {273,2596}. Radiographi- are positive by immunohistochemistry these tumours as well. It has been specu-
cal studies may give the impression of a for vimentin and S100 protein and show lated that these granular cell tumours and
smoothly contoured tumour, but pituicy- nuclear staining forTTF1 {273,1452,1654, spindle cell oncocytomas constitute pi-
tomas can be firmly adherent to adjacent 1966}. GFAP staining is highly variable, tuicytomas that are composed of tumour
structures in the suprasellar space. ranging from faint and focal to moderate cells with lysosome-rich and mitochon-
and patchy, and is only rarely strongly drion-rich cytoplasm, respectively, giving
Microscopy
positive. Strong, diffuse staining is more rise to distinct morphologies {1452,165}.
Pituicytomas have a solid, compact ar-
typical for S100 protein and vimentin. The derivation of three morphologically
chitecture and consist almost entirely of
BCL2 staining is variable, but can be distinct tumours from pituicytes might
elongate, bipolar spindle cells arranged
intense {1654,1966}. Stains for cytokerat- be explained by the existence of multiple
in a fascicular or storiform pattern {273,
ins are negative, and those for EMA may subtypes of pituicytes in the normal neu-
1452,1654,1966}. Although the tumours
show a patchy pattern that is cytoplas- rohypophysis {1654,2499}.
can show stubborn adherence to adja-
mic rather than membranous. Pituicyto-
cent structures in the suprasellar space, Genetic profile
mas do not demonstrate immunostaining
an infiltrative pattern is generally not seen A genetic signature for pituicytoma has
for pituitary hormones or for neuronal or
under the microscope. Individual tumour not been defined. The limited number of
neuroendocrine markers such as syn-
cells contain abundant eosinophilic cyto- cases that have been tested to date have
aptophysin and chromogranin. NFP
plasm, and cell shapes range from short not shown R132H-mutant IDH1, V600E-
immunoreactivity is limited to axons in
and plump to elongate and angulated. mutant BRAF, or KIAA1549-BRAF fusion
peritumoural neurohypophyseal tissue
Cell borders are readily apparent, es- {165}. Microarray-based comparative
and is not present within the tumour. The
pecially on cross sections of fascicles. genomic hybridization analysis of a sin-
proliferation of these tumours is low as
In strictly defined pituicytomas, there is gle case demonstrated losses of chro-
measured by immunoreactivity for MIB1,
not a significant amount of cytoplasmic mosome arms 1 p, 14q, and 22q, with
with the reported Ki-67 proliferation index
granularity or vacuolization, and periodic gains on 5p {1966}.
ranging from 0.5% to 2.0% {273,1355}.
acid-Schiff staining shows only minimal
Prognosis and predictive factors
reaction. Similarly, substantial oncocytic Cell of origin
Pituicytomas are slowly enlarging, local-
change is not a recognized feature of Pituicytomas presumptively arise from
ized tumours for which the current treat-
pituicytoma. The nuclei are moderately specialized glial cells of the neurohy-
ment is surgical resection {687,2877}. Lo-
sized and oval to elongate, with only mild pophysis, called pituicytes {1150,1514,
cal adherence of pituicytomas to regional
irregularity of nuclear borders. Mitotic 2261}. Such an origin accounts for the
structures may preclude complete resec-
figures are rare. Reticulin fibres show a anatomical distribution of pituicytomas
tion, and residual disease may gradually
perivascular distribution, and intercellu- and is consistent with the tumour’s mor-
regrow over a period of several years.
lar reticulin is sparse. Importantly for the phological and immunophenotypic char-
There has been no correlation of prolif-
differential diagnosis with pilocytic as- acteristics. The finding that pituicytomas
eration with clinical outcome. No instanc-
trocytoma and normal neurohypophysis, strongly express the nuclear transcrip-
es of malignant transformation or distant
pituicytomas show no Rosenthal fibres, tion factor TTF1, like pituicytes of the de-
metastasis have been reported to date.
eosinophilic granular bodies, or Herring veloping and mature neurohypophysis,
Pituicytoma 333
Lopes M.B.S
Spindle cell oncocytoma Fuller G.N.
Roncaroli F.
Wesseling P.
Definition
A spindled to epithelioid, oncocytic,
non-neuroendocrine neoplasm of the pi-
tuitary gland.
Spindle cell oncocytomas manifest in
adults and tend to follow a benign clinical
course. Like pituicytomas and granular
cell tumours of the sellar region, spindle
cell oncocytomas show nuclear expres-
sion of TTF1, suggesting that these three
tumours may constitute a spectrum of a
single nosological entity.
ICD-0 code 8290/0
Grading
Spindle cell oncocytoma corresponds Fig. 17.21 Spindle cell oncocytoma. A Coronal T2-weighted MRI demonstrates a very large multilobulated sellar
histologically to WHO grade I. mass with osseous remodelling and suprasellar extension; the mass laterally displaces the internal carotid arteries
(arrowheads) and exerts mass effect on the right aspect of the optic chiasm (asterisk). B Coronal postcontrast
Synonyms and historical annotation volumetric interpolated brain examination sequence demonstrates mildly heterogeneous enhancement with a small
In the initial report of the entity in 2002, central non-enhancing component.
Roncaroli et al. {2169} described spin-
dle cell oncocytoma as spindle cell on- Epidemiology Localization
cocytoma of the adenohypophysis. On Spindle cell oncocytoma is a rare tumour, Spindle cell oncocytoma is a pituitary
the basis of the similar ultrastructural and but its true incidence is difficult to deter- tumour that may have a mixed intrasellar
immunohistochemical features of these mine. In the experience of one institution, and suprasellar location. Clinical mani-
neoplasms, derivation from folliculos- spindle cell oncocytomas accounted for festation with a purely intrasellar tumour
tellate cells of the anterior pituitary was 0.4% of all sellar tumours {2169}. About is relatively rare {504}. Extension into the
suspected {2169}. However, more recent 25 cases have been reported in the litera- cavernous sinus {243,519} and invasion
data on the shared TTF1 immunoreactiv- ture {1719}. Based on the limited number of the sellar floor have been reported
ity of non-neoplastic pituicytes, pituicyto- of cases reported, spindle cell oncocyto- {1305}.
mas, granular cell tumours, and spindle ma is assumed to be a tumour of adults,
cell oncocytomas may suggest a similar Clinical features
with reported patient ages of 24-76 years
origin of these tumours and a shared link The clinical presentation and neuroimag-
and a mean age of 56 years. The distri-
to the posterior pituitary {1452,1654}. ing characteristics of spindle cell onco-
bution is equal between the sexes {1719}.
cytoma are indistinguishable from those
Fig. 17.22 Spindle cell oncocytoma. A The lesion is composed of interlacing fascicles of spindle cells with eosinophilic cytoplasm and mildly to moderately atypical nuclei. B The
Ki-67 proliferation index is usually low.
of a non-functioning pituitary adenoma. can be heterogeneous {504}. Calcifica- described {753}. A clear margin or a
Visual disturbances have been found to tion may be seen on CT imaging {239}. pseudocapsule, as can be seen in some
be the most common presenting symp- Recurrent intratumoural bleeding has pituitary adenomas, is usually absent.
tom, followed by pituitary hypofunction been reported, leading to an erroneous Microscopy
and (less frequently) headache, nausea, preoperative diagnosis of craniophar- Spindle cell oncocytomas are typically
and vomiting {504,171,2169}. Decreased yngioma {239}. The rich tumoural blood composed of interlacing fascicles and
libido, sexual dysfunction, and oligomen- supply can be seen on MR angiography; poorly defined lobules of spindle to epi-
orrhoea or amenorrhoea secondary to pi- one study reported predominant feeding thelioid cells with eosinophilic and vari-
tuitary stalk effect, with mild hyperprolac- from the bilateral internal carotid arteries ably oncocytic cytoplasm. Oncocytic
tinaemia, have been documented {1719}. {753}. changes can be focal or widespread.
None of the patients reported to date had The spectrum of morphological features
Macroscopy
diabetes insipidus at onset {504}. One that can be seen in spindle cell oncocy-
On gross inspection, spindle cell onco-
patient with aggressive spindle cell onco- toma is broad. Formations of whorls, fo-
cytoma is often indistinguishable from pi-
cytoma and involvement of the skull base cal stromal myxoid changes {2189}, clear
tuitary adenoma. Most are large tumours,
presented with epistaxis {1305}. cells, osteoclastic-like giant cells, and
with an average craniocaudal dimension
follicle-like structures {2605,2830} have
Imaging of 2.5-3 cm and a maximum reported
all been reported in individual cases,
The neuroimaging features of spindle size of 6.5 cm {519}. They vary from soft,
in addition to the more typical features.
cell oncocytoma are similar to those of creamy, and easily resectable lesions to
Mild to moderate nuclear atypia and even
pituitary adenoma, but spindle cell onco- firm tumours that adhere to surrounding
marked pleomorphism may be seen. Fo-
cytomas often avidly enhance following structures, and infrequently show de-
cal infiltrates of mature lymphocytes are
administration of paramagnetic contrast, struction of the sellar floor {519,1305}. In-
seen in many lesions. The mitotic count
because of their greater vascular sup- tratumoural haemorrhage can occur, and
is typically low, often with an average
ply relative to adenomas. Enhancement severe intraoperative bleeding has been
Fig. 17.24 Immunophenotype of spindle cell oncocytoma. A S100 protein. B Annexin. CGalectin-1. D Antimitochondrial antigen. EVimentin. F EMA.
of < 1 mitotic figure per 10 high-power case {2605}. Galectin-3 and annexin A1 to distinct morphologies {1452,165}.
fields. Recurrent lesions may or may not are also commonly expressed; although The derivation of three morphologically
show increased mitotic activity {1305, these markers are non-specific, they ini- distinct tumours from pituicytes might
1719}. tially suggested a link to the folliculostel- be explained by the existence of multiple
late cell {2169}. subtypes of pituicytes in the normal neu-
Electron microscopy
rohypophysis {1654,2499}.
Proliferation
Ultrastructural examination is useful in
The Ki-67 proliferation index is usually Genetic profile
the diagnosis of spindle cell oncocytoma
low, with a reported range of 1-8% and In a study that included 7 spindle cell
{1305,2169}. Neoplastic cells appear
an average value of 3%. One recurrent oncocytomas, none of the neoplasms
spindled or polygonal in configuration
example had a Ki-67 proliferation index showed positive immunostaining for
and are often filled with mitochondria,
of 20%, but no data were available on the R132H-mutant IDH1 or any evidence of
which may appear abnormal. The tu-
proliferation rate of the primary tumour BRAF V600E mutation or KIAA-BRAF fu-
mour cells lack secretory granules, a
{1305}. sion {165}.
key distinction from pituitary adenomas.
Well-formed desmosomes and interme- Cell of origin Prognosis and predictive factors
diate-type junctions are encountered. The histogenesis of spindle cell onco- Most spindle cell oncocytomas follow
Intracytoplasmic lumina with microvillous cytoma remains unresolved. Initially, a a benign clinical course, but about one
projections have been reported {2605}. derivation from folliculostellate cells of the third of reported cases have recurred, af-
adenohypophysis was postulated on the ter 3-15 years {1719}. In only a small num-
Immunophenotype
basis of the immunoprofile (in particular ber of cases with recurrence did the orig-
Unlike pituitary adenomas, spindle cell
galectin-3 and annexin A1 expression) inal neoplasm show an increased Ki-67
oncocytomas lack Immunoreactivity for
and ultrastructural features {2169}. How- proliferation index (ranging from 10% to
neuroendocrine markers and pituitary
ever, the finding that not only pituicyto- 20%) or marked cytological atypia {243,
hormones. Typically, spindle cell onco-
mas, but also granular cell tumours of the 1719}. Additional follow-up is needed to
cytomas express vimentin, S100 protein,
sellar region and spindle cell oncocyto- definitively determine the prognostic sig-
BCL2, and EMA, and show staining with
mas express the nuclear transcription nificance of such features. Incomplete
the antimitochondrial antibody MU213-
factor TTF1, like pituicytes of the devel- resection is a risk factor for recurrence.
UC clone 131-1, as well as nuclear
oping and mature neurohypophysis, sug- Moderate tumour volume and absence
staining for TTF1 {1305,1452,1654,2167,
gests a pituicyte derivation {1452,165}. of invasion into surrounding structures
2169}. EMA expression can vary from
It has been speculated that granular cell facilitate complete resection, whereas
weak and focal to diffuse. The tumours
tumours of the sellar region and spindle hypervascularity may hamper the proce-
are only focally positive for GFAR CD44
cell oncocytomas constitute variants of dure {1816}. Recurrent tumours can fol-
and nestin have been reported in a sin-
pituicytoma in which the tumour cells dis- low a more aggressive course, with an
gle case, suggesting a possible neuronal
play lysosome-rich and mitochondrion- increased Ki-67 proliferation index and
precursor component {47}, and alpha-
rich cytoplasm, respectively, giving rise necrosis {1305}.
crystallin B chain was seen in another
Epidemiology
Incidence
Due to underdiagnosis and inaccurate
reporting, the incidence rates for brain
metastases reported in the literature
probably underestimate the true inci- Brain
dence {731,248}. In a large, population- metastases
based study in Sweden, the incidence
of patients admitted to hospital with
brain metastases doubled to 14 cases
per 100 000 population between 1987 Fig. 18.01 Relative frequencies of primary tumours and of brain metastases derived thereof {354,2032}. Tumours with
and 2006. More efficient control of dis- a high propensity to metastasize to the brain are lung cancer, breast cancer, renal cell carcinoma, and melanoma. In
ease spread outside the CNS and the this series of brain metastases, about 14% of cases in males and 8% of cases in females were diagnosed as carcinoma
use of more advanced neuroimaging of unknown primary (CUP). Based on the histology of archival tissue samples {874 cases collected in 1990-2011 at the
Institute of Neurology/Neuropathology in Vienna); metastases for which surgery was not performed are not represented.
techniques may have contributed to this The relative frequency of brain metastases may differ substantially in other regions of the world.
increase {2371}. Autopsy studies have
reported that CNS metastases occur in
about 25% of patients who die of can- at an age of 50-59 years; and with breast a predilection for brain involvement (e.g.
cer {792}. Leptomeningeal metastases cancer at an age of 20-39 years {248}. lung cancer), and the introduction of new
occur in 4-15% of patients with solid tu- The incidence of CNS metastases may therapeutic agents that prolong life and
mours {400,2490} and dural metastases be increasing, in part due to increased are relatively efficacious overall but inef-
in 8-9% of patients with advanced can- detection with improved imaging, an in- fective at preventing or treating metastat-
cer {1419}. Spinal epidural metastases crease in the incidence of tumours with ic disease within the CNS {1868,248}.
are found in 5-10% and are much more
frequent than spinal leptomeningeal or
intramedullary metastases {1728}.
Age and sex distribution
CNS metastases are the most common
CNS neoplasms in adults, but metasta-
ses account for only about 2% of all pae-
diatric CNS tumours. As many as 30% of
adults and 6-10% of children with cancer
develop brain metastases. The relative
proportions of various primary tumours
are different between the two sexes, but
sex has no significant independent effect
on the occurrence of CNS metastasis for
most tumour types {130,731,2749}. The
incidence of brain metastases has been
reported to be highest among patients di-
agnosed with primary lung cancer at an
age of 40-49 years; with primary mela-
Fig. 18.02 Metastasis of an adenocarcinoma in the right frontal lobe. A Gadolinium-enhanced T1-weighted MRI
noma, renal cancer, or colorectal cancer
showing a contrast-enhancing tumour surrounded by a large hypointense area corresponding to perifocal oedema.
B Both the tumour and perifocal oedema show bright T2-hyperintensity.
Origin of CNS metastases hemispheres (particularly in arterial bor- melanoma, and haematopoietic tumours
der zones and at the junction of cerebral {2490}. Spinal epidural metastases are
The most common source of brain me- more common in cancer of the prostate,
cortex and white matter), 15% in the cer-
tastasis in adults is lung cancer (espe- breast, lung, and kidney, non-Hodgkin
ebellum, and 5% in the brain stem. Fewer
cially adenocarcinoma and small cell lymphoma, and multiple myeloma. In-
than half of all brain metastases are sin-
carcinoma), followed by breast cancer, tramedullary spinal cord metastases are
gle (i.e. the only metastatic lesion in the
melanoma, renal cell carcinoma, and brain), and very few are solitary (i.e. the more common in small cell lung carci-
colorectal cancer {354,1783,2032}. Pros- noma {1728}.
only metastasis in the body) {792,1923}.
tate, breast, and lung cancer are the most
Other intracranial sites include the dura
common origins of spinal epidural metas- Clinical features
and leptomeninges; in these sites, ex-
tasis, followed by non-Hodgkin lympho-
tension from or to other compartments Symptoms and signs
ma, multiple myeloma, and renal cancer
is more common {1419,1760}. The vast The neurological signs and symptoms
{1728}. Tumours and their molecular sub- majority of metastases affecting the spi-
types vary in their propensity to metas- of intracranial metastases are generally
nal cord expand from the vertebral body caused by increased intracranial pres-
tasize to the CNS {130,510,2297}. In as
or paravertebral tissues into the epidural sure or local effect of the tumour on the
many as 10% of patients with brain me-
space {1728}. Occasionally, metastatic adjacent brain tissue. The signs and
tastases, no primary tumour is found at
CNS tumours seed along the walls of the symptoms may progress gradually and
presentation {2032}. In children, the most
ventricles or are located in the pituitary include headache, altered mental sta-
common sources of CNS metastases are gland or choroid plexus. Rarely, tumour-
leukaemias and lymphomas, followed tus, paresis, ataxia, visual changes, nau-
to-tumour metastasis occurs, with lung sea, and sensory disturbances. Some
by non-haematopoietic CNS neoplasms
and breast cancer being the most com- patients present acutely with seizure,
such as germ cell tumours, osteosarco-
mon donor tumours and meningioma the infarct, or haemorrhage {1453}. The in-
ma, neuroblastoma, Ewing sarcoma, and
most common recipient {1711}. Of par- terval between diagnosis of the primary
rhabdomyosarcoma {510,2749}. Occa-
ticular diagnostic challenge is metastasis tumour and the CNS metastasis is gener-
sionally, primary neoplasms in the head of renal cell carcinoma to haemangio-
and neck region extend intracranially by ally < 1 year for lung carcinoma, but can
blastoma in the setting of von Hippel-Lin- be multiple years for breast cancer and
direct invasion (per continuitatem), some-
dau disease {62,1138}. Dural metastases melanoma {2297}. Many patients with
times along cranial nerves, and present
are relatively common in cancer of the leptomeningeal metastasis have multi-
as intracranial tumours {2323}.
prostate, breast, and lung, and in hae- ple, varied neurological symptoms and
Localization matological malignancies {1419,1760}. signs at presentation, including head-
Approximately 80% of all brain me- Leptomeningeal metastases are more ache, mental alteration, ataxia, cranial
tastases are located in the cerebral common in lung and breast cancer,
Fig. 18.04 Patterns of CNS metastasis. A Extensive CSF spread of small cell lung carcinoma cells along the walls of both lateral ventricles and the third ventricle. B Intraventricular
metastasis of a lung adenocarcinoma infiltrating the choroid plexus with (C) TTF1 staining of tumour cell nuclei.
nerve dysfunction, and radiculopathy. and peritumoural oedema. Metastases demonstrate a pushing margin and/or in-
Cytological examination reveals malig- of adenocarcinomas may contain collec- vasion via Virchow-Robin spaces rather
nant cells in the initial cerebrospinal fluid tions of mucoid material. Haemorrhage is than a single-cell infiltration pattern (es-
sample in about 50% of such patients; relatively frequent in metastases of cho- pecially in focal areas) and can therefore
this proportion may increase to > 80% riocarcinoma, melanoma, and clear cell occasionally be confused for metastatic
when cerebrospinal fluid sampling is re- renal cell carcinoma. Melanoma metasta- tumours on a morphological basis.
peated and adequate volumes (> 10 mL) ses with abundant melanin pigment have
Immunophenotype
are available for cytological analysis a brown to black colour. Leptomeningeal
The immunohistochemical characteristics
{400,1453}. Spinal metastases generally metastasis may produce diffuse opacifi-
of secondary CNS tumours are generally
result in compression of the spinal cord cation of the membranes or present as
similar to those of the tumours from which
or nerve roots and may cause back pain, multiple nodules {1923}. Dural metas-
they originate. Immunohistochemical
weakness of the extremities, sensory tases can grow as localized plaques or
disturbances, and incontinence over the analysis is often very helpful for
nodules and as diffuse lesions. Primary
distinguishing primary from secondary
course of hours, days, or weeks {1453}. neoplasms in the head and neck region
CNS tumours and for assessment of the
that extend intracranially by direct inva-
Imaging exact nature and origin of the metastatic
sion generally cause significant destruc-
On MRI, intraparenchymal metastases neoplasm (particularly in cases with an
tion of the skull bones. However, in some
are generally circumscribed and show unknown primary tumour) {149,1923}.
cases, the skull is penetrated by rela-
mild T1-hypointensity, T2-hyperintensi-
tively subtle, perivascular or perineural
Proliferation
ty, and diffuse or ring-like contrast en-
invasion, without major bone destruction
Metastatic CNS tumours show variable
hancement with a surrounding zone of
{2323}. and often marked mitotic activity. The
parenchymal oedema. Haemorrhagic
proliferation index may be significantly
metastases and metastatic melanomas Microscopy
higher than in the primary neoplasm
containing melanin pigment may dem- The histological and immunohisto-
{171}.
onstrate hyperintensity on non-contrast chemical features of secondary CNS tu-
MRI or CT {2833}. In patients with lepto- mours are as diverse as those of the pri- Pathogenesis
meningeal metastasis, MRI can show fo- mary tumours from which they arise. Most Before they present as haematogenous
cal or diffuse leptomeningeal thickening brain metastases are fairly well demarcat- metastases in the CNS, tumour cells must
and contrast enhancement (sometimes ed, with variable perivascular growth (so- successfully complete a series of steps:
with dispersed tumour nodules in the called vascular cooption) in the adjacent escape from the primary tumour, entry
subarachnoid space). Enhancement and CNS tissue {172}. On occasion, small cell into and survival in the blood stream, ar-
enlargement of the cranial nerves and carcinomas and lymphomas may show rest and extravasation in the CNS, and
communicating hydrocephalus may also more diffuse infiltration (pseudoglioma- survival and growth in the CNS micro-
be found {848,1728}. MRI can depict du- tous growth) in the adjacent brain pa- environment {1264,2032}. The molecu-
ral metastases as nodular masses or du- renchyma {145,1770}. Tumour necrosis lar basis of CNS spread in the various
ral thickening along the bone structures, may be extensive, leaving recognizable tumour types is poorly elucidated and
whereas metastases in vertebral bodies tumour tissue only at the periphery of the requires further study. Secondary CNS
are visualized as discrete, confluent or lesion and around blood vessels {1923}. tumours may also develop by direct ex-
diffuse areas of low signal intensity. CT In leptomeningeal metastasis, the tumour tension from primary tumours in adjacent
scan may be useful for detection of bone cells are dispersed in the subarachnoid anatomical structures (e.g. paranasal si-
involvement {1419}. and Virchow-Robin spaces and may in- nuses and bone) {2323}. Such tumours
vade the adjacent CNS parenchyma and are not formally considered metastases,
Macroscopy
nerve roots {2490}. Although the pattern because they remain in continuity with
Metastases in the brain and spinal cord
of infiltration is often helpful in distin- the primary neoplasm. Once in contact
parenchyma often form grossly circum-
guishing a metastatic tumour from a pri- with the cerebrospinal fluid-containing
scribed and rounded, greyish-white or
mary CNS tumour (e.g. a diffuse glioma), compartments, cells of those tumours
tan masses with variable central necrosis
occasional cases of glioblastoma can
NCAM1
CK5/6 CK7 CK20 TTF1 NapA GCDFP15 CDX2 RCCm PSA EMA PAX8 Vim Melan-A
(CD56)
Squamous cell carcinoma + - + - - - - - - - + - - -
Colorectal adenocarcinoma - - - + - - - + - - + - - -
Stomach adenocarcinoma - - + + - - - + - - + - - -
Prostate adenocarcinoma - - - - - - - - - + + - - -
Urothelial carcinoma + - + + - - - - - - + - - -
Melanoma - - - - - - - - - - - - + +
may disseminate (seed) throughout the expression in breast cancer, BRAF mu- prognostic scores taking these param-
CNS. tation in melanoma, RAS mutation in eters into account have been described,
colorectal cancer, and ERBB2 amplifica- but require validation in independent
Molecular genetics and
tion in gastro-oesophageal cancer {170}. and prospective studies {1328,2404}.
predictive factors
For some markers, there are significant Other factors of prognostic significance
A wide range of tumour types cause
discordance rates between primary tu- include the specific tumour type and the
brain metastases, and some molecularly
mours and brain metastases, which may molecular drivers involved (e.g. ERBB2 in
defined tumour subtypes have higher
influence the necessity of performing breast cancer) {1505}. Neuroradiological
propensity to metastasize to the CNS
biomarker analyses on brain metastasis parameters such as peritumoural brain
(e.g. ERBB2-positive and triple-negative
tissue samples for therapy planning {170, oedema may also provide prognostic
breast cancer) {1505}. Systemic therapy
102). information {2401}. In more recent stud-
with novel targeted agents is increasingly
ies, the reported improvement in overall
being used for patients with CNS metas- Prognostic factors
survival of patients with CNS metastases
tases. Biomarker tests to be considered The main established prognostic fac-
may be attributable to improvements in
for such therapies include EGFR muta- tors for patients with brain metastases
focal and systemic therapies in combina-
tion and ALK rearrangement in non-small are patient age, Karnofsky performance
tion with earlier detection of such metas-
cell lung cancer, ERBB2 amplification status, number of brain metastases, and
tases {1783}.
and estrogen and progesterone receptor status of extracranial disease. Several
Dr Herbert BUDKA
Dr Albert J. BECKER Dr Ingmar Blümcke
Institute of Neuropathology
Department of Neuropathology University of Erlangen
University Hospital Zurich
University of Bonn Medical Center Institute of Neuropathology
Schmelzbergstrasse 12
Sigmund-Freud-Strasse 25 Schwabachanlage 6
8091 Zurich
53105 Bonn 91054 Erlangen
SWITZERLAND
GERMANY GERMANY
Tel. +41 44 255 25 02
Tel. +49 228 287 1352 bluemcke@uk-erlangen.de
Fax +41 44 255 44 02
Fax +49 228 287 4331 herbert.budka@usz.ch
albert_becker@uni-bonn.de
'Indicates participation in the Working Group Meeting on the WHO Classification of Tumours of the Central Nervous System that was held
Heidelberg, Germany, 21-24 June 2015.
# Indicates disclosure of interests.
342 Contributors
Dr Peter C. BURGER* Dr Elizabeth B. CLAUS Dr Judith A. FERRY
Department of Pathology Department of Biostatistics/ Department of Pathology
Johns Hopkins Medical Institutions Epidemiology/Neurosurgery Massachusetts General Hospital
Pathology Building, Zayed Tower Yale University School of Medicine 55 Fruit Street
Room 2101, 1800 Orleans Street 60 College Street, Box 208034 Boston MA 02114
Baltimore MD 21231 New Haven CT 06520-8034 USA
USA USA Tel. +1 617 726 4826
Tel. +1 410 955 8378 Tel. +1 203 785 2838 Fax +1 617 726 7474
Fax +1 410 614 9310 Fax +1 203 785 6912 jferry@mgh.harvard.edu
pburger@jhmi.edu elizabeth.claus@yale.edu
Dr Rolf BUSLEI
University of Erlangen Dr V. Peter COLLINS* Dr Dominique FIGARELLA-BRANGER*
Institute of Neuropathology Department of Pathology Laboratoire d’anatomie
Schwabachanlage 6 University of Cambridge pathologique-neuropathologique
91054 Erlangen Tennis Court Road Hdpital de la Timone
GERMANY Cambridge CB2 1QP 264 rue Saint-Pierre
Tel. +49 9131 852 60 31 UNITED KINGDOM 13385 Marseille Cedex 05
Fax +49 9131 852 60 33 Tel. +44 1223 336 072; +44 1223 217 164 FRANCE
rolf.buslei@uk-erlangen.de Fax+44 1223 216 980 Tel. +33 4 13 42 90 38
vpc20@cam.ac.uk Fax +33 4 91 38 44 11
dominique.figarella-
branger@univ-amu.fr
Dr J. Gregory CAIRNCROSS Dr Martina DECKERT Dr Gregory N. FULLER*
Department of Clinical Neurosciences Department of Neuropathology Department of Pathology
University of Calgary and University of Cologne University of Texas
Foothills Medical Centre Kerpener Strasse 62 MD Anderson Cancer Center
HRIC 2AA-19 3280 Hospital Drive NW 50931 Cologne 1515 Holcombe Boulevard, Unit 085
Calgary AB T2N 4Z6 GERMANY Houston TX 77030
CANADA Tel. +49 221 478 52 65 USA
Tel. +1 403 210 3934 Fax +49 221 478 72 37 Tel. +1 713 792 2042
Fax +1 403 210 8135 martina.deckert@uni-koeln.de Fax +1 713 792 3696
jgcairnx@ucalgary.ca gfuller@mdanderson.org
Dr Felice GIANGASPERO*
Dr Webster K. CAVENEE* Dr David W. ELLISON* Department of Radiological, Oncological and
Cellular and Molecular Medicine East Department of Pathology Anatomopathological Sciences
University of California, San Diego St. Jude Children’s Research Hospital Policlinico Umberto I, Sapienza University
9500 Gilman Drive, #0660, Room 3080 262 Danny Thomas Place, MS 250 Viale Regina Elena, 324
La Jolla, San Diego CA 92093-0660 Room C-5001 00161 Rome
USA Memphis TN 38105-3678 ITALY
Tel. +1 858 534 7805 USA Tel. +39 06 49 73 710; +39 06 44 46 86 06
Fax +1 858 534 7750 Tel. +1 901 595 5438 Fax +39 06 48 97 91 75
wcavenee@ucsd.edu Fax +1 901 595 3100 felice.giangaspero@uniroma1.it
david.ellison@stjude.org
Dr Caterina GIANNINI*
Anatomic Pathology
Dr Leila CHIMELLI Dr Charis ENG Mayo Clinic College of Medicine
Department of Pathology Genomic Medicine Institute 200 First Street SW
University Hospital CFF - UFRJ Cleveland Clinic Lerner Research Institute Rochester MN 55905
Avenida Epitacio Pessoa 4720/501 9500 Euclid Avenue, NE-50 USA
Rio de Janeiro 22471-003 Cleveland OH 44195 Tel. +1 507 538 1181
BRAZIL USA Fax +1 507 284 1599
Tel. +55 21 99604 4880; +55 21 2226 9998 Tel. +1 216 444 3440 giannini.caterina@mayo.edu
Fax +55 21 3207 6548 Fax +1 216 636 0655
leila.chimelli@gmail.com engc@ccf.org
Contributors 343
Dr Hannu HAAPASALO Dr Takanori HIROSE* Dr Koichi ICHIMURA#
Department of Pathology Department of Pathology Division of Brain Tumor
University of Tampere / Finlab Laboratories Kobe University Hospital Translational Research
POB 66 7-5-2 Kusunoki-cho, Chuo-ku National Cancer Center Research Institute
SF-335101 Tampere Hyogo Prefecture 5-1-1 Tsukiji, Chuo-ku
FINLAND Kobe City 650-0017 Tokyo 104-0045
Tel. +358 3 247 65 60 JAPAN JAPAN
Fax +358 3 247 55 03 thirose@hp.pref.hyogo.jp Tel. +81 3 3547 52 01 ext. 28 26
hannu.haapasalo@pshp.fi Fax +81 3 3542 25 30
kichimur@ncc.go.jp
Dr David JONES#
Dr Johannes A. HAINFELLNER# Dr Mrinalini HONAVAR Division of Pediatric Neurooncology
Institute of Neurology Department of Anatomical Pathology German Cancer Research Center
Medical University of Vienna Pedro Hispano Hospital Im Neuenheimer Feld 280
Wahringer Gurtel 18-20 Rua de Alfredo Cunha 365 69120 Heidelberg
1090 Vienna Matosinhos GERMANY
AUSTRIA PORTUGAL Tel. +49 6221 42 45 94
Tel. +43 1 404 00 55 000 minalhonavar@gmail.com Fax +49 6221 42 46 39
Fax+43 1 404 00 55 110 mrinalini.honavar@ulsm.min-saude.pt david.jones@dkfz.de
johannes.hainfellner@meduniwien.ac.at
Dr Paul KLEIHUES*
Dr Cynthia HAWKINS* Dr Stephen HUNTER Faculty of Medicine
Division of Pathology, Department of Department of Pathology University of Zurich
Paediatric Laboratory Medicine Emory University School of Medicine Pestalozzistrasse 5
Hospital for Sick Children 1364 Clifton Road NE 8032 Zurich
555 University Avenue Atlanta GA 30322 SWITZERLAND
Toronto ON M5G 1X8 USA Tel. +41 44 362 21 10
CANADA Tel. +1 404 712 4278 kleihues@pathol.uzh.ch
Tel. +1 416 813 5938 Fax +1 404 712 0714
Fax +1 416 813 5974 stephen_hunter@em
cynthia.hawkins@sickkids.ca ory.org
Dr Monika HEGI#
Department of Clinical Neurosciences Dr Jason T. HUSE Dr Bette K. KLEINSCHMIDT-DeMASTERS
University of Lausanne Hospital Department of Pathology Department of Neuropathology
Chemin des Boveresses Memorial Sloan Kettering Cancer Center University of Colorado
1066 Epalinges 1275 York Avenue Anschutz Medical Campus
SWITZERLAND New York NY 10065 12605 East 16th Avenue, Room 3017
Tel. +41 21 314 25 82 USA Aurora CO 80045
Fax +41 21 314 25 87 Tel. +1 646 888 2642 USA
monika.hegi@chuv.ch Fax +1 646 422 0856 bk.demasters@ucdenver.edu
husej@mskcc.org
344 Contributors
Dr Philip M. KLUIN Dr Ivo LEUSCHNER Dr Christian MAWRIN
Department of Pathology and Medical Biology Kiel Pediatric Tumor Registry Department of Neuropathology
University of Groningen Department of Pediatric Pathology Otto-von-Guericke University
Hanzeplein 1 University of Kiel Leipziger Strasse 44
9713 GZ Groningen Arnold-Heller-Strasse 3, House 14 39120 Magdeburg
THE NETHERLANDS 24105 Kiel GERMANY
Tel. +31 50 361 46 84 GERMANY christian.mawrin@med.ovgu.de
p.m.kluin@umcg.nl Tel. +49 431 597 34 44
Fax +49 431 597 34 86
ileuschner@path.uni-kiel.de
Dr Marcel KOOL
Division of Pediatric Neurooncology Dr Jay LOEFFLER Dr Michel MITTELBRONN
German Cancer Research Center Department of Radiation Oncology Institute of Neurology (Edinger Institute)
Im Neuenheimer Feld 280 Massachusetts General Hospital Goethe University Frankfurt
69120 Heidelberg Clark Center for Radiation Oncology Heinrich-Hoffmann-Strasse 7
GERMANY 100 Blossom Street 60528 Frankfurt am Main
Tel. +49 6221 42 46 36 Boston MA 02114-2606 GERMANY
Fax +49 6221 42 46 39 USA Tel. +49 69 6301 841 69
m.kool@dkfz.de Tel. +1 617 724 1548 Fax +49 69 9301 841 50
Fax +1 617 724 8334 michel.mittelbronn@kgu.
jloeffler@partners.org de
Contributors 345
Dr Hiroko OHGAKI* Dr Stefan PFISTER*# Dr Fausto RODRIGUEZ
Section of Molecular Pathology Division of Pediatric Neurooncology and Department of Pathology
International Agency for Research on Cancer Pediatrics Clinic III Division of Neuropathology
150 Cours Albert Thomas German Cancer Research Center Johns Hopkins Hospital
69372 Lyon Cedex 08 Im Neuenheimer Feld 280 and 430 Sheikh Zayed Tower, Room M2101
FRANCE 69120 Heidelberg 1800 Orleans Street
Tel. +33 4 72 73 8534 GERMANY Baltimore MD 21231
Fax +33 4 72 73 8698 Tel. +49 6221 42 46 18 USA
ohgakih@iarc.fr Fax +49 6221 42 46 39 Tel. +1 443 287 6646
stefan.pfister@med.uni Fax +1 410 614 9310
-heidelberg.de frodrig4@jhmi.edu
Dr Magali OLIVIER Dr Torsten PIETSCH*#
Molecular Mechanisms and Department of Neuropathology Dr Frederico RONCAROLI
Biomarkers Group University of Bonn Medical Center Department of Pathology
International Agency for Research on Cancer Sigmund-Freud-Strasse 25 Salford Royal Foundation Hospital
150 Cours Albert Thomas 53105 Bonn University of Manchester
69372 Lyon Cedex 08 GERMANY Stott Lane
FRANCE Tel. +49 228 287 166 06 Salford, Manchester M68HD
Tel. +33 4 72 73 86 69 Fax+49 228 287 143 31 UNITED KINGDOM
Fax +33 4 72 73 83 45 t.pietsch@uni-bonn.de Tel: +44 161 206 5013
olivierm@iarc.fr federico.roncaroli@manchester.ac.uk
346 Contributors
Dr Felix SAHM# Dr M.C. SHARMA Dr Dominik STURM
Department of Neuropathology Department of Pathology German Cancer Research Center and
Heidelberg University and Clinical All India Institute of Medical Sciences Heidelberg University Medical Center for
Cooperation Unit Neuropathology Ansari Nagar Children and Adolescents
German Cancer Research Center New Delhi 110029 Im Neuenheimer Feld 580
Im Neuenheimer Feld 224 INDIA 69120 Heidelberg
69120 Heidelberg Tel. +91 11 659 33 71 GERMANY
GERMANY Fax +91 11 686 26 63 Tel. +49 6221 42 46 76
Tel. +49 6221 56 378 86 sharmamehar@yahoo.co.in Fax +49 6221 42 46 39
felix.sahm@med.uni-heidelberg.de d.sturm@dkfz.de
Dr Sandro SANTAGATA#
Dr Dov SOFFER Dr Mario L. SUVA
Department of Pathology James Homer Wright Pathology Laboratories
Division of Neuropathology Department of Pathology
Tel Aviv Sourasky Medical Center Massachusetts General Hospital
Brigham and Women's Hospital, Harvard 149 13th Street, Office 6.010
Medical School, Harvard Institute of Medicine 6 Weizman Street
64239 Tel Aviv Charlestown MA 02129
HIM-921, 77 Avenue Louis Pasteur USA
Boston MA 02115 ISRAEL
Tel. +972 3 694 75 72 Tel. +1 617 726 5695
USA Fax +1 617 724 1813
Tel. +1 617 525 5686 Fax +972 3 697 46 48
soffer@cc.huji.ac.il suva.mario@mgh.har
ssantagata@partners.org vard.edu
Dr Mariarita SANTI
Division of Neuropathology Dr Figen S0YLEMEZOGLU Dr Uri TABORI
Children’s Hospital of Philadelphia Department of Pathology Paediatric Haematology/Oncology
34th Street and Civic Center Boulevard Hacettepe University Hospital for Sick Children
Philadelphia PA 19104 Tip Fakultesi, Patoloji Anabilim Dali 555 University Avenue
USA 06100 Ankara Toronto ON M5G 1X8
Tel. +1 215 590 3184 TURKEY CANADA
santim@chop.edu Tel. +90 312 241 99 51 Tel. +1 416 813 8221
Fax+90 312 305 26 21 Fax +1 416 813 5327
figensoylemezoglu@gmail.com uri.tabori@sickkids.ca
Contributors 347
Dr Erwin G. VAN MEIR Dr Alexander O. VORTMEYER Dr Hai YAN#
Winship Cancer Institute Department of Pathology Molecular Oncogenomics Laboratory
Emory University School of Medicine Yale University School of Medicine Duke University
1365-C Clifton Road NE, Suite C 5078 310 Cedar Street, LH416 199B MSRB, DUMC3156
Atlanta GA 30322 New Haven CT 06520 Durham NC 27710
USA USA USA
Tel. +1 404 778 5563 Tel. +1 203 785 6843 Tel. +1 919 668 7850
Fax +1 404 778 5550 Fax +1 203 785 6899 hai.yan@duke.edu
evanmei@emory.edu alexander.vortmeyer
@yale.edu
348 Contributors
Declaration of interest statements
Dr Capper reports receiving income from two Dr McLendon reports being part of a pending Dr Varlet reports receiving travel support
patents held by the German Cancer Research patent application, with Duke University, for a from Hoffmann-La Roche and Boehringer
Center (DKFZ): one for an antibody to detect technique to identify and measure FUBP1 and Ingelheim. Dr Varlet reports that a close rela-
R132H-mutant IDH1 in fixed glioma samples, CIC in brain tumours. tive is employed by Novartis France.
licensed to Dianova, and one for an antibody
Dr Osborn reports having been a founder and Dr Vinters reports that the UCLA Department
to detect V600E-mutant BRAF in formalin-fixed
shareholder of Amirsys and Amirsys Publish- of Pathology and Laboratory Medicine con-
paraffin-embedded tumour samples, licensed
ing. Dr Osborn reports receiving personal ducts contract work for Neuroindex funded
to Ventana Medical Systems (a member of the
consultancy fees from Elsevier. Dr Osborn re- by an NIH grant. Dr Vinters reports receiving
Roche Group).
ports having received personal speaker’s fees royalties from Mosby Elsevier. Dr Vinters re-
Dr Hainfellner reports that the Austrian Brain from Mallinckrodt. ports holding shares in 3M Company; Gen-
Tumour Registry at the Institute of Neurology, eral Electric; Teva Pharmaceutical Indus-
Dr Pfister reports receiving non-financial re-
Medical University of Vienna, receives re- tries; Pfizer; GlaxoSmithKline; and Becton,
search support from lllumina. Dr Pfister re-
search support from Roche. Dickinson and Company.
ports having a patent pending for a brain tu-
Dr Hartmann reports having received per- mour classification based on DNA methylation Dr Weller reports receiving personal con-
sonal consultancy fees from Apogenix. Dr fingerprinting. sultancy fees from MagForce AG, Isar-
Hartmann reports receiving income from a na Therapeutics, Celldex Therapeutics,
Dr Pietsch reports having received travel sup-
patent held by DKFZ for an antibody to detect ImmunoCellular Therapeutics, Roche, and
port from Affymetrix. Dr Pietsch reports having
R132H-mutant IDH1, licensed to Dianova Merck Serono. Dr Weller reports receiving per-
received personal speaker’s fees from Roche.
Dr Hegi reports that her department at sonal speaker’s fees from Isarna Therapeutics,
Dr Reifenberger reports having received re- MSD, Roche, and Merck Serono. Dr Weller
the Lausanne University Hospital has re-
search funding from Roche and Merck and reports that the University Hospital Zurich
ceived non-financial research support from
honoraria for advisory boards or lectures from and University of Zurich receive research
MDxHealth.
Amgen, Roche and Celldex. support from Roche, Merck Serono, Bayer,
Dr Ichimura reports receiving research sup- Isarna Therapeutics, Piqur Therapeutics, and
Dr Rushing reports having received research
port from SRL. Dr Ichimura reports receiving Novocure.
funding from Novartis.
travel support from MSD K.K. (a subsidiary
of Merck & Co.). Dr Ichimura reports receiv- Dr Sahm reports having a patent pending for a Dr Wick reports holding patents related to
ing personal speaker’s fees from Eisai Co., method for detecting the presence of antigens CD95L as a diagnostic marker, IDH1 immuno-
Astellas Pharma, Otsuka Pharmaceutical, in situ. therapy, and IDH1 antibody.
Sanofi K.K., Daiichi Sankyo, Chugai Pharma- Dr Santagata reports having cofounded Dr Yan reports being the chief security officer
ceutical, and Teijin Pharma. Bayesian Diagnostics. Dr Santagata reports of Genentron Health and having substantial
Dr Jones reports receiving non-financial re- having received personal consultancy fees shareholding in the company. Dr Yan reports
search support from lllumina. Dr Jones reports from Bayesian Diagnostics. Dr Santagata re- receiving personal consultancy fees from
having a patent pending for a brain tumour ports that a close relative receives royalties Sanofi and Blueprint Medicines and reports re-
classification based on DNA methylation fin- from BioReference Laboratories for intellectual ceiving royalties for IDH-targeted therapy and
gerprinting. property rights for a targeted genotyping plat- diagnosis from Agios and Personal Genome
form for cancer diagnostics. Diagnostics. Dr Yan reports having received
Dr Leung reports that the Department of royalties from Blueprint Medicines. Dr Yan re-
Pathology at the University of Hong Kong ports having a patent pending for IDH1 and
has a collaborative research agreement with TERT mutations in gliomas. Dr Yan reports that
Merck, Pfizer, and Servier. his laboratory at the Duke University Medical
Center received research support from Gilead
Sciences and Sanofi.
Dr Leslie H. SOBIN
Frederick National Laboratory for
Cancer Research
The Cancer Human Biobank
National Cancer Institute
6110 Executive Boulevard, Suite 250
Rockville MD 20852, USA
Tel. +1 301 443 7947
Fax +1 301 402 9325
leslie.sobin@nih.gov
1. Abe M, Tabuchi K, Tanaka S, Hodozuka A, PMID:22271522 Dev. 27(3)164-71. PMID15737696 44. Alcedo J, Noll M (1997). Hedgehog and its
Kunishio K, Kubo N, et al. (2004). Capillary 16. Aerts I, Pacquement H, Doz F, Mosseri V, 30A. Aizer AA, Bi WL, Kandola MS, Lee EQ, patched-smoothened receptor complex: a novel
hemangioma of the central nervous system. J Desjardins L, Sastre X, et al. (2004). Outcome Nayak L, Rinne ML, et al. (2015). Extent of signalling mechanism at the cell surface. Biol
Neurosurg. 101(1)73-81. PMID:15255254 of second malignancies after retinoblastoma: a resection and overall survival for patients with Chem. 378(7):583-90. PMID:9278137
2. Abedalthagafi MS, Merrill PH, Bi WL, Jo- retrospective analysis of 25 patients treated at atypical and malignant meningioma. Cancer. 45. Alderson L, Fetell MR, Sisti M, Hochberg F,
nes RT, Listewnik ML, Ramkissoon SH, et the Institut Curie. Eur J Cancer. 40(10):1522-9. 121(24):4376-81. PMID:26308667 Cohen M, Louis DN (1996). Sentinel lesions of
al. (2014). Angiomatous meningiomas have PMID:15196536 31. Akamatsu Y, Utsunomiya A, Suzuki S, Endo primary CNS lymphoma. J Neurol Neurosurg
a distinct genetic profile with multiple chro- 17. Agaimy A (2014). Microscopic intraneural T, Suzuki I, Nishimura S, et al. (2010). Sub- Psychiatry. 60(1)102-5. PMID:8558135
mosomal polysomies including polysomy of perineurial cell proliferations in patients with ependymoma in the lateral ventricle manifes- 45A. Alentom A, Dehais C, Ducray F, Carpen-
chromosome 5. Oncotarget. 5(21):10596^606. neurofibromatosis type 1. Ann Diagn Pathol. ting as intraventricular hemorrhage. Neurol Med tier C, Mokhtari K, Figarella-Branger D, et al.
PMID:25347344 18(2):95-8. PMID:24461704 Chir (Tokyo). 50(11)1020-3. PMID:21123990 (2015). Allelic loss of 9p21.3 is a prognostic
3. Abel TW, Baker SJ, Fraser MM, Tihan T, 18. Agaimy A, BarthelmelJ S, Geddert H, Boltze 32. Aker FV, Ozkara S, Eren P, Peker O, Ar- factor in 1p/19q codeleted anaplastic gliomas.
Nelson JS, Yachnis AT, et al. (2005). Lhermit- C, Moskalev EA, Koch M, et al. (2014). Pheno- magan S, Hakan T (2005). Cerebellar lipon- Neurology. 85(15)1325-31. PMID:26385879
te-Dudos disease: a report of 31 cases with typical and molecular distinctness of sinonasal eurocytoma/lipidized medulloblastoma. J Neu- 46. Alexander RT, McLendon RE, Cummings
immunohistochemical analysis of the PTEN/ haemangiopericytoma compared to solitary rooncol. 71(1):53-9. PMID15719276 TJ (2004). Meningioma with eosinophilic granu-
AKT/mTOR pathway. J Neuropathol Exp Neu- fibrous tumour of the sinonasal tract. Histopa- 33. Akers AL, Johnson E, Steinberg GK, lar inclusions. Clin Neuropathol. 23(6):292-7.
rol. 64(4):341-9. PMID:15835270 thology. 65(5):667-73. PMID:24807787 Zabramski JM, Marchuk DA (2009). Biallelic PMID15584214
4. Abrey LE, DeAngelis LM, Yahalom J (1998). 19. Agamanolis DP, Katsetos CD, Klonk CJ, somatic and germline mutations in cerebral ca- 47. Alexandrescu S, Brown RE, Tandon N,
Long-term survival in primary CNS lymphoma. J Bartkowski HM, Ganapathy S, Staugaitis SM, et vernous malformations (CCMs): evidence for a Bhattacharjee MB (2012). Neuron precursor
Clin Oncol. 16(3):859-63. PMID:9508166 al. (2012). An unusual form of superficially dis- two-hit mechanism of CCM pathogenesis. Hum features of spindle cell oncocytoma of adenohy-
5. Achatz Ml, Olivier M, Le Calvez F, Mar- seminated glioma in children: report of 3 cases. Mol Genet. 18(5):919-30. PMID19088123 pophysis. Ann Clin Lab Sci. 42(2)123-9.
tel-Planche G, Lopes A, Rossi BM, et al. (2007). J Child Neurol. 27(6)727-33. PMID:22596013 34. Akhaddar A, Zrara I, Gazzaz M, El Moust- PMID:22585606
The TP53 mutation, R337H, is associated with 20. Agaram NP, Prakash S, Antonescu CR archid B, Benomar S, Boucetta M (2003). 48. Alexandrescu S, Korshunov A, Lai SH,
Li-Fraumeni and Li-Fraumeni-like syndromes (2005). Deep-seated plexiform schwannoma: a Cerebellar liponeurocytoma (lipomatous me- Dabiri S, Patil S, Li R, et al. (2015). Epithelioid
in Brazilian families. Cancer Lett. 245(1-2):96- pathologic study of 16 cases and comparative dulloblastoma). J Neuroradiol. 30(2)121-6. Glioblastomas and Anaplastic Epithelioid Ple-
102. PMID:16494995 analysis with the superficial variety. Am J Surg PMID12717299 omorphic Xanthoastrocytomas-Same Entity or
6. Acker T, Plate KH (2004). Hypoxia and hy- Pathol. 29(8):1042-8. PMID:16006798 35. Akyurek S, Chang EL, Yu TK, Little D, First Cousins? Brain Pathol. PMID:26238627
poxia inducible factors (HIF) as important regu- 21. Agarwal S, Sharma MC, Sarkar C, Suri V, Allen PK, McCutcheon I, et al. (2006). Spinal 49. Alexiou GA, Moschovi M, Georgoulis G,
lators of tumor physiology. Cancer Treat Res. Jain A, Sharma MS, et al. (2011). Extraventri- myxopapillary ependymoma outcomes in pati- Neroutsou R, Stefanaki K, Sfakianos G, et al.
117:219-48. PMID:15015563 cular neurocytomas: a morphological and his- ents treated with surgery and radiotherapy at (2010). Anaplastic oligodendrogliomas after
7. Actor B, Cobbers JM, Biischges R, Wolter togenetic consideration. A study of six cases. M.D. Anderson Cancer Center. J Neurooncol. treatment of acute lymphoblastic leukemia in
M, Knobbe CB, Lichter P, et al. (2002). Com- Pathology. 43(4):327-34. PMID:21532524 80(2)177-83. PMID16648988 children: report of 2 cases. J Neurosurg Pediatr.
prehensive analysis of genomic alterations in 22. Agarwal S, Sharma MC, Singh G, Suri V, 36. Al-Hussaini M, Abuirmeileh N, Swaidan M, 5(2)179-83. PMID:20121367
gliosarcoma and its two tissue components. Sarkar C, Garg A, et al. (2012). Papillary gli- Al-Jumaily U, Rajjal H, Musharbash A, et al. 50. Alexiou GA, Stefanaki K, Vartholomatos
Genes Chromosomes Cancer. 34(4):416-27. oneuronal tumor-a rare entity: report of four (2011). Embryonal tumor with abundant neuro- G, Sfakianos G, Prodromou N, Moschovi M
PMID:12112531 cases and brief review of literature. Childs Nerv pil and true rosettes: a report of three cases of (2013). Embryonal tumor with abundant neuro-
8. Adair JE, Johnston SK, Mrugala MM, Beard Syst. 28(11):1897-904. PMID:22868530 a rare tumor, with an unusual case showing rh- pil and true rosettes: a systematic literature re-
BC, Guyman LA, Baldock AL, et al. (2014). 23. Aghi MK, Carter BS, Cosgrove GR, Oje- abdomyoblastic and melanocytic differentiation. view and report of 2 new cases. J Child Neurol.
Gene therapy enhances chemotherapy toleran- mann RG, Amin-Hanjani S, Martuza RL, et al. Neuropathology. 31 (6):620-5. PMID:22103481 28(12)1709-15. PMID:23334078
ce and efficacy in glioblastoma patients. J Clin (2009). Long-term recurrence rates of atypical 37. al-Sarraj ST, Parmar D, Dean AF, Phook- 51. Ali JB, Sepp T, Ward S, Green AJ, Yates JR
Invest. 124(9):4082-92. PMID:25105369 meningiomas after gross total resection with un G, Bridges LR (1998). Clinicopathological (1998). Mutations in the TSC1 gene account for
9. Adam C, Polivka M, Carpentier A, George or without postoperative adjuvant radiation. study of seven cases of spinal cord teratoma: a minority of patients with tuberous sclerosis. J
B, Gray F (2007). Papillary glioneuronal tumor: Neurosurgery. 64(1 ):56-60, discussion 60. a possible germ cell origin. Histopathology. Med Genet. 35(12):969-72. PMID:9863590
not always a benign tumor? Clin Neuropathol. PMID:19145156 32(1):51-6. PMID:9522216 52. Alimova I, Birks DK, Harris PS, Knipstein
26(3):119-24. PMID:19157003 24. Agozzino L, Ferraraccio F, Accardo M, 38. Alameda F, Lloreta J, Galito E, Roquer J, JA, Venkataraman S, Marquez VE, et al.
10. Adamek D, Sofowora KD, Cwiklinska M, Esposito S, Agozzino M, Cuccurullo L (2006). Serrano S (1998). Meningeal melanocytoma: (2013). Inhibition of EZH2 suppresses self-re-
Herman-Sucharska I, Kwiatkowski S (2013). Morphological and ultrastructural findings of a case report and literature review. Ultrastruct newal and induces radiation sensitivity in atypi-
Embryonal tumor with abundant neuropil and prognostic impact in craniopharyngiomas. Ul- Pathol. 22(4):349-56. PMID:9805360 cal rhabdoid teratoid tumor cells. Neuro Oncol.
true rosettes: an autopsy case-based update trastruct Pathol. 30(3)143-50. PMID16825115 39. Albrecht S, Connelly JH, Bruner JM (1993). 15(2)149-60. PMID:23190500
and review of the literature, Childs Nerv Syst. 25. Agrawal D, Singhal A, Hendson G, Durity Distribution of p53 protein expression in glios- 53. Alkadhi H, Keller M, Brandner S, Yonekawa
29(5):849-54. PMID:23358909 FA (2007). Gyriform differentiation in me- arcomas: an immunohistochemical study. Acta Y, Kollias SS (2001). Neuroimaging of cerebel-
11. Adams S, Teo C, McDonald KL, Zinger dulloblastoma - a radiological predictor of Neuropathol. 85(2):222-6. PMID:8382897 lar liponeurocytoma. Case report. J Neurosurg.
A, Bustamante S, Lim CK, et al. (2014). In- histology. Pediatr Neurosurg. 43(2)142-5. 40. Albrecht S, Goodman JC, Rajagopolan S, 95(2):324-31. PMID11780904
volvement of the kynurenine pathway in PMID17337929 Levy M, Cech DA, Cooley LD (1994). Malignant 54. Alkindy A, Chuzhanova N, Kini U, Cooper
human glioma pathophysiology. PLoS One. 26. Ahlsen G, Gillberg 1C, Lindblom R, Gill- meningioma in Gorlin's syndrome: cytogenetic DN, Upadhyaya M (2012). Genotype-pheno-
9(11):e112945. PMID:25415278 berg C (1994). Tuberous sclerosis in Western and p53 gene analysis. Case report. J Neuro- type associations in neurofibromatosis type 1
12. Adams SA, Hilton DA (2002). Recurrent Sweden. A population study of cases with early surg. 81 (3):466-71. PMID:8057157 (NF1): an increased risk of tumor complications
haemangioblastoma with glial differentiation. childhood onset. Arch Neurol. 51(1)76-81. 41. Albrecht S, Rouah E, Becker LE, Bruner J in patients with NF1 splice-site mutations? Hum
Neuropathol Appl Neurobiol. 28(2):142-6. PMID:8274113 (1991). Transthyretin Immunoreactivity in cho- Genomics. 6:12. PMID:23244495
PMID:11972801 27. Ahmadi R, Stockhammer F, Becker N, Hoh- roid plexus neoplasms and brain metastases. 55. Allen JC, Judkins AR, Rosenblum MK,
13. Adamson TE, Wiestler OD, Kleihues P, len K, Misch M, Christians A, et al. (2012). No Mod Pathol. 4(5):610-4. PMID.1758873 Biegel JA (2006). Atypical teratoid/rhabdoid
Ya§argil MG (1990). Correlation of clinical and prognostic value of IDH1 mutations in a series 42. Albrecht S, von Deimling A, Pietsch T, Gi- tumor evolving from an optic pathway ganglio-
pathological features in surgically treated cra- of 100 WHO grade II astrocytomas. J Neuroon- angaspero F, Brandner S, Kleihues P, et al. glioma: case study. Neuro Oncol. 8(1)79-82.
niopharyngiomas. J Neurosurg. 73(1):12-7. col. 109(1)15-22. PMID:22528790 (1994), Microsatellite analysis of loss of hetero- PMID16443951
PMID:2352012 28. Ahmed KA, Allen PK, Mahajan A, Brown PD, zygosity on chromosomes 9q, 11 p and 17p in 56. Alles JU, Bosslet K, Schachenmayr W
14. Adeleye AO, Okolo CA, Akang EE, Adesina GhiaAJ (2014). Astroblastomas: a Surveillance, medulloblastomas. Neuropathol Appl Neuro- (1986). Hemangioblastoma of the cerebellum-
AM (2012). Cerebral pleomorphic xanthoast- Epidemiology, and End Results (SEER)-based biol. 20(1)74-81. PMID:8208343 an immunocytochemical study. Clin Neuropa-
rocytoma associated with NF1: an updated patterns of care analysis. World Neurosurg. 43. Albright AL, Wisoff JH, Zeltzer P, Boyett J, thol. 5(6):238-41. PMID:3815934
review with a rare atypical case from Africa. 82(1 -2):e291 -7. PMID:24141003 Rorke LB, Stanley P, et al. (1995). Prognostic 57. Alleyne CH Jr, Hunter S, Olson JJ, Barrow
Neurosurg Rev. 35(3):313-9, discussion 319. 29. Ahuja A, Sharma MC, Suri V, Sarkar C, factors in children with supratentorial (non- DL (1998). Lipomatous glioneurocytoma of
PMID:22020543 Sharma BS, Garg A (2011). Pineal anlage tu- pineal) primitive neuroectodermal tumors. A the posterior fossa with divergent differentiati-
15. Adriani KS, Stenvers DJ, Imanse JG (2012). mour - a rare entity with divergent histology. J neurosurgical perspective from the Children’s on: case report. Neurosurgery. 42(3):639-43.
Pearls & oy-sters: Lumbar paraganglioma: can Clin Neurosci. 18(6):811-3. PMID:21435885 Cancer Group. Pediatr Neurosurg. 22(1)1-7. PMID:9526999
you see it in the eyes? Neurology. 78(4):e27-8. 30. Aicardi J (2005). Aicardi syndrome. Brain PMID7888387 58. Allinson KS, O’Donovan DG, Jena R, Cross
356 References
JJ, Santarius TS (2015). Rosette-forming glio- Tatagiba M, Thomas S, Brandis A, et al. (1997). Leptomeningeal dissemination of malignant MGMT methylation analysis of glioblastoma
neuronal tumor with dissemination throughout Proliferation potential and histological features gliomas. Incidence, diagnosis and outco- on the infinium methylation BeadChip identifies
the ventricular system: a case report. Clin Neu- in neurofibromatosis 2-associated and spora- me. Acta Neurochir (Wien). 126(2-4):84-92. two distinct CpG regions associated with gene
ropathol. 34(2):64-9. PMID:25373141 dic meningiomas. J Neurosurg. 87(4):610-4. PMID:8042560 silencing and outcome, yielding a prediction
59. Almefty R, Webber BL, Arnautovic Kl (2006). In PMID:9322850 91. Arivazhagan A, Anandh B, Santosh V, model for comparisons across datasets, tumor
traneural perineurioma of the third cranial ner- 75. Antinheimo J, Haapasalo H, Seppälä M, Chandramoull BA (2008). Pineal parenchy- grades, and CIMP-status. Acta Neuropathol.
ve: occurrence and identification. Case report. J Sainlo M, Carpen 0, Jääskeläinen J (1995). mal tumors-utility of immunohistochemical 124(4):547-60. PMID:22810491
Neurosurg. 104(5):824-7. PMID:16703891 Proliferative potential of sporadic and neuro- markers in prognostication. Clin Neuropathol. 106. Baehring JM, Dickey PS, Bannykh SI
60. Aloman AK, Kelley BJ, Damisah E, Marks fibromatosis 2-associated schwannomas as 27(5):325-33. PMID:18808064 (2004). Epithelioid hemangioendothelioma
A, Hul P, DiLuna M, et al. (2015). Cranio- studied by MIB-1 (Ki-67) and PCNA labeling. 92. Arnold MA, Stallings-Archer K, Marlin E, of the suprasellar area: a case report and re-
pharyngioma arising in a Rathke’s cleft cyst: J Neuropathol Exp Neurol. 54(6):776-82. Grondin R, Olshefski R, Blegel JA, et al. (2013). view of the literature. Arch Pathol Lab Med.
case report, J Neurosurg Pediatr. 15(3):250-4. PMID:7595650 Cribriform neuroepithelial tumor arising in the 128( 11 ): 1289-93. PMID:15504067
PMID:25555112 76. Antinheimo J, Sankila R, Carpen O, Puk- lateral ventricle. Pediatr Dev Pathol. 16(4):301- 107. Bailey P, Buey PC (1929). Oligodendroglio-
61. Alpers CE, Davis RL, Wilson CB (1982). kala E, Sainio M, Jääskeläinen J (2000). Po- 7. PMID:23495723 mas of the brain. J Path Bact. 32:735-51.
Persistence and late malignant transforma- pulation-based analysis of sporadic and type 93. Aronica E, Boer K, Becker A, Redeker S, 108. Bailey P, Cushing H (1926). A classification
tion of childhood cerebellar astrocytoma. 2 neurofibromatosis-associated meningiomas Spliet WG, van Rijen PC, et al. (2008). Gene of tumors of the glioma group on a hlstogenetic
Case report. J Neurosurg. 57(4):548-51. and schwannomas. Neurology. 54(1):71-6. expression profile analysis of epilepsy-associa- basis with a correlation study of prognosis. Phi-
PMID:7108605 PMID:10636128 ted gangliogliomas. Neuroscience. 151(1):272- ladelphia: Lippincott.
62. Altinoz MA, Santaguida C, Gulot MC, Del 77. Anton T, Guttierez J, Rock J (2006). Ten- 92. PMID:18093740 109. Bailey P, Cushing H (1926). Classification
Maestro RF (2005). Spinal hemangioblastoma torial schwannoma: a case report and review 94. Aronica E, Leenstra S, van Veelen CW, of the Tumors of the Glioma Group. Philadelph-
containing metastatic renal cell carcinoma in of the literature. J Neurooncol. 76(3):307-11. van Rijen PC, Hulsebos TJ, Tersmette AC, et ia: Lippincott.
von Hippel-Lindau disease. Case report and PMID:16200344 al. (2001). Glioneuronal tumors and medically 110. Bainbrldge MN, Armstrong GN, Gramat-
review of the literature. J Neurosurg Spine. 78. Antonelli M, Korshunov A, Mastronuzzi A, intractable epilepsy: a clinical study with long- ges MM, Bertuch AA, Jhangianl SN, Dodda-
3(6):495-500. PMID:16381215 Dlomedi Camassel F, Carai A, Colafati GS, term follow-up of seizure outcome after surgery. paneni H, et al.; Gliogene Consortium (2015).
63. Altundag MK, Oziçik Y, Yalcln S, Akyol F, et al. (2015). Long-term survival in a case of Epilepsy Res. 43(3):179-91. PMID:11248530 Germline mutations in shelterin complex genes
Uner A (2000). Primary low grade В-cell lym- ETANTR with histological features of neuron- 94A. Arvela E, Söderström M, Korhonen M, are associated with familial glioma. J Natl Can-
phoma of the dura in an immunocompetent al maturation after therapy. Virchows Arch. Halmesmäki К, Albäck A, Lepäntalo M, et al. cer inst. 107(1 ):384. PMID:25482530
patient. J Exp Clin Cancer Res. 19(2):249-51. 466(5):603-7. PMID:25697539 (2010). Finnvasc score and modified Prevent 111. Baisden BL, Brat DJ, Melhem ER, Rosen-
PMID:10965827 79. Antonescu CR (2006). The role of genetic III score predict long-term outcome after inf- blum MK, King AP, Burger PC (2001). Dysem-
64. Amano K, Kubo O, Komori T, Tanaka M, Ka- testing in soft tissue sarcoma. Histopathology. ralnguinal surgical and endovascular revas- bryoplastic neuroepithelial tumor-like neoplasm
wamata T, Horl T, et al. (2013). Clinicopatholo- 48(1 ):13-21. PMID:16359533 cularization for critical limb ischemia.J Vase of the septum pellucidum: a lesion often misdi-
gical features of sellar region xanthogranuloma: 80. Antonescu CR, Le Loarer F, Mosquera JM, Surg52(5):1218-25. PMID:20709482 agnosed as glioma: report of 10 cases. Am J
correlation with Rathke's cleft cyst. Brain Tumor Sboner A, Zhang L, Chen CL, et al. (2013). 95. Asha U, Mahadevan A, Sathiyabama D, Ra- Surg Pathol. 25(4):494-9. PMID:11257624
Pathol. 30(4):233-41. PMID:23322180 Novel YAP1-TFE3 fusion defines a distinct vindra T, Sagar BK, Bhat DI, et al. (2015). Lack 112. Baker KB, Moran CJ, Wlppold FJ 2nd,
65. Amemiya S, Shibahara J, Aokl S, Takao H, subset of epithelioid hemangioendothelioma. of IDH1 mutation in astroblastomas suggests Smimiotopoulos JG, Rodriguez FJ, Meyers SP,
Ohtomo К (2008). Recently established entities Genes Chromosomes Cancer. 52(8):775-84. putative origin from ependymoglial cells? Neu- et al. (2000). MR imaging of spinal hemangiob-
of central nervous system tumors: review of PMID:23737213 ropathology. 35(4):303-11. PMID:25786545 lastoma. AJRAmJ Roentgenol. 174(2):377-82.
radiological findings. J Comput Assist Tomogr. 81. Antonescu CR, Suurmeijer AJ, Zhang L, 96. Astrinidis A, Henske EP (2005). Tuberous PMID:10658709
32(2):279-85. PMID:18379318 Sung YS, Jungbluth AA, Travis WD, et al. sclerosis complex: linking growth and energy 113. Bakry D, Aronson M, Durno C, Rlmawi
66. Amirlan ES, Goodman JC, New P, Scheurer (2015). Molecular characterization of inflam- signaling pathways with human disease. Onco- H, Farah R, Alharbi QK, et al. (2014). Genetic
ME (2014). Pediatric and adult malignant peri- matory myofibroblastic tumors with frequent gene. 24(50):7475-81. PMID:16288294 and clinical determinants of constitutional mis-
pheral nerve sheath tumors: an analysis of data ALK and ROS1 gene fusions and rare no- 96A. Athar M, Li C, Kim AL, Spiegelman VS, match repair deficiency syndrome: report from
from the surveillance, epidemiology, and end vel RET rearrangement. Am J Surg Pathol. Bickers DR (2014). Sonic hedgehog signaling the constitutional mismatch repair deficien-
results program. J Neurooncol. 116(3):609-16. 39(7):957-67. PMID:25723109 in basal cell nevus syndrome. Cancer Res. cy consortium. Eur J Cancer. 50(5):987-96.
PMID:24390465 82. Antonescu CR, Woodruff JM (2006). Pri- 74(18):4967-75. PMID:25172843 PMID:24440087
67. Amlashi SF, Riffaud L, Brassier G, Morandi mary Tumors and Cranial, Spinal and Periphe- 97. Au KS, Williams AT, Roach ES, Batchelor 114. Bakshi R, Shaikh ZA, Kamran S, Kinkel PR
X (2003). Nevoid basal cell carcinoma syndro- ral Nerves. In: McLendon RE, Rosenblum MK, L, Sparagana SP, Delgado MR, et al. (2007). (1999). MRI findings in 32 consecutive lipomas
me: relation with desmoplastic medulloblasto- Bigner DD, editors. Russel and Rubinstein’s Pa- Genotype/phenotype correlation in 325 indi- using conventional and advanced sequences. J
ma in infancy. A population-based study and thology of the Nervous System. Hoder Arnold; viduals referred for a diagnosis of tuberous Neuroimaging. 9(3):134^40. PMID:10436754
review of the literature. Cancer. 98(3):618-24. pp. 787-835. sclerosis complex in the United States. Genet 115. Baldini F, Baiocchlni A, Schlninà V, Agra-
PMID: 12879481 83. Aoki Y, Nilhorl T, Narumi Y, Kure S, Mat- Med. 9(2):88-100. PMID:17304050 ti C, Giancola ML, Alba L, et al. (2013). Brain
68. Anan M, inoue R, ishli K, Abe T, Fujlki M, subara Y (2008). The FtAS/MAPK syndromes: 98. Awaya H, Kaneko M, Amatya VJ, Takes- localization of Kaposi's sarcoma in a patient tre-
Kobayashi H, et al. (2009). A rosette-forming novel roles of the RAS pathway in human ge- hima Y, Oka S, inai К (2003). Myxopapillary ated by combination antiretroviral therapy. BMC
glioneuronal tumor of the spinal cord: the first netic disorders. Hum Mutât. 29(8):992-1006. ependymoma with anaplastic features. Pathol infect Dis. 13:600. PMID:24359263
case of a rosette-forming glioneuronal tumor PMID:18470943 int. 53(10):700-3. PMID:14516321 116. Balik V, Srovnal J, Sulla I, Kalita O, Folta-
originating from the spinal cord. Hum Pathol. 84. Aoyama I, Kondo A, Ogawa H, Ikai Y (1994). 99. Aydin F, Ghatak NR, Salvant J, Muizelaar nova T, Vaverka M, et al. (2013). MEG3: a novel
40(6):898-901. PMID:19269010 Germinoma in siblings: case reports. Surg Neu- P (1993). Desmoplastic cerebral astrocytoma of long noncoding potentially tumour-suppressing
69. Anan M, ishii K, Nakamura T, Yamashita M, rol. 41(4):313-7. PMID:8165502 infancy. A case report with immunohistochemi- RNA in meningiomas. J Neurooncol. 112(1):1-
Katayama S, Salnoo M, et al. (2006). Postope- 85. Appin CL, Gao J, Chisolm C, Torian M, Alexis cal, ultrastructural and proliferation studies. Acta 8. PMID:23307326
rative adjuvant treatment for pineal parenchy- D, Vincentelli C, et al. (2013). Glioblastoma with Neuropathol. 86(6):666-70. PMID:7906073 117. Balmaceda CM, Fetell MR, O'Brien JL,
mal tumour of intermediate differentiation. J Clin oligodendroglioma component (GBM-O): mole- 100. Aziz M, Chaurasia JK, Khan R, Afroz N Housepian EH (1993). Nevus of Ota and lep-
Neurosci. 13(9):965-8. PMID:16904896 cular genetic and clinical characteristics. Brain (2014). Primary low-grade diffuse small lympho- tomeningeal melanocytic lesions. Neurology.
70. Andoniadou CL, Gaston-Massuet C, Reddy Pathol. 23(4):454-61. PMID:23289977 cytic lymphoma of the central nervous system. 43(2):381-6. PMID:8437707
R, Schneider RP, Blasco MA, Le Tlssier P, et al. 86. Aquilina К, Kamel M, Kallmuthu SG, Marks BMJ Case Rep. 2014:2014. PMID:24729110 118. Balss J, Meyer J, Mueller W, Korshunov
(2012). Identification of novel pathways invol- JC, Keohane C (2006). Granular cell tumour of 101. Azzarelll B, Rekate HL, Roessmann A, Hartmann C, von Deimling A (2008). Ana-
ved in the pathogenesis of human adamantino- the neurohypophysis: a rare sellar tumour with U (1977). Subependymoma: a case report lysis of the IDH1 codon 132 mutation in brain
matous craniopharyngioma. Acta Neuropathol. specific radiological and operative features. Br J with ultrastructural study. Acta Neuropathol. tumors. Acta Neuropathol. 116(6):597-602.
124(2):259-71. PMID:22349813 Neurosurg. 20(1):51-4. PMID:16698612 40(3):279-82. PMID:203160 PMID:18985363
71. Andreasson A, Kiss NB, Caramuta S, Su- 87. Aquilina K, Nanra JS, Allcutt DA, Farrell M 102. Baccl C, Sestini R, ProvenzanoA, Paganin 118A. Bandopadhayay P, Ramkissoon LA, Jain
lalman L, Svahn F, Bäckdahl M, et al. (2013). (2005). Choroid plexus adenoma: case report i I, Mancinl I, Porfirio B, et al. (2010). Schwan- P, Bergthold G, Wala J, Zeid R, et al. (2016).
The VHL gene is epigenetically inactivated and review of the literature. Childs Nerv Syst. nomatosls associated with multiple meningi- MYB-QKI rearrangements in angiocentric glioma
in pheochromocytomas and abdominal pa- 21(5):410-5. PMID:15565450 omas due to a familial SMARCB1 mutation. drive tumorigenicity through a tripartite mecha-
ragangliomas. Eplgenetics. 8(12):1347-54. 88. Arai H, Ikota H, Sugawara K, Nobusawa Neurogenetics. 11(1)73-80. PMID:19582488 nism. Nat Genet. 48(3): 273-82. PMID:26829751
PMID:24149047 S, Hirato J, Nakazato Y (2012). Nestln expres- 103. Badalian-Very G, Vergilio JA, Degar BA, 119. Banerjee AK, Sharma BS, Kak VK, Ghatak
72. Andreiuolo F, Puget S, Peyre M, Dan- sion in brain tumors: its utility for pathological MacConaill LE, Brandner B, Calicchlo ML, et al. NR (1989). Gliosarcoma with cartilage formati-
tas-Barbosa C, Boddaert N, Philippe C, et al. diagnosis and correlation with the prognosis (2010). Recurrent BRAF mutations in Langer- on. Cancer. 63(3):518-23. PMID:2643455
(2010). Neuronal differentiation distinguishes of high-grade gliomas. Brain Tumor Pathol. hans cell histiocytosis. Blood. 116(11):1919-23. 120. Bannykh S, Strugar J, Baehring J (2005).
supratentorial and infratentorial childhood 29(3):160-7. PMID:22350668 PMID:20519626 Paraganglioma of the lumbar spinal canal. J
ependymomas. Neuro Oncol. 12(11):1126-34. 89. Arita H, Narita Y, Fukushima S, Tateishi K, 104. Badiali M, Glelze V, Paris S, Moi L, Elhoua- Neurooncol. 75(2):119. PMID:16283440
PMID:20615923 Matsushita Y, Yoshlda A, et al. (2013). Upregu- dani S, Arcella A, et al. (2012). Kl AA1549-BRAF 121. Bannykh SI, Stolt CC, Kim J, Perry A,
73. Anghileri E, Eoli M, Paterra R, Ferroli P, Pol- lating mutations in the TERT promoter com- fusions and IDH mutations can coexist in diffu- Wegner M (2006). Oligodendroglial-specific
io B, Cuccarlni V, et al. (2012). FABP4 is a can- monly occur in adult malignant gliomas and are se gliomas of adults. Brain Pathol. 22(6):841-7. transcriptional factor SOX10 is ubiquitously
didate marker of cerebellar llponeurocytomas. strongly associated with total 1p19q loss. Acta PMID:22591444 expressed in human gliomas. J Neurooncol.
J Neurooncol. 108(3):513-9. PMID:22476608 Neuropathol. 126(2):267-76. PMID:23764841 105. Bady P, Sciusclo D, Diserens AC, Bloch 76(2):115-27. PMID:16205963
74. Antinhelmo J, Haapasalo H, Haltla M, 90. Arita N, Taneda M, Hayakawa T (1994). J, van den Bent MJ, Marosi C, et al. (2012). 122. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q,
References 357
Hjelmeland AB, et al. (2006). Glioma stem cells 139. Bastian BC (2014). The molecular pa- Brain Pathol. 20(2):441-50. PMID49725831 Invasion patterns in brain metastases of so-
promote radioresistance by preferential acti- thology of melanoma: an integrated taxonomy 158. Beier D, Hau P, Proescholdt M, Lohmei- lid cancers. Neuro Oncol. 15(12)4 664-72.
vation of the DNA damage response. Nature. of melanocytic neoplasia. Annu Rev Pathol. er A, Wischhusen J, Oefner PJ, et al. (2007). PMID:24084410
444(7120):756-60. PMID:17051156 9:239-71. PMID:24460190 CD133(+) and CD133(-) glioblastoma-derived 173. Berho M, Suster S (1994). Mucinous
123. Bar EE, Lin A, Tihan T, Burger PC, Eber- 140. Batchelor T, Loeffler JS (2006). Primary cancer stem cells show differential growth cha- meningioma. Report of an unusual variant of
hart CG (2008). Frequent gains at chromosome CNS lymphoma. J Clin Oncol. 24(8)4281-8. racteristics and molecular profiles. Cancer Res. meningioma that may mimic metastatic mu-
7q34 involving BRAF in pilocytic astrocytoma. PMID46525183 67(9):4010-5. PMID47483311 cin-producing carcinoma. Am J Surg Pathol.
J Neuropathol Exp Neurol. 67(9):878-87. 141. Batchelor TT, Reardon DA, de Groot JF, 159. Bell DA, Woodruff JM, Scully RE (1984). 18(1)400-6. PMID:8279622
PMID:18716556 Wick W, Weller M (2014). Antiangiogenic the- Ependymoma of the broad ligament. A report 174. Beristain X, Azzarelli B (2002). The
124. Baraniskin A, Kuhnhenn J, Schlegel U, rapy for glioblastoma: current status and future of two cases. Am J Surg Pathol. 8(3):203-9. neurological masquerade of intravascular
Chan A, Decked M, Gold R, etal. (2011). Identi- prospects. Clin Cancer Res. 20(22):5612-9. PMID:6703196 lymphomatosis. Arch Neurol. 59(3)439-43.
fication of microRNAs in the cerebrospinal fluid PMID:25398844 159A. Bell RJ, Rube HT, Kreig A, Mancini A, PMID41890850
as marker for primary diffuse large B-cell lym- 142. Batora NV, Sturm D, Jones DT, Kool M, Fouse SD, Nagarajan RP, et al. (2015). Can- 175. Berkman RA, Clark WC, Saxena A, Ro-
phoma of the central nervous system. Blood. Pfister SM, Northcott PA (2014). Transitioning cer. The transcription factor GABP selectively bertson JT, Oldfield EH, Ali IU (1992). Clonal
117(11):3140-6. PMID:21200023 from genotypes to epigenotypes: why the time binds and activates the mutant TERT promo- composition of glioblastoma multiforme. J Neu-
125. Baraniskin A, Kuhnhenn J, Schlegel U, has come for medulloblastoma epigenomics. ter in cancer. Science. 348(6238)4036-9. rosurg. 77(3)432-7. PMID4324297
Schmiegel W, Hahn S, Schroers R (2012). Neuroscience. 264:171-85. PMID:23876321 PMID:25977370 176. Bemell WR, Kepes JJ, Seitz EP (1972).
MicroRNAs in cerebrospinal fluid as biomarker 143. Batzdorf U, Malamud N (1963). The pro- 160. Bellail AC, Hunter SB, Brat DJ, Tan C, Van Late malignant recurrence of childhood cere-
for disease course monitoring in primary cen- blem of multicentric gliomas. J Neurosurg. Meir EG (2004). Microregional extracellular ma- bellar astrocytoma. Report of two cases. J Neu-
tral nervous system lymphoma. J Neurooncol. 20:122-36. PMID44192080 trix heterogeneity in brain modulates glioma cell rosurg. 37(4)470-4. PMID:5070873
109(2):239-44. PMID:22729947 144. Bauman GS, Wara WM, Ciricillo SF, Da- invasion. Int J Biochem Cell Biol. 36(6)4046- 177. Berns S, Pearl G (2006). Review of pineal
126. Barker FG 2nd, Davis RL, Chang SM, vis RL, Zoger S, Edwards MS (1997). Primary 69. PMID45094120 anlage tumor with divergent histology. Arch Pa-
Prados MD (1996). Necrosis as a prognostic intracerebral osteosarcoma: a case report. J 161. Bello MJ, Leone PE, Vaquero J, de Cam- thol Lab Med. 130(8)4233-5. PMID46879032
factor in glioblastoma multiforme. Cancer. Neurooncol. 32(3):209-13. PMID:9049882 pos JM, Kusak ME, Sarasa JL, et al. (1995). 178. Bernthal NM, Jones KB, Monument MJ,
77(6):1161-6. PMID:8635139 145. Baumert BG, Rutten I, Dehing-Oberije C, Allelic loss at 1p and 19q frequently occurs in Liu T, Viskochil D, Randall RL (2013). Lost in
127. Barkovich AJ, Guerrini R, Kuzniecky Rl, Twijnstra A, Dirx MJ, Debougnoux-Huppertz association and may represent early oncogenic translation: ambiguity in nerve sheath tumor
Jackson GD, Dobyns WB (2012). A develop- RM, et al. (2006). A pathology-based substra- events in oligodendroglial tumors. Int J Cancer. nomenclature and its resultant treatment effect.
mental and genetic classification for malfor- te for target definition in radiosurgery of brain 64(3):207-10. PMID7622310 Cancers (Basel). 5(2):519-28. PMID:24216989
mations of cortical development: update 2012, metastases. Int J Radiat Oncol Biol Phys. 162. Bello MJ, Rey JA, de Campos JM, Ku- 179. Bernthal NM, Putnam A, Jones KB, Vis-
Brain. 135(Pt 5):1348-69. PMID:22427329 66(1)487-94. PMID46814946 sak ME (1993). Chromosomal abnormalities kochil D, Randall RL (2014). The effect of
128. Barnard RO, Geddes JF (1987). The inci- 146. Baumgarten P, Harter PN, Tonjes M, Cap- in a pineocytoma. Cancer Genet Cytogenet. surgical margins on outcomes for low grade
dence of multifocal cerebral gliomas. A histolo- per D, Blank AE, Sahm F, etal. (2014). Loss of 71(2)485-6. PMID:8281527 MPNSTs and atypical neurofibroma. J Surg On-
gic study of large hemisphere sections. Cancer. FUBP1 expression in gliomas predicts FUBP1 163. Belloni E, Muenke M, Roessler E, Traver- col. 110(7):813-6. PMID:25111615
60(7):1519-31. PMID:3113716 mutation and is associated with oligodendroglial so G, Siegel-Bartelt J, Frumkin A, et al. (1996). 180. Beschorner R, Pantazis G, Jeibmann
129. Barnard ZR, Agarwalla PK, Jeyaretna differentiation, IDH1 mutation and 1p/19q loss Identification of Sonic hedgehog as a candidate A, Boy J, Meyermann R, Mittelbronn M, et al.
DS, Farrell CJ, Gerstner ER, Tian D, et al. of heterozygosity. Neuropathol Appl Neurobiol. gene responsible for holoprosencephaly. Nat (2009). Expression of EAAT-1 distinguishes
(2011). Sporadic primary malignant intrace- 40(2):205-16. PMID:24117486 Genet. 14(3):353-6. PMID:8896571 choroid plexus tumors from normal and reactive
rebral nerve sheath tumors: case report and 147. Baysal BE (2002). Hereditary paragangli- 164. Benesch M, Frappaz D, Massimino M choroid plexus epithelium. Acta Neuropathol.
literature review. J Neurooncol. 104(2):605-10. oma targets diverse paraganglia. J Med Genet. (2012). Spinal cord ependymomas in chil- 117(6):667-75. PMID49283393
PMID:21327709 39(9):617-22. PMID42205103 dren and adolescents. Childs Nerv Syst. 181. Bethke L, Murray A, Webb E, Schoemaker
130. Barnholtz-Sloan JS, Sloan AE, Davis FG, 148. Beaumont TL, Kupsky WJ, Barger GR, 28(12):2017-28. PMID:22961356 M, Muir K, McKinney P, et al. (2008). Compre-
Vigneau FD, Lai P, Sawaya RE (2004). Inciden- Sloan AE (2007). Gliosarcoma with multiple ex- 165. Beni-Adani L, Gomori M, Spektor S, hensive analysis of DNA repair gene variants
ce proportions of brain metastases in patients tracranial metastases: case report and review Constantini S (2000). Cyst wall enhancement and risk of meningioma. J Natl Cancer Inst.
diagnosed (1973 to 2001) in the Metropolitan of the literature. J Neurooncol. 83(1):39-46. in pilocytic astrocytoma: neoplastic or reactive 100(4):270-6. PMID48270339
Detroit Cancer Surveillance System. J Clin On- PMID47171442 phenomena. Pediatr Neurosurg. 32(5):234-9. 182. Bettegowda C, Adogwa O, Mehta V,
col. 22(14):2865-72. PMID:15254054 149. Becher MW, Abel TW, Thompson RC, PMID40965269 Chaichana KL, Weingart J, Carson BS, et al.
131. Barrande G, Kujas M, Gancel A, Turpin Weaver KD, Davis LE (2006). Immunohisto- 166. Benites Filho PR, Sakamoto D, Machuca (2012). Treatment of choroid plexus tumors: a
G, Bruckert E, Kuhn JM, et al. (1995). [Gra- chemical analysis of metastatic neoplasms of TN, Serapiao MJ, Ditzel L, Bleggi Torres LF 20-year single institutional experience. J Neu-
nular cell tumors. Rare tumors of the neu- the central nervous system. J Neuropathol Exp (2005). Granular cell tumor of the neurohy- rosurg Pediatr. 10(5):398^405. PMID:22938081
rohypophysis]. Presse Med. 24(30):1376-80. Neurol. 65(10):935-44. PMID:17021398 pophysis: report of a case with unusual age 183. Bettegowda C, Agrawal N, Jiao Y, Sausen
PMID:8545314 150. Bechet D, Gielen GG, Korshunov A, Pfister presentation. Virchows Arch. 447(3):649-52. M, Wood LD, Hruban RH, et al. (2011). Muta-
132. Barresi V, Cerasoli S, Morigi F, Cremonini SM, Rousso C, Faury D, et al. (2014). Specific PMID46133355 tions in CIC and FUBP1 contribute to human oli-
AM, Volpini M, Tuccari G (2006). Gliosarcoma detection of methionine 27 mutation in histo- 167. Bennett JP Jr, Rubinstein LJ (1984). The godendroglioma. Science. 333(6048)4453-5.
with features of osteoblastic osteosarcoma: a ne 3 variants (H3K27M) in fixed tissue from biological behavior of primary cerebral neurob- PMID:21817013
review. Arch Pathol Lab Med. 130(8)4208-11. high-grade astrocytomas. Acta Neuropathol. lastoma: a reappraisal of the clinical course in 184. Bettegowda C, Agrawal N, Jiao Y, Wang
PMID:16879025 128(5)733-41. PMID:25200321 a series of 70 cases. Ann Neurol. 16(1):21-7. Y, Wood LD, Rodriguez FJ, et al. (2013). Exo-
133. Barresi V, Vitarelli E, Branca G, Antonelli 151. Beck DJK, Russell DS (1942). Oligo- PMID:6431897 mic sequencing of four rare central nervous
M, Giangaspero F, Barresi G (2012). Expressi- dendrogliomatosis of the cerebrospinal pa- 168. Bennett KL, Mester J, Eng C (2010). system tumor types. Oncotarget. 4(4):572-83.
on of brachyury in hemangioblastoma: potential thway. Brain. 352-72. Germline epigenetic regulation of KILLIN in PMID:23592488
use in differential diagnosis. Am J Surg Pathol. 152. Becker DH, Wilson CB (1981). Sympto- Cowden and Cowden-like syndrome. JAMA. 185. Betz BL, Strobeck MW, Reisman DN,
36(7)4052-7. PMID:22446946 matic parasellar granular cell tumors. Neurosur- 304(24):2724-31. PMID:21177507 Knudsen ES, Weissman BE (2002). Re-expres-
134. Barrett AW, Hopper C, Landon G (2002). gery. 8(2)473-80. PMID:6259552 169. Benzagmout M, Karachi C, Mokhtari K, sion of hSNF5/INI1/BAF47 in pediatric tumor
Intra-osseous soft tissue perineurioma of the in- 153. Becker I, Paulus W, Roggendorf W Capelle L (2013). Hemorrhagic papillary glio- cells leads to G1 arrest associated with inducti-
ferior alveolar nerve. Oral Oncol. 38(8)793-6. (1989). Histogenesis of stromal cells in cere- neuronal tumor mimicking cavernoma: two case on of p1 6ink4a and activation of RB. Oncogene.
PMID42570059 bellar hemangioblastomas. An immunohisto- reports. Clin Neurol Neurosurg. 115(2):200-3. 21 (34):5193-203. PMID42149641
135. Bartels U, Hawkins C, Vezina G, Kun L, chemical study. Am J Pathol. 134(2):271-5. PMID:22717600 186. Bhagavathi S, Greiner TC, Kazmi SA, Fu
Souweidane M, Bouffet E (2011). Proceedings PMID:2916647 170. Berghoff AS, Bartsch R, WohrerA, Streu- K, Sanger WG, Chan WC (2008). Extranodal
of the diffuse intrinsic pontine glioma (DIPG) 154. Becker RL, Becker AD, Sobel DF (1995). bel B, BirnerP, Kros JM, etal. (2014). Predictive marginal zone lymphoma of the dura mater with
Toronto Think Tank: advancing basic and trans- Adult medulloblastoma: review of 13 cases with molecular markers in metastases to the central IgH/MALT 1 translocation and review of litera-
lational research and cooperation in DIPG. J emphasis on MRI. Neuroradiology. 37(2)404- nervous system: recent advances and future ture. J Hematop. 1(2)431-7. PMID49669212
Neurooncol. 105(1)419-25. PMID:21901544 8. PMID7760992 avenues. Acta Neuropathol. 128(6):879-91. 187. Bhargava D, Sinha P, Chumas P, Al-Tami-
136. Barzilay Jl, Pazianos AG (1989). Ad- 155. Beert E, Brems H, Daniels B, De We- PMID:25287912 mi Y, Shivane A, Chakrabarty A, et al. (2013).
renocortical carcinoma. Urol Clin North Am. ver I, Van Calenbergh F, Schoenaers J, et al. 171. Berghoff AS, Ilhan-Mutlu A, Dinhof C, Occurrence and distribution of pilomyxoid
16(3):457-68. PMID:2665272 (2011). Atypical neurofibromas in neurofibro- Magerle M, Hackl M, Widhalm G, et al. (2015). astrocytoma. Br J Neurosurg. 27(4)413-8.
137. Baser ME, Friedman JM, Joe H, Shen- matosis type 1 are premalignant tumors. Ge- Differential role of angiogenesis and tumour PMID:23281683
ton A, Wallace AJ, Ramsden RT, et al. (2011). nes Chromosomes Cancer. 50(12)4021-32. cell proliferation in brain metastases according 188. Bhattacharjee MB, Armstrong DD, Vogel
Empirical development of improved diagnostic PMID:21987445 to primary tumour type: analysis of 639 cases. H, Cooley LD (1997). Cytogenetic analysis of
criteria for neurofibromatosis 2. Genet Med. 156. Beert E, Brems H, Renard M, Ferreira Neuropathol Appl Neurobiol. 41(2):e41-55. 120 primary pediatric brain tumors and literature
13(6):576-81. PMID:21451418 JF, Melotte C, Thoelen R, et al. (2012). Bialle- PMID:25256708 review. Cancer Genet Cytogenet. 97(1):39-53.
138. Baser ME, Kuramoto L, Joe H, Friedman lic inactivation of NF1 in a sporadic plexiform 171 A. Berghoff AS, Preusser M (2014). BRAF PMID:9242217
JM, Wallace AJ, Gillespie JE, et al. (2004). Ge- neurofibroma. Genes Chromosomes Cancer. alterations in brain tumours: molecular patho- 189. Bhatti P, Veiga LH, Ronckers CM, Sigurd-
notype-phenotype correlations for nervous sys- 51 (9):852-7. PMID:22585738 logy and therapeutic opportunities. Curr Opin son AJ, Stovall M, Smith SA, et al. (2010). Risk
tem tumors in neurofibromatosis 2: a populati- 157. Behdad A, Perry A (2010). Central nervous Neurol. 27(6):689-96. PMID:25268071 of second primary thyroid cancer after radiothe-
on-based study. Am J Hum Genet. 75(2):231-9. system primitive neuroectodermal tumors: a cli- 172. Berghoff AS, Rajky O, Winkler F, Bartsch rapy for a childhood cancer in a large cohort
PMID45190457 nicopathologic and genetic study of 33 cases. R, Furtner J, Hainfellner JA, et al. (2013). study: an update from the childhood canc er
358 References
survivor study. Radiat Res. 174(6):741-52. Res. 68(19)7838-45. PMID:18829539 223. Blümcke I, Lobach M, Wolf HK, Wiestler 238. Boop FA (2011). Repeat surgery for re-
PMID.21128798 207. Birch BD, Johnson JP, Parsa A, Desai OD (1999). Evidence for developmental pre- sidual ependymoma. J Neurosurg Pediatr.
190. Bianco AdeM, Madeira LV, Rosemberg S, RD, Yoon JT, Lycette CA, et al. (1996). Fre- cursor lesions in epilepsy-associated glioneu- 8(3):244-5, discussion 245. PMID:21882913
Shibata MK (2006). Cortical seeding of a cra- quent type 2 neurofibromatosis gene transcript ronal tumors. Microsc Res Tech. 46(1):53-8. 239. Borges MT, Lillehei KO, Kleinschmidt-De-
niopharyngioma after craniotomy: Case report. mutations in sporadic intramedullary spinal cord PMID40402272 Masters BK (2011). Spindle cell oncocytoma
Surg Neurol. 66(4):437-40, discussion 440. ependymomas. Neurosurgery. 39(1):135-40. 224. Blümcke I, Muller S, Buslei R, Riederer with late recurrence and unique neuroimaging
PMID:17015135 PMID:8805149 BM, Wiestler OD (2004). Microtubule-asso- characteristics due to recurrent subclinical in-
191. Biegel JA (1999). Cytogenetics and mole- 208. Birch JM, Blair V, Kelsey AM, Evans DG, ciated protein-2 immunoreactivity: a useful tratumoral bleeding. J Neurooncol. 101(1)445-
cular genetics of childhood brain tumors. Neuro Harris M, Tricker KJ, et al. (1998). Cancer phe- tool in the differential diagnosis of low-grade 54. PMID:20495848
Oncol. 1(2):139-51. PMID:11550309 notype correlates with constitutional TP53 ge- neuroepithelial tumors. Acta Neuropathol. 240. BoritA, Blackwood W, MairWG (1980). The
192. Biegel JA (2006). Molecular genetics of notype in families with the Li-Fraumeni syndro- 108(2):89-96. PMID45146346 separation of pineocytoma from pineoblastoma.
atypical teratoid/rhabdoid tumor. Neurosurg me. Oncogene. 17(9):1061-8. PMID:9764816 225. Blümcke I, Thom M, Aronica E, Armstrong Cancer. 45(6)4408-18. PMID:6986979
Focus. 20(1):E11. PMID:16459991 209. Bisceglia M, Galliani C, Giannatempo G, DD, Vinters HV, Palmini A, et al. (2011). The 241. Borkowska J, Schwartz RA, Kotulska K,
193. Biegel JA, Busse TM, Weissman BE Lauriola W, Bianco M, D'angelo V, et al. (2011). clinicopathologic spectrum of focal cortical dys- Jozwiak S (2011). Tuberous sclerosis complex:
(2014) . SWI/SNF chromatin remodeling com- Solitary fibrous tumor of the central nervous plasias: a consensus classification proposed by tumors and tumorigenesis. Int J Dermatol.
plexes and cancer. Am J Med Genet C Semin system: a 15-year literature survey of 220 ca- an ad hoc Task Force of the ILAE Diagnostic 50(1)43-20. PMID:21182496
Med Genet. 166C(3):350-66. PMID:25169151 ses (August 1996-July 2011). Adv Anat Pathol. Methods Commission. Epilepsia. 52(1)458-74. 242. Borota OC, Scheie D, Bjerkhagen B, Ja-
194. Biegel JA, Zhou JY, Rorke LB, Stenstrom 18(5):356-92. PMID:21841406 PMID:21219302 cobsen EA, Skullerud K (2006). Gliosarcoma
C, Wainwright LM, Fogelgren B (1999). Germ- 210. Bjornsson J, Scheithauer BW, Okazaki H, 226. Blümcke I, Wiestler OD (2002). Ganglio- with liposarcomatous component, bone infiltra-
line and acquired mutations of INI1 in atypical Leech RW (1985). Intracranial germ cell tumors: gliomas: an intriguing tumor entity associated tion and extracranial growth. Clin Neuropathol.
teratoid and rhabdoid tumors. Cancer Res, pathobiological and immunohistochemical as- with focal epilepsies. J Neuropathol Exp Neurol. 25(4):200-3. PMID46866302
59(1 ):74-9. PMID:9892189 pects of 70 cases. J Neuropathol Exp Neurol. 61 (7):575-84. PMID42125736 243. Borota OC, Scheithauer BW, Fougner
195. Bielle F, Navarro S, Bertrand A, Cornu 44(1 ):32-46. PMID:4038412 227. Bodey B, Bodey B Jr, Siegel SE (1995). SL, Hald JK, Ramm-Pettersen J, Bollers-
P, Mazeron JJ, Jouvet A, et al. (2014). Late 211. Blades DA, Hardy RW, Cohen M (1991). Immunophenotypic characterization of infiltra- lev J (2009). Spindle cell oncocytoma of the
dural relapse of a resected and irradiated Cervical paraganglioma with subsequent in- ting polynuclear and mononuclear cells in child- adenohypophysis: report of a case with marked
pineal parenchymal tumor of intermediate dif- tracranial and intraspinal metastases. Case re- hood brain tumors. Mod Pathol. 8(3):333-8. cellular atypia and recurrence despite adju-
ferentiation. Clin Neuropathol. 33(6):424-7. port. J Neurosurg. 75(2):320-3. PMID:2072174 PMID7617661 vant treatment. Clin Neuropathol. 28(2):91-5.
PMID:24887399 212. Blandino G, Levine AJ, Oren M (1999). 228. Bodi I, Curran O, Selway R, Elwes R, PMID49353839
196. Bielle F, Villa C, Giry M, Bergemer-Fou- Mutant p53 gain of function: differential ef- Burrone J, Laxton R, et al. (2014). Two ca- 244. Borovich B, Doran Y (1986). Recurrence
quetAM, Polivka M, VasiljevicA, et al.; RENOP fects of different p53 mutants on resistance ses of multinodular and vacuolating neuron- of intracranial meningiomas: the role played by
(2015) . Chordoid gliomas of the third ventricle of cultured cells to chemotherapy. Oncogene. al tumour. Acta Neuropathol Commun. 2:7. regional multicentricity. J Neurosurg. 64(1):58-
share TTF-1 expression with organum vasculo- 18(2):477-85. PMID:9927204 PMID:24444358 63. PMID:3941351
sum of the lamina terminalis. Am J Surg Pathol. 213. Blaser SI, Harwood-Nash DC (1996). 229. Bodi I, Selway R, Bannister P, Doey L, 245. Bosman FT, Carneiro F, Hruban RH, The-
39(7):948-56. PMID:25786084 Neuroradiology of pediatric posterior fossa Mullatti N, Elwes R, et al. (2012). Diffuse form ise ND, editors. (2010). WHO Classification of
197. Biernat W, Aguzzi A, Sure U, Grant JW, medulloblastoma. J Neurooncol. 29(1 ):23-34. of dysembryoplastic neuroepithelial tumour: Tumours of the Digestive System. 4th ed. Lyon:
Kleihues P, Hegi ME (1995). Identical muta- PMID:8817413 the histological and immunohistochemical fea- International Agency for Research on Cancer.
tions of the p53 tumor suppressor gene in the 214. Bleeker FE, Atai NA, Lamba S, Jonker A, tures of a distinct entity showing transition to 246. Bostrom J, Meyer-Puttlitz B, Wolter M,
gliomatous and the sarcomatous components Rijkeboer D, Bosch KS, et al. (2010). The prog- dysembryoplastic neuroepithelial tumour and Blaschke B, Weber RG, Lichter P, et al. (2001).
of gliosarcomas suggest a common origin nostic IDH1( R132) mutation is associated with ganglioglioma. Neuropathol Appl Neurobiol. Alterations of the tumor suppressor genes
from glial cells. J Neuropathol Exp Neurol. reduced NADP+-dependent IDH activity in gli- 38(5)411-25. PMID:21988102 CDKN2A (p16(INK4a)), p14(ARF), CDKN2B
54(5):651-6. PMID7666053 oblastoma. Acta Neuropathol. 119(4):487-94. 230. Bodo S, Colas C, Buhard O, Collura A, (p15(INK4b)), and CDKN2C (p18(INK4c)) in
198. Biernat W, Huang H, Yokoo H, Kleihues PMID:20127344 Tinat J, Lavoine N, et al.; European Consor- atypical and anaplastic meningiomas. Am J Pa-
P, Ohgaki H (2004). Predominant expression 215. Bleistein M, Geiger K, Franz K, Stoldt P, tium “Care for CMMRD” (2015). Diagnosis of thol. 159(2):661-9. PMID41485924
of mutant EGFR (EGFRvlll) is rare in primary Schlote W (2000). Transthyretin and transferrin Constitutional Mismatch Repair-Deficiency 247. Bouffard JP, Sandberg GD, Golden JA,
glioblastomas. Brain Pathol. 14(2):131-6. in hemangioblastoma stromal cells. Pathol Res Syndrome Based on Microsatellite Instabili- Rorke LB (2004). Double immunolabeling
PMID:15193025 Pract. 196(10):675-81. PMID:11087054 ty and Lymphocyte Tolerance to Methylating of central nervous system atypical teratoid/
199. Biernat W, Kleihues P, Yonekawa Y, Oh- 216. Blesa D, Mollejo M, Ruano Y, de Lope AR, Agents. Gastroenterology. 149(4)4017-1029. rhabdoid tumors. Mod Pathol. 17(6):679-83.
gaki H (1997). Amplification and overexpres- Fiano C, Ribalta T, et al. (2009). Novel genomic e3. PMID:26116798 PMID4 5105808
sion of MDM2 in primary (de novo) glioblasto- alterations and mechanisms associated with 231. Boehm D, Bacher J, Neumann HP (2007). 248. Bouffet E, Perilongo G, Canete A, Mas-
mas. J Neuropathol Exp Neurol. 56(2):180-5. tumor progression in oligodendroglioma and Gross genomic rearrangement involving the simino M (1998). Intracranial ependymomas
PMID:9034372 mixed oligoastrocytoma. J Neuropathol Exp TSC2-PKD1 contiguous deletion syndro- in children: a critical review of prognostic
200. Biernat W, Tohma Y, Yonekawa Y, Klei- Neurol. 68(3):274-85. PMID:19225409 me: characterization of the deletion event by factors and a plea for cooperation. Med Pedi-
hues P, Ohgaki H (1997). Alterations of cell 216A. Blitshteyn S, Crook JE, Jaeckle KA quantitative polymerase chain reaction dele- atr Oncol. 30(6):319-29, discussion 329-31.
cycle regulatory genes in primary (de novo) and (2008). Is there an association between menin- tion assay. Am J Kidney Dis. 49(1 ):e11-21. PMID:9589080
secondary glioblastomas. Acta Neuropathol. gioma and hormone replacement therapy? J PMID47185137 249. Bourdeaut F, Lequin D, Brugieres L, Reyn-
94(4):303-9. PMID:9341929 Clin Oncol. 26(2):279-82. PMID:18182668 232. Boerman RH, Anderl K, Herath J, Borell aud S, Dufour C, Doz F, et al. (2011). Frequent
201. Bigelow DC, Eisen MD, Smith PG, Yousem 217. Blough MD, Al-Najjar M, Chesnelong C, T, Johnson N, Schaeffer-Klein J, et al. (1996). hSNF5/INI1 germline mutations in patients with
DM, Levine RS, Jackler RK, et al. (1998). Lipo- Binding CE, Rogers AD, Luchman HA, et al. The glial and mesenchymal elements of glio- rhabdoid tumor. Clin Cancer Res. 17(1):31-8.
mas of the internal auditory canal and cerebel- (2012). DNA hypermethylation and 1p Loss si- sarcomas share similar genetic alterations. PMID:21208904
lopontine angle. Laryngoscope, 108(10):1459- lence NHE-1 in oligodendroglioma. Ann Neurol. J Neuropathol Exp Neurol. 55(9):973-81. 249A. Bourdeaut F, Miquel C, Richer W, Grill
69. PMID:9778284 71(6):845-9. PMID:22718548 PMID:8800093 J, Zerah M, Grison C, et al. (2014). Rubin-
202. Biggs PJ, Garen PD, Powers JM, Garvin 218. Blount JP, Elton S (2001). Spinal lipomas. 233. Bognar L, Balint K, Bardoczy Z (2002). stein-Taybi syndrome predisposing to non-WNT,
AJ (1987). Malignant rhabdoid tumor of the cen- Neurosurg Focus. 10(1):e3. PMID:16749755 Symptomatic osteolipoma of the tuber cinere- non-SHH, group 3 medulloblastoma. Pediatr
tral nervous system. Hum Pathol. 18(4):332-7. 219. Blümcke I, Aronica E, Urbach H, Alexopou- um. Case report. J Neurosurg. 96(2):361-3. Blood Cancer. 61(2):383-6. PMID:24115570
PMID:3030922 los A, Gonzalez-Martinez JA (2014). A neuropa- PMID41838812 250. Bourekas EC, Bell SD, Ladwig NR, Gand-
203. Bigner SH, McLendon RE, Fuchs H, thology-based approach to epilepsy surgery 234. Boguski MS, McCormick F (1993). Pro- he AR, Shilo K, McGregor JM, et al. (2014).
McKeever PE, Friedman HS (1997). Chromo- in brain tumors and proposal for a new termi- teins regulating Ras and its relatives. Nature. Anaplastic papillary glioneuronal tumor with
somal characteristics of childhood brain tu- nology use for long-term epilepsy-associated 366(6456):643-54. PMID:8259209 extraneural metastases. J Neuropathol Exp
mors. Cancer Genet Cytogenet. 97(2):125-34. brain tumors. Acta Neuropathol. 128(1):39-54. 235. Bolcekova A, Nemethova M, Zatkova Neurol. 73(5):474-6. PMID:24709681
PMID:9283596 PMID:24858213 A, Hlinkova K, Pozgayova S, Hlavata A, et al. 251. Bourgeois M, Sainte-Rose C, Lellouch-Tu-
204. Bijlsma EK, Merel P, Bosch DA, Wester- 220. Blumenthal GM, Dennis PA (2008). PTEN (2013). Clustering of mutations in the 5‘ fertile biana A, Malucci C, Brunelle F, Maixner W,
veld A, Delattre O, Thomas G, et al. (1994). hamartoma tumor syndromes. Eur J Hum Ge- of the NF1 gene in Slovakia patients with optic et al. (1999). Surgery of epilepsy associated
Analysis of mutations in the SCH gene in net. 16(11):1289-300. PMID:18781191 pathway glioma. Neoplasma. 60(6):655-65. with focal lesions in childhood. J Neurosurg.
schwannomas. Genes Chromosomes Cancer. 221. Blümcke I, Becker AJ, Normann S, Hans V, PMID:23906300 90(5):833-42. PMID40223448
11(1):7-14. PMID:7529050 Riederer BM, Krajewski S, et al. (2001). Distinct 236. Bonnin JM, Rubinstein LJ (1989). Astrob- 252. Bourn D, Carter SA, Mason S, Gareth D,
205. Bilsky MH, Schefler AC, Sandberg Dl, Dun- expression pattern of microtubule-associated lastomas: a pathological study of 23 tumors, Evans R, Strachan T (1994). Germline muta-
kel IJ, Rosenblum MK (2000). Sclerosing epit- protein-2 in human oligodendrogliomas and with a postoperative follow-up in 13 patients. tions in the neurofibromatosis type 2 tumour
helioid fibrosarcomas involving the neuraxis: re- glial precursor cells. J Neuropathol Exp Neurol. Neurosurgery. 25(1):6-13. PMID:2755581 suppressor gene. Hum Mol Genet. 3(5):813-6.
port of three cases. Neurosurgery. 47(4):956-9, 60(10):984-93. PMID:11589429 237. Booman M, Douwes J, Glas AM, Rie- PMID:8081368
discussion 959-60. PMID:11014436 222. Blümcke I, Giencke K, Wardelmann E, mersma SA, Jordanova ES, Kok K, et al. 253. Bourne TD, Mandell JW, Matsumoto JA,
206. Binning MJ, Niazi T, Pedone CA, Lai B, Beyenburg S, Krai T, Sarioglu N, et al. (1999). (2006). Mechanisms and effects of loss of Jane JA Jr, Lopes MB (2006). Primary dissemi-
Eberhart CG, Kim KJ, et al. (2008). Hepatocyte The CD34 epitope is expressed in neopla- human leukocyte antigen class II expression nated leptomeningeal oligodendroglioma with
growth factor and sonic Hedgehog expression stic and malformative lesions associated with in immune-privileged site-associated B-cell 1p deletion. Case report. J Neurosurg. 105(6)
in cerebellar neural progenitor cells costimulate chronic, focal epilepsies. Acta Neuropathol. lymphoma. Clin Cancer Res. 12(9):2698-705. Suppl:465-9. PMID47184079
medulloblastoma initiation and growth. Cancer 97(5)481-90. PMID:10334485 PMID46675561 254. Bourne TD, Schiff D (2010). Update on
References 359
molecular findings, management and outco- outcome. Am J Surg Pathol. 25(10):1252-60. MM, Proko E, Kocak M, et al. (2007). Clinical Degl’innocenti DR, Moncini D, Spacca B, Gior-
me in low-grade gliomas. Nat Rev Neurol. PMID:11688459 and molecular characteristics of malignant dano F, et al. (2013). Angiocentric glioma: cli-
6(12):695-701. PMID:21045797 270. Brat DJ, Scheithauer BW, Fuller GN, Tihan transformation of low-grade glioma in children. nical, morphological, immunohistochemical and
255. Bouvier C, Bertucci F, Metellus P, Finetti T (2007). Newly codified glial neoplasms of the J Clin Oncol. 25(6):682-9. PMID:17308273 molecular features in three pediatric cases. Clin
P, Maues de Paula A, Forest F, et al. (2013). 2007 WHO Classification of Tumours of the 285. Broniscer A, Tatevossian RG, Sabin ND, Neuropathol. 32(2):107-13. PMID:23073165
ALDH1 is an immunohistochemical diagnostic Central Nervous System: angiocentric glioma, Klimo P Jr, Dalton J, Lee R, et al. (2014). Clini- 301. Buccoliero AM, Castiglione F, Rossi De-
marker for solitary fibrous tumours and hae- pilomyxoid astrocytoma and pituicytoma. Brain cal, radiological, histological and molecular cha- gl’innocenti D, Franchi A, Paglierani M, Sanzo
mangiopericytomas of the meninges emerging Pathol. 17(3):319-24. PMID:17598825 racteristics of paediatric epithelioid glioblasto- M, et al. (2010). Embryonal tumor with abun-
from gene profiling study. Acta Neuropathol 271. Brat DJ, Scheithauer BW, Medina-Flores ma. Neuropathol Appl Neurobiol. 40(3):327-36. dant neuropil and true rosettes: morphologi-
Commun. 1:10. PMID:24252471 R, Rosenblum MK, Burger PC (2002). Infiltra- P MID :24127995 cal, immunohistochemical, ultrastructural and
256. Bouvier C, Metellus P, de Paula AM, Vasil- tive astrocytomas with granular cell features 286. Brown AE, Leibundgut K, Niggli FK, Betts molecular study of a case showing features of
jevic A, Jouvet A, Guyotat J, et al. (2012). Soli- (granular cell astrocytomas): a study of histo- DR (2006). Cytogenetics of pineoblastoma: four medulloepithelioma and areas of mesenchymal
tary fibrous tumors and hemangiopericytomas pathologic features, grading, and outcome. Am new cases and a literature review. Cancer Ge- and epithelial differentiation. Neuropathology.
of the meninges: overlapping pathological fea- J Surg Pathol. 26(6):750-7. PMID:12023579 net Cytogenet. 170(2):175-9. PMID:17011992 30(1 ):84-91. PMID:19563506
tures and common prognostic factors suggest 272. Brat DJ, Scheithauer BW, Staugaitis SM, 287. Brown HG, Burger PC, Olivi A, Sills AK, 302. Buccoliero AM, Franchi A, Castiglio-
the same spectrum of tumors. Brain Pathol. Cortez SC, Brecher K, Burger PC (1998). Third Barditch-Crovo PA, Lee RR (1999). Intracranial ne F, Gheri CF, Mussa F, Giordano F, et al.
22(4):511-21. PMID:22082190 ventricular Chordoid glioma: a distinct clinico- leiomyosarcoma in a patient with AIDS. Neuro- (2009). Subependymal giant cell astrocytoma
257. Bouvier-Labit C, Daniel L, Dufour H, Grisoli pathologic entity. J Neuropathol Exp Neurol. radiology. 41(1):35-9. PMID:9987766 (SEGA): Is it an astrocytoma? Morphological,
F, Figarella-Branger D (2000). Papillary glioneu- 57(3):283-90. PMID:9600220 288. Brown HG, Kepner JL, Perlman EJ, Fried- immunohistochemical and ultrastructural study.
ronal tumour: clinicopathological and biochemi- 273. Brat DJ, Scheithauer BW, Staugaitis SM, man HS, Strother DR, Duffner PK, et al. (2000). Neuropathology. 29(1):25-30. PMID:18564101
cal study of one case with 7-year follow up. Acta Holtzman RN, Morgello S, Burger PC (2000). “Large cell/anaplastic" medulloblastomas: a 303. Buccoliero AM, Giordano F, Mussa F,
Neuropathol. 99(3):321-6. PMID:10663977 Pituicytoma: a distinctive low-grade glioma Pediatric Oncology Group Study. J Neuropathol Taddei A, Genitori L, Taddei GL (2006). Pa-
258. Bowers DC, Gargan L, Kapur P, Reisch JS, of the neurohypophysis. Am J Surg Pathol. Exp Neurol. 59(10):857-65. PMID:11079775 pillary glioneuronal tumor radiologically mimi-
Mulne AF, Shapiro KN, et al. (2003). Study of 24(3):362-8. PMID:10716149 289. Brown JA, Gianino SM, Gutmann DH cking a cavernous hemangioma with hemorr-
the MIB-1 labeling index as a predictor of tumor 273A. Bredel M, Scholtens DM, Yadav AK, (2010). Defective cAMP generation under- hagic onset. Neuropathology. 26(3):206-11.
progression in pilocytic astrocytomas in children Alvarez AA, Renfrow JJ, Chandler JP, et al. lies the sensitivity of CNS neurons to neu- PMID:16771176
and adolescents. J Clin Oncol. 21(15):2968-73. (2011). NFKBIA deletion in glioblastomas. N rofibromatosis-1 heterozygosity. J Neurosci. 304. Buczkowicz P, Bartels U, Bouffet E, Be-
PMID:12885817 Engl J Med. 364(7):627-37. PMID:21175304 30(16):5579-89. PMID:20410111 cher O, Hawkins C (2014). Histopathological
259. Bowers DC, Mulne AF, Weprin B, Bruce 274. Brekke HR, Ribeiro FR, Kolberg M, 290. Brown NA, Furtado LV, Betz BL, Kiel MJ, spectrum of paediatric diffuse intrinsic ponti-
DA, Shapiro K, Margraf LR (2002). Progno- Agesen TH, Lind GE, Eknaes M, et al. (2010). Weigelin HC, Lim MS, et al. (2014). High preva- ne glioma: diagnostic and therapeutic impli-
stic factors in children and adolescents with Genomic changes in chromosomes 10,16, and lence of somatic MAP2K1 mutations in BRAF cations. Acta Neuropathol. 128(4):573-81.
low-grade oligodendrogliomas. Pediatr Neuro- X in malignant peripheral nerve sheath tumors V600E-negative Langerhans cell histiocytosis. PMID:25047029
surg. 37(2):57-63. PMID:12145513 identify a high-risk patient group. J Clin Oncol. Blood. 124(10):1655-8. PMID:24982505 305. Buczkowicz P, Hoeman C, Rakopoulos
260. Boyd C, Smith MJ, Kluwe L, Balogh A, 28(9): 1573-82. PMID:20159821 291. Brown PD, Buckner JC, O’Fallon JR, Iturria P, Pajovic S, Letourneau L, Dzamba M, et al.
Maccollin M, Plotkin SR (2008). Alterations 275. Brems H, Chmara M, Sahbatou M, Denay- NL, Brown CA, O'Neill BP, et al.; North Central (2014). Genomic analysis of diffuse intrinsic
in the SMARCB1 (INI1) tumor suppressor er E, Taniguchi K, Kato R, et al. (2007). Germ- Cancer Treatment Group; Mayo Clinic (2004). pontine gliomas identifies three molecular sub-
gene in familial schwannomatosis. Clin Genet. line loss-of-function mutations in SPRED1 cau- Adult patients with supratentorial pilocytic ast- groups and recurrent activating ACVR1 muta-
74(4):358-66. PMID:18647326 se a neurofibromatosis 1-like phenotype. Nat rocytomas: a prospective multicenter clinical tri- tions. Nat Genet. 46(5):451-6. PMID:24705254
261. Brannan Cl, Perkins AS, Vogel KS, Ratner Genet. 39(9):1120-6. PMID:17704776 al. Int J Radiat Oncol Biol Phys. 58(4):1153-60. 306. Budka H (1974). Intracranial lipomatous
N, Nordlund ML, Reid SW, et al. (1994). Targe- 276. Brennan C (2011). Genomic profiles of gli- PMID:15001258 hamartomas (intracranial “lipomas"). A study
ted disruption of the neurofibromatosis type-1 oma. Curr Neurol Neurosci Rep. 11 (3):291-7. 292. Brown R, Zlatescu M, Sijben A, Roldan of 13 cases including combinations with me-
gene leads to developmental abnormalities in PMID:21465149 G, Easaw J, Forsyth P, et al. (2008). The use dulloblastoma, colloid and epidermoid cysts,
heart and various neural crest-derived tissues. 277. Brennan CW, Verhaak RG, McKenna A, of magnetic resonance imaging to noninvasi- angiomatosis and other malformations. Acta
Genes Dev. 8(9):1019-29. PMID:7926784 Campos B, Noushmehr H, Salama SR, et al.; vely detect genetic signatures in oligodendro- Neuropathol. 28(3):205-22. PMID:4611131
262. Brastianos PK, Horowitz PM, Santagata S, TCGA Research Network (2013). The somatic glioma. Clin Cancer Res. 14(8):2357-62. 307. Budka H (1975). Partially resected and
Jones RT, McKenna A, Getz G, et al. (2013). genomic landscape of glioblastoma. Cell. PMID:18413825 irradiated cerebellar astrocytoma of childhood:
Genomic sequencing of meningiomas identifies 155(2):462-77. PMID:24120142 293. Brownstein MH, Wolf M, Bikowski JB malignant evolution after 28 years. Acta Neu-
oncogenic SMO and AKT1 mutations. Nat Ge- 278. Bridge JA, Liu XQ, Sumegi J, Nelson M, (1978). Cowden’s disease: a cutaneous mar- rochir (Wien). 32(1-2):139-46. PMID:1163315
net. 45(3):285-9. PMID:23334667 Reyes C, Bruch LA, et al. (2013). Identification ker of breast cancer. Cancer. 41(6):2393-8. 308. Budka H, Chimelli L (1994). Lipomatous
263. Brastianos PK, Taylor-Weiner A, Manley of a novel, recurrent SLC44A1-PRKCA fusion PMID:657103 medulloblastoma in adults: a new tumor type
PE, Jones RT, Dias-Santagata D, Thorner in papillary glioneuronal tumor. Brain Pathol. 294. Brugieres L, Remenieras A, Pierron G, with possible favorable prognosis. Hum Pathol.
AR, et al. (2014). Exome sequencing identifies 23(2):121-8. PMID:22725730 Varlet P, Forget S, Byrde V, et al. (2012). High 25(7):730-1. PMID:8026834
BRAF mutations in papillary craniopharyngio- 279. Bridge RS, Rajaram V, Dehner LP, Pfei- frequency of germline SUFU mutations in chil- 309. Bukhtoiarov AP, Zil’berberg LB, Levitski?
mas. Nat Genet. 46(2):161-5. PMID:24413733 fer JD, Perry A (2006). Molecular diagnosis of dren with desmoplastic/nodular medulloblasto- VA (1975). [Evacuation hospitals in Pyatigorsk
264. Brat DJ, Castellano-Sanchez AA, Hunter Ewing sarcoma/primitive neuroectodermal tu- ma younger than 3 years of age. J Clin Oncol. during the Great Patriotic War] . Zdravookhr
SB, Pecot M, Cohen C, Hammond EH, et al. mor in routinely processed tissue: a comparison 30(17):2087-93. PMID:22508808 Ross Fed: 22-3. PMID:131445
(2004). Pseudopalisades in glioblastoma are of two FISH strategies and RT-PCR in malig- 296. Brunn A, Nagel I, Montesinos-Rongen M, 310. Bunin GR, Surawicz TS, Witman PA, Pres-
hypoxic, express extracellular matrix protea- nant round cell tumors. Mod Pathol. 19(1):1-8. Klapper W, Vater I, Paulus W, et al. (2013). ton-Martin S, Davis F, Bruner JM (1998). The
ses, and are formed by an actively migrating PMID:16258512 Frequent triple-hit expression of MYC, BCL2, descriptive epidemiology of craniopharyngio-
cell population. Cancer Res. 64(3):920-7. 280. Briscoe J, Therond PP (2013). The me- and BCL6 in primary lymphoma of the central ma. J Neurosurg. 89(4):547-51. PMID:9761047
PMID:14871821 chanisms of Hedgehog signalling and its roles nervous system and absence of a favorable 311. Burger PC (1996). Pathology of brain stem
265. Brat DJ, Cohen KJ, Sanders JM, Feuer- in development and disease. Nat Rev Mol Cell MYC(low)BCL2 (low) subgroup may underlie astrocytomas. Pediatr Neurosurg. 24(1):35-40.
stein BG, Burger PC (1999). Clinicopathologic Biol. 14(7):416-29. PMID:23719536 the inferior prognosis as compared to systemic PMID:8817613
features of astroblastoma. J Neuropathol Exp 281. Brock JE, Perez-Atayde AR, Kozakewich diffuse large B cell lymphomas. Acta Neuropa- 312. Burger PC (2009). Smears and frozen sec-
Neurol. 58:509. HP, Richkind KE, Fletcher JA, Vargas SO thol. 126(4):603-5. PMID:24061549 tions in surgigal neuropathology. PB Medical
266. Brat DJ, Giannini C, Scheithauer BW, Bur- (2005). Cytogenetic aberrations in perineurio- 297. Bruno A, Boisselier B, Labreche K, Marie Publishing: Baltimore.
ger PC (1999). Primary melanocytic neoplasms ma: variation with subtype. Am J Surg Pathol. Y, Polivka M, Jouvet A, et al. (2014). Mutatio- 313. Burger PC (2012). Paraganglioma of the
of the central nervous systems. Am J Surg Pa- 29(9):1164-9. PMID:16096405 nal analysis of primary central nervous sys- filum terminate. In: Burger PC, Scheithauer BW,
thol. 23(7):745-54. PMID:10403296 282. Brodbelt A, Greenberg D, Winters T, Wil- tem lymphoma. Oncotarget. 5(13):5065-75. Kleinschmidt-DeMaster BK, Ersen A, Rodriguez
267. Brat DJ, Hirose Y, Cohen KJ, Feuer- liams M, Vernon S, Collins VP; (UK) National PMID:24970810 FJ, Tihan T, et al., editors. Diagnostic Patholo-
stein BG, Burger PC (2000). Astroblastoma: Cancer Information Network Brain Tumour 298. Bruck W, Brunn A, Klapper W, Kuhlmann gy, Neuropathology. Salt Lake City: Amysys.
clinicopathologic features and chromosomal Group (2015). Glioblastoma in England: T, Metz I, Paulus W, etal.; Netzwerk Lymphome 314. Burger PC, Grahmann FC, Bliestle A,
abnormalities defined by comparative geno- 2007-2011. Eur J Cancer. 51(4):533-42. und Lymphomatoide Lasionen des Nervensys- Kleihues P (1987). Differentiation in the medul-
mic hybridization. Brain Pathol. 10(3):342-52. PMID:25661102 tems (2013). [Differential diagnosis of lymphoid loblastoma. A histological and immunohistoche-
PMID:10885653 282A. Broderick DK, Di C, Parrett TJ, Samuels infiltrates in the central nervous system: experi- mical study. Acta Neuropathol. 73(2):115-23.
268. Brat DJ, Ryken TC, Kalkanis SN, Olson JJ; YR, Cummins JM, McLendon RE, et al. (2004). ence of the Network Lymphomas and Lympho- PMID:3604579
AANS/CNS Joint Guidelines Committee (2014). Mutations of PIK3CA in anaplastic oligodendro- matoid Lesions in the Nervous System], Patho- 315. Burger PC, Green SB (1987). Patient age,
The role of neuropathology in the management gliomas, high-grade astrocytomas, and me- loge. 34(3):186-97. PMID:23471726 histologic features, and length of survival in
of progressive glioblastoma : a systematic dulloblastomas. Cancer Res. 64(15):5048-50. 299. Buccoliero AM, Bacci S, Mennonna P, patients with glioblastoma multiforme. Cancer.
review and evidence-based clinical practice PMID:15289301 Taddei GL (2004). Pathologic quiz case: in- 59(9):1617-25. PMID:3030531
guideline. J Neurooncol. 118(3):461-78. 283. Broholm H, Madsen FF, Wagner AA, Lau- fratentorial tumor in a middle-aged woman. 316. Burger PC, Heinz ER, Shibata T, Kleihues
PMID:24733643 rsen H (2002). Papillary glioneuronal tumor-a Oncocytic variant of choroid plexus papillo- P (1988). Topographic anatomy and CT correla-
269. Brat DJ, Scheithauer BW, Eberhart new tumor entity. Clin Neuropathol. 21(1):1-4. ma. Arch Pathol Lab Med. 128(12):1448-50. tions in the untreated glioblastoma multiforme.
CG, Burger PC (2001). Extraventricular neu- PMID:11846038 PMID:15578895 J Neurosurg. 68(5):698-704. PMID:2833587
rocytomas: pathologic features and clinical 284. Broniscer A, Baker SJ, West AN, Fraser 300. Buccoliero AM, Castiglione F, 317. Burger PC, Kleihues P (1989). Cytologic
360 References
composition of the untreated glioblastoma with 59(3):229-40. PMID:10744061 348. Campos AR, Clusmann H, von Lehe M, PMID:24929912
implications for evaluation of needle biopsies. 333. Biischges R, Ichimura K, Weber RG, Rei- Niehusmann P, Becker AJ, Schramm J, et al. 363. Carlotti CG Jr, Salhia B, Weitzman S,
Cancer. 63(10):2014-23. PMID:2539242 fenberger G, Collins VP (2002). Allelic gain and (2009). Simple and complex dysembryoplastic Greenberg M, Dirks PB, Mason W, etal. (2002).
318. Burger PC, Pearl DK, Aldape K, Yates AJ, amplification on the long arm of chromosome neuroepithelial tumors (DNT) variants: clinical Evaluation of proliferative index and cell cycle
Scheithauer BW, Passe SM, et at. (2001). Small 17 in anaplastic meningiomas. Brain Pathol. profile, MRI, and histopathology. Neuroradiolo- protein expression in choroid plexus tumors
cell architecture-a histological equivalent of 12(2):145-53. PMID:11958368 gy. 51(7):433-43. PMID:19242688 in children. Acta Neuropathol. 103(1):1-10.
EGFR amplification in glioblastoma multiforme? 334. Buttner A, Marquart KH, Mehraein P, Weis 349. Brat DJ, Verhaak RG, Aldape KD, Yung PMID:11837741
J Neuropathol Exp Neurol. 60(11):1099-104. S (1997). Kaposi’s sarcoma in the cerebel- WK, Salama SR, Cooper LA, et al.; Cancer 364. Carlson GJ, Nivatvongs S, Snover DC
PMID:11706939 lum of a patient with AIDS. Clin Neuropathol. Genome Atlas Research Network (2015). Com- (1984). Colorectal polyps in Cowden’s disease
319. Burger PC, Scheithauer B (2008).Tumors 16(4):185-9. PMID:9266142 prehensive, Integrative Genomic Analysis of (multiple hamartoma syndrome). Am J Surg Pa-
of the Central Nervous System. AFIP Atlas of 335. Bohling T, Hatva E, Kujala M, Claes- Diffuse Lower-Grade Gliomas. N Engl J Med. thol. 8(10)763-70. PM ID :6496844
Tumour Pathology, Series 4, Fascicle 7 Was- son-Welsh L, Alitalo K, Haltia M (1996). Ex- 372(26):2481-98. PMID:26061751 365. Carneiro SS, Scheithauer BW, Nascimen-
hington DC: American Registry of Pathology. pression of growth factors and growth factor 350. Cancer Genome Atlas Research Network to AG, Hirose T, Davis DH (1996). Solitary fi-
320. Burger PC, Scheithauer BW (1994). Tu- receptors in capillary hemangioblastoma. (2008). Comprehensive genomic characteriz- brous tumor of the meninges: a lesion distinct
mors of the Central Nervous System. Washing- J Neuropathol Exp Neurol. 55(5):522-7. ation defines human glioblastoma genes and from fibrous meningioma. A clinicopathologic
ton: Armed Forces Institute of Pathology. PMID:8627342 core pathways. Nature. 455(7216):1061-8. and immunohistochemical study. Am J Clin Pa-
321. Burger PC, Scheithauer BW, Vogel FS 336. Bohling T, Maenpaa A, Timonen T, Van- PMID:18772890 thol. 106(2):217-24. PMID:8712177
(2002). Surgical Pathology of the Nervous tunen L, Paetau A, Haltia M (1996). Different 351. Cannon DM, Mohindra P, Gondi V, Kruser 366. Carney EM, Banerjee P, Ellis CL, Alba-
System and Its Coverings. 4th ed. London: expression of adhesion molecules on stromal TJ, Kozak KR (2015). Choroid plexus tumor dine R, Sharma R, Chaux AM, et al. (2011).
Churchill Livingston. cells and endothelial cells of capillary heman- epidemiology and outcomes: implications for PAX2(-)/PAX8(-)/inhibin A(+) immunoprofile in
322. Burger PC, Vogel FS, Green SB, Strike gioblastoma. Acta Neuropathol. 92(5):461-6. surgical and radiotherapeutic management. J hemangioblastoma: A helpful combination in
TA (1985). Glioblastoma multiforme and ana- PMID:8922057 Neurooncol. 121 (1 ):151-7. PMID:25270349 the differential diagnosis with metastatic clear
plastic astrocytoma. Pathologic criteria and 337. Bohling T, Turunen O, Jaaskelainen J, 352. Cannon TC, Bane BL, Kistler D, Schoen- cell renal cell carcinoma to the central ner-
prognostic implications. Cancer. 56(5): 1106-11. Carpen O, Sainio M, Wahlstrom T, et al. (1996). hals GW, Hahn M, Leech RW, et al. (1998). vous system. Am J Surg Pathol. 35(2):262-7.
PMID:2990664 Ezrin expression in stromal cells of capillary he- Primary intracerebellar osteosarcoma arising PMID:21263247
323. Burger PC, Vollmer RT (1980). Histologic mangioblastoma. An immunohistochemical sur- within an epidermoid cyst. Arch Pathol Lab 367. Carney JA (1990). Psammomatous me-
factors of prognostic significance in the gliob- vey of brain tumors. Am J Pathol. 148(2):367- Med. 122(8):737-9. PMID:9701337 lanotic schwannoma. A distinctive, heritable tu-
lastoma multiforme. Cancer. 46(5):1179-86. 73. PMID:8579099 353. Cao D, Liu A, Wang F, Allan RW, Mei K, mor with special associations, including cardiac
PMID:6260329 338. Cabello A, Madero S, Castresana A, Di- Peng Y, et al. (2011). RNA-binding protein myxoma and the Cushing syndrome. Am J Surg
324. Burger PC, Yu IT, Tihan T, Friedman HS, az-Lobato R (1991). Astroblastoma: electron LIN28 is a marker for primary extragonadal Pathol. 14(3):206-22. PMID:2305928
Strother DR, Kepner JL, et al. (1998). Atypical microscopy and immunohistochemical fin- germ cell tumors: an immunohistochemical 368. Carney JA, Gordon H, Carpenter PC,
teratoid/rhabdoid tumor of the central nervous dings: case report. Surg Neurol. 35(2):116-21. study of 131 cases. Mod Pathol. 24(2):288-96. Shenoy BV, Go VL (1985). The complex of
system: a highly malignant tumor of infancy and PMID:1990478 PMID:21057460 myxomas, spotty pigmentation, and endocrine
childhood frequently mistaken for medullob- 339. Caccamo DV, Ho KL, Garcia JH (1992), 354. Capper D, Berghoff AS, Magerle M, overactivity. Medicine (Baltimore). 64(4):270-
lastoma: a Pediatric Oncology Group study. Am Cauda equina tumor with ependymal and llhan A, Wohrer A, Hackl M, et al. (2012). Im- 83. PMID:4010501
J Surg Pathol. 22(9):1083-92. PMID:9737241 paraganglionic differentiation. Hum Pathol. munohistochemical testing of BRAF V600E 369. Carrasco R, Pascual JM, Navas M, Fra-
325. Burkhard C, Di Patre PL, Schuler D, Schu- 23(7):835-8. PMID:1612583 status in 1,120 tumor tissue samples of pati- ga J, Manzanares-Soler R, Sola RG (2010).
ler G, Ya§argil MG, Yonekawa Y, et al. (2003). 340. Cachia D, Prado MP, Theeler B, Hamilton ents with brain metastases. Acta Neuropathol. Spontaneous acute hemorrhage within a sub-
A population-based study of the incidence J, McCutcheon I, Fuller GN (2014). Synchro- 123(2):223-33. PMID:22012135 ependymoma of the lateral ventricle: successful
and survival rates in patients with pilocytic nous rosette-forming glioneuronal tumor and 355. Capper D, Preusser M, Habel A, Sahm emergent surgical removal through a frontal
astrocytoma. J Neurosurg. 98(6):1170-4. diffuse astrocytoma with molecular charac- F, Ackermann U, Schindler G, et al. (2011). transcortical approach. Neurocirugia (Astur).
PMID:12816259 terization: a case report. Clin Neuropathol. Assessment of BRAF V600E mutation status 21(6):478-83. PMID:21165545
326. Burkitt Wright EM, Sach E, Sharif S, Quar- 33(6):407-11. PMID:24986181 by immunohistochemistry with a mutation-spe- 370. Carstens PH, Johnson GS, Jelsma LF
rell O, Carroll T, Whitehouse RW, et al. (2013). 341. Cady FM, O'Neill BP, Law ME, Decker cific monoclonal antibody. Acta Neuropathol. (1995). Spinal gliosarcoma: a light, immunohis-
Can the diagnosis of NF1 be excluded clini- PA, Kurtz DM, Giannini C, et al. (2008). Del(6) 122(1):11-9. PMID:21638088 tochemical and ultrastructural study. Ann Clin
cally? A lack of pigmentary findings in families (q22) and BCL6 rearrangements in primary 356. Capper D, Reuss D, Schittenhelm J, Hart- Lab Sci. 25(3):241-6. PMID7605106
with spinal neurofibromatosis demonstrates a CNS lymphoma are indicators of an aggressive mann C, Bremer J, Sahm F, etal. (2011). Muta- 371. Carter JM, O’Hara C, Dundas G, Gilchrist
limitation of clinical diagnosis. J Med Genet. clinical course. J Clin Oncol. 26(29):4814-9. tion-specific IDH1 antibody differentiates oli- D, Collins MS, Eaton K, et al. (2012). Epithe-
50(9):606-13. PMID:23812910 PMID:18645192 godendrogliomas and oligoastrocytomas from lioid malignant peripheral nerve sheath tumor
327. Burnett ME, White EC, Sih S, von Haken 342. Cahill DP, Levine KK, Betensky RA, Codd other brain tumors with oligodendroglioma-like arising in a schwannoma, in a patient with
MS, Cogen PH (1997). Chromosome arm 17p PJ, Romany CA, Reavie LB, et al. (2007). Loss morphology. Acta Neuropathol. 121(2):241-52. ■neuroblastoma-like" schwannomatosis and a
deletion analysis reveals molecular genetic he- of the mismatch repair protein MSH6 in human PMID:21069360 novel germline SMARCB1 mutation. Am J Surg
terogeneity in supratentorial and infratentorial glioblastomas is associated with tumor progres- 357. Capper D, Sahm F, Hartmann C, Meyer- Pathol. 36(1):154-60. PMID:22082606
primitive neuroectodermal tumors of the cent- sion during temozolomide treatment. Clin Can- mann R, von Deimling A, Schittenhelm J (2010). 372. Carter M, Nicholson J, Ross F, Crolla J,
ral nervous system. Cancer Genet Cytogenet. cer Res. 13(7):2038-45. PMID:17404084 Application of mutant IDH1 antibody to differen- Allibone R, Balaji V, et al. (2002). Genetic ab-
97(1):25-31. PMID:9242214 343. Cai DX, James CD, Scheithauer BW, tiate diffuse glioma from nonneoplastic central normalities detected in ependymomas by com-
328. Bush K, Bateman DE (2014). Papilloede- Couch FJ, Perry A (2001). PS6K amplificati- nervous system lesions and therapy-induced parative genomic hybridisation. Br J Cancer.
ma secondary to a spinal paraganglioma. Pract on characterizes a small subset of anaplastic changes. Am J Surg Pathol. 34(8): 1199-204. 86(6):929-39. PMID:11953826
Neurol. 14(3):179-81. PMID:23918468 meningiomas. Am J Clin Pathol. 115(2):213-8. PMID:20661018 373. Carvalho AT, Linhares P, Castro L, Sa MJ
329. Buslei R, Nolde M, Hofmann B, Meissner PMID:11211609 358. Capper D, Simon M, Langhans CD, Okun (2014). Multiple sclerosis and oligodendroglio-
S, Eyupoglu IY, Siebzehnriibl F, et al. (2005). 344. Cairncross G, Wang M, Shaw E, Jen- JG, Tonn JC, Weller M, et al.; German Glioma ma: an exceptional association. Case Rep Neu-
Common mutations of beta-catenin in adaman- kins R, Brachman D, Buckner J, et al. (2013). Network (2012). 2-Hydroxyglutarate concen- rol Med. 2014:546817. PMID:25180114
tinomatous craniopharyngiomas but not in other Phase III trial of chemoradiotherapy for ana- tration in serum from patients with gliomas 374. Casadei GP, Arrigoni GL, D’Angelo V, Biz-
tumours originating from the sellar region. Acta plastic oligodendroglioma: long-term results does not correlate with IDH1/2 mutation sta- zozero L (1990). Late malignant recurrence of
Neuropathol. 109(6):589-97. PMID:15891929 of RTOG 9402. J Clin Oncol. 31(3):337^f3. tus or tumor size. Int J Cancer. 131(3)766-8. childhood cerebellar astrocytoma. Clin Neuro-
330. Butler MG, Dasouki MJ, Zhou XP, Talebi- PMID:23071247 PMID:21913188 pathol. 9(6):295-8. PMID:2286021
zadeh Z, Brown M, Takahashi TN, et al. (2005). 345. Cairncross JG, Ueki K, Zlatescu MC, Lis- 359. Capper D, Weissert S, Balss J, Habel 375. Casadei GP, Komori T, Scheithauer BW,
Subset of individuals with autism spectrum le DK, Finkelstein DM, Hammond RR, et al. A, Meyer J, Jager D, et al. (2010). Characte- Miller GM, Parisi JE, Kelly PJ (1993). Intracra-
disorders and extreme macrocephaly associ- (1998). Specific genetic predictors of chemo- rization of R132H mutation-specific IDH1 an- nial parenchymal schwannoma. A clinicopatho-
ated with germline PTEN tumour suppressor therapeutic response and survival in patients tibody binding in brain tumors. Brain Pathol. logical and neuroimaging study of nine cases. J
gene mutations. J Med Genet. 42(4):318-21. with anaplastic oligodendrogliomas. J Natl Can- 20(1):245-54. PMID:19903171 Neurosurg. 79(2):217-22. PMID:8331403
PMID:15805158 cer Inst. 90(19):1473-9. PMID:9776413 360. Capper D, Zentgraf H, Balss J, Hartmann 376. Casadei GP, Scheithauer BW, Hirose T,
331. Byeon SJ, Cho HJ, Baek HW, Park CK, 346. Cairncross JG, Wang M, Jenkins RB, C, von Deimling A (2009). Monoclonal antibody Manfrini M, Van Houton C, Wood MB (1995).
Choi SH, Kim SH, et al. (2014). Rhabdoid Shaw EG, Giannini C, Brachman DG, et al. specific for IDH1 R132H mutation. Acta Neuro- Cellular schwannoma. A clinicopathologic,
glioblastoma is distinguishable from classi- (2014). Benefit from procarbazine, lomustine, pathol. 118(5):599-601. PMID:19798509 DNA flow cytometric, and proliferation marker
cal glioblastoma by cytogenetics and mole- and vincristine in oligodendroglial tumors is 361. Cardoso C, Lutz Y, Mignon C, Compe E, study of 70 patients. Cancer. 75(5):1109-19.
cular genetics. Hum Pathol. 45(3):611-20. associated with mutation of IDH. J Clin Oncol. Depetris D, Mattei MG, et al. (2000). ATR-X PMID7850709
PMID:24457079 32(8):783-90. PMID:24516018 mutations cause impaired nuclear location and 377. Cassarino DS, Auerbach A, Rushing EJ
332. Buhren J, Christoph AH, Buslei R, Albrecht 347. Camelo-Piragua S, Jansen M, Ganguly A, altered DNA binding properties of the XNP/ (2003). Widely invasive solitary fibrous tumor
S, Wiestler OD, Pietsch T (2000). Expression of Kim JC, Cosper AK, Dias-Santagata D, et al. ATR-X protein. J Med Genet. 37(10)746-51. of the sphenoid sinus, cavernous sinus, and
the neurotrophin receptor p75NTR in medullob- (2011). Asensitive and specific diagnostic panel PMID:11015451 pituitary fossa. Ann Diagn Pathol. 7(3):169-73.
lastomas is correlated with distinct histological to distinguish diffuse astrocytoma from astrocy- 362. Caretti V, Bugiani M, Freret M, Schellen PM ID: 12808569
and clinical features: evidence for a medul- tosis: chromosome 7 gain with mutant isocitrate P, Jansen M, van Vuurden D, et al. (2014). 378. Cassol CA, Winer D, Liu W, Guo M, Ezzat
loblastoma subtype derived from the external dehydrogenase 1 and p53. J Neuropathol Exp Subventricular spread of diffuse intrinsic pon- S, Asa SL (2014). Tyrosine kinase receptors as
granule cell layer, J Neuropathol Exp Neurol. Neurol. 70(2):110-5. PMID:21343879 tine glioma. Acta Neuropathol. 128(4):605-7. molecular targets in pheochromocytomas and
References 361
paragangliomas. Mod Pathol. 27(8):1050-62. ependymomas of the cauda equina. A review 411. Chang S, Prados MD (1994). Identical hemangioblastomas and its correlation with
PMID:24390213 of the clinical characteristics]. Minerva Chir. twins with Ollier's disease and intracranial gli- cyst formation. J Neurooncol. 80(3):219-25.
379. Castellano-Sanchez AA, Schemankewitz 52(5):629-33. PMID:9297152 omas: case report. Neurosurgery. 34(5):903-6, PM ID: 17077939
E, Mazewski C, Brat DJ (2001). Pediatric Chor- 396. Chacko G, Chacko AG, Dunham CP, Jud- discussion 906. PMID:8052390 429. Chen Z, Liu C, Patel AJ, Liao CP, Wang
doid glioma with chondroid metaplasia. Pediatr kins AR, Biegel JA, Perry A (2007). Atypical te- 412. Chang SM, Lillis-Hearne PK, Lar- Y, Le LQ (2014). Cells of origin in the embryo-
Dev Pathol. 4(6):564-7. PMID:11826363 ratoid/rhabdoid tumor arising in the setting of a son DA, Wara WM, Bollen AW, Prados MD nic nerve roots for NF1-associated plexiform
380. Castro-Vega LJ, Buffet A, De Cubas AA, pleomorphic xanthoastrocytoma. J Neurooncol. (1995). Pineoblastoma in adults. Neuro- neurofibroma. Cancer Cell. 26(5):695-706.
Cascon A, Menara M, Khalifa E, et al. (2014). 84(2):217-22. PMID:17431546 surgery. 37(3):383-90, discussion 390-1. PMID:25446898
Germline mutations in FH confer predisposition 397. Chacon-Quesada T, Rodriguez GJ, Maud PMID:7501100 430. Cheng TM, Coffey RJ, Gelber BR, Scheit-
to malignant pheochromocytomas and para- A, Ramos-Duran L, Torabi A, Fitzgerald T, et al. 413. Chao L, Tao XB, Jun YK, Xia HH, Wan WK, hauer BW (1993). Simultaneous presentation
gangliomas. Hum Mol Genet. 23(9):2440-6. (2015). Trans-arterial Onyx Embolization of a Tao QS (2013). Recurrence and histological of symptomatic subependymomas in sib-
PMID:24334767 Functional Thoracic Paraganglioma. Neuroin- evolution of dysembryoplastic neuroepithelial lings: case reports and review. Neurosurgery.
381. Castro-Vega LJ, Letouze E, Burnichon N, tervention. 10(1):34-8. PMID:25763296 tumor: A case report and review of the literature. 33(1):145-50. PMID:8355833
Buffet A, Disderot PH, Khalifa E, et al. (2015). 398. Chakraborty R, Hampton OA, Shen X, Oncol Lett. 6(4):907-14. PMID:24137435 431. Chentli F, Belhimer F, Kessaci F, Man-
Multi-omics analysis defines core genomic alte- Simko SJ, Shih A, Abhyankar H, et al. (2014). 414. Chappe C, Padovani L, Scavarda D, souri B (2012). Congenital craniopharyngi-
rations in pheochromocytomas and paragangli- Mutually exclusive recurrent somatic mutations Forest F, Nanni-Metellus I, Loundou A, et al. oma: a case report and literature review. J
omas. Nat Commun. 6:6044. PMID:25625332 in MAP2K1 and BRAF support a central role for (2013). Dysembryoplastic neuroepithelial tu- Pediatr Endocrinol Metab. 25(11-12):1181-3.
382. Cataitepe O, Turanli G, Yalnizoglu D, ERK activation in LCH pathogenesis. Blood. mors share with pleomorphic xanthoastrocyto- PMID:23329768
Topgu M, Akalan N (2005). Surgical manage- 124(19):3007-15. PMID:25202140 mas and gangliogliomas BRAF(V600E) mutati- 432. Chetty R (1999). Cytokeratin expression
ment of temporal lobe tumor-related epilepsy 399. Chalasani S, Hennick MR, Hocking WG, on and expression. Brain Pathol. 23(5):574-83. in cauda equina paragangliomas. Am J Surg
in children. J Neurosurg. 102(3) Suppl:280-7. Shaw GR, Lawler B (2013). Unusual presen- PMID:23442159 Pathol. 23(4):491. PMID:10199484
PMID:15881751 tation of a rare cancer: histiocytic sarcoma in 415. Charles NA, Holland EC, Gilbertson R, 433. Chi SN, Zimmerman MA, Yao X, Cohen KJ,
383. Cavalli G, Guglielmi B, Berti A, Cam- the brain 16 years after treatment for acute lym- Glass R, Kettenmann H (2012). The brain tu- Burger P, Biegel JA, et al. (2009). Intensive mul-
pochiaro C, Sabbadini MG, Dagna L (2013). phoblastic leukemia. Clin Med Res. 11(1):31-5. mor microenvironment. Glia. 60(3):502-14. timodality treatment for children with newly dia-
The multifaceted clinical presentations and PMID:22997353 PMID:22379614 gnosed CNS atypical teratoid rhabdoid tumor. J
manifestations of Erdheim-Chester disease: 400. Chamberlain M, Soffietti R, Raizer J, Ruda 416. Chaskis C, Michotte A, Goossens A, Clin Oncol. 27(3):385-9. PMID:19064966
comprehensive review of the literature and of R, Brandsma D, Boogerd W, et al. (2014). Stadnik T, Koerts G, D'Haens J (2002). Pri- 434. Chidambaram B, Santhosh V, Shankar
10 new cases. Ann Rheum Dis. 72(10):1691-5. Leptomeningeal metastasis: a Response As- mary intracerebral myxoid chondrosarcoma. SK (1998). Identical twins with medulloblasto-
PMID:23396641 sessment in Neuro-Oncology critical review Case illustration. J Neurosurg. 97(1):228. ma occurring in infancy. Childs Nerv Syst.
384. Ceccom J, Bourdeaut F, Loukh N, Rigau of endpoints and response criteria of publis- PMID:12134922 14(9):421-5. PMID:9808250
V, Milin S, Takin R, et al. (2014). Embryonal tu- hed randomized clinical trials. Neuro Oncol. 417. Chaudhry NS, Ahmad F, Blieden C, Mor- 435. Chiechi MV, Smirniotopoulos JG, Mena H
mor with multilayered rosettes: diagnostic tools 16(9):1176-85. PMID:24867803 cos JJ (2013). Suprasellar and sellar paragan- (1995). Pineal parenchymal tumors: CT and MR
update and review of the literature. Clin Neuro- 401. Chan AK, Pang JC, Chung NY, Li KK, glioma presenting as a nonfunctioning pituitary features. J Comput Assist Tomogr. 19(4):509-
pathol. 33(1 ):15-22. PMID:23863344 Poon WS, Chan DT, et al. (2014). Loss of macroadenoma. J Clin Neurosci. 20(11):1615- 17. PMID:7622675
385. Ceeraz S, Nowak EC, Noelle RJ (2013). CIC and FUBP1 expressions are potential 8. PMID:23876285 436. Chik K, Li C, Shing MM, Leung T, Yuen PM
B7 family checkpoint regulators in immune markers of shorter time to recurrence in oligo- 418. Cheadle JP, Reeve MP, Sampson JR, (1999). Intracranial germ cell tumors in children
regulation and disease. Trends Immunol. dendroglial tumors. Mod Pathol. 27(3):332-42. Kwiatkowski DJ (2000). Molecular genetic with and without Down syndrome. J Pediatr
34(11 ):556-63. PMID:23954143 PMID:24030748 advances in tuberous sclerosis. Hum Genet. Hematol Oncol. 21(2):149-51. PMID:10206462
387. Cenacchi G, Giangaspero F (2004). Emer- 402. Chan AS, Leung SY, Wong MP, Yuen ST, 107(2):97-114. PMID:11030407 437. Chikai K, Ohnishi A, Kato T, Ikeda J, Sawa-
ging tumor entities and variants of CNS neo- Cheung N, Fan YW, et al. (1998). Expression of 419. Chelliah D, Mensah Sarfo-Poku C, Stea mura Y, Iwasaki Y, et al. (2004). Clinico-patholo-
plasms. J Neuropathol Exp Neurol. 63(3):185- vascular endothelial growth factor and its recep- BD, Gardetto J, Zumwalt J (2010). Medullob- gical features of pilomyxoid astrocytoma of the
92. PMID:15055442 tors in the anaplastic progression of astrocyto- lastoma with extensive nodularity undergoing optic pathway. Acta Neuropathol. 108(2):109-
388. Cenacchi G, Giangaspero F, Cerasoli S, ma, oligodendroglioma, and ependymoma. Am post-therapeutic maturation to a gangliocytoma: 14. PMID:15168135
Manetto V, Martinelli GN (1996). Ultrastructural J Surg Pathol. 22(7):816-26. PMID:9669344 a case report and literature review. Pediatr Neu- 438. Chikwava K, Jaffe R (2004). Langerin
characterization of oligodendroglial-like cells in 403. Chan CC, Koch CA, Kaiser-Kupfer Ml, rosurg. 46(5):381-4. PMID:21389751 (CD207) staining in normal pediatric tissues,
central nervous system tumors. Ultrastruct Pa- Parry DM, Gutmann DH, Zhuang Z, et al. 420. Chen BJ, Marino-Enriquez A, Fletcher reactive lymph nodes, and childhood histiocytic
thol. 20(6):537-47. PMID:8940761 (2002). Loss of heterozygosity for the NF2 gene CD, Hornick JL (2012). Loss of retinoblastoma disorders. Pediatr Dev Pathol. 7(6):607-14.
389. Cenacchi G, Roncaroli F, Cerasoli S, Fi- in retinal and optic nerve lesions of patients with protein expression in spindle cell/pleomorphic PMID:15630529
carra G, Merli GA, Giangaspero F (2001). Chor- neurofibromatosis 2. J Pathol. 198(1):14-20. lipomas and cytogenetically related tumors: 439. Chinot OL, Wick W, Mason W, Henriksson
doid glioma of the third ventricle: an ultrastruc- PMID:12210058 an immunohistochemical study with diagnostic R, Saran F, Nishikawa R, et al. (2014). Beva-
tural study of three cases with a histogenetic 404. Chan CH, Bittar RG, Davis GA, Kalnins implications. Am J Surg Pathol. 36(8):1119-28. cizumab plus radiotherapy-temozolomide for
hypothesis. Am J Surg Pathol. 25(3):401-5. RM, Fabinyi GC (2006). Long-term seizure PMID:22790852 newly diagnosed glioblastoma. N Engl J Med.
PMID:11224612 outcome following surgery for dysembryoplastic 421. Chen CJ, Williams EA, McAneney TE, 370(8)709-22. PMID:24552318
390. Cepeda C, Andre VM, Yamazaki I, Haupt- neuroepithelial tumor. J Neurosurg. 104(1 ):62- Williams BJ, Mandell JW, Shaffrey ME (2015). 440. Chintagumpala M, HassallT, Palmer S, As-
man JS, Chen JY, Vinters HV, et al. (2010). 9. PMID:16509148 Histiocytic sarcoma of the cavernous sinus: hley D, Wallace D, Kasow K, et al. (2009). A pi-
Comparative study of cellular and synaptic 405. Chan GL, Little JB (1983). Cultured diploid case report and literature review. Brain Tumor lot study of risk-adapted radiotherapy and che-
abnormalities in brain tissue samples from pe- fibroblasts from patients with the nevoid basal Pathol. 32(1 ):66-71. PMID:24807104 motherapy in patients with supratentorial PNET.
diatric tuberous sclerosis complex and cortical cell carcinoma syndrome are hypersensitive 422. Chen G, Luo Z, Liu T, Yang H (2011). Fun- Neuro Oncol. 11(1):33-40. PMID:18796696
dysplasia type II. Epilepsia. 51 Suppl 3:160-5. to killing by ionizing radiation. Am J Pathol. ctioning paraganglioma of the cervical spine. 441. Chirindel A, Chaudhry M, Blakeley JO,
PMID:20618424 111(1):50-5. PMID:6837723 Orthopedics. 34(10):e700-2. PMID:21956072 Wahl R (2015). 18F-FDG PET/CT qualitative
391. Cerami E, Gao J, Dogrusoz U, Gross 406. Chan JA, Zhang H, Roberts PS, Jozwiak 423. Chen J, McKay RM, Parada LF (2012). and quantitative evaluation in neurofibromat-
BE, Sumer SO, Aksoy BA, et al. (2012). The S, Wieslawa G, Lewin-Kowalik J, et al. (2004). Malignant glioma: lessons from genomics, osis type 1 patients for detection of malignant
cBio cancer genomics portal: an open plat- Pathogenesis of tuberous sclerosis subependy- mouse models, and stem cells. Cell. 149(1):36- transformation: comparison of early to de-
form for exploring multidimensional cancer mal giant cell astrocytomas: biallelic inactivation 47. PMID:22464322 layed imaging with and without liver activity
genomics data. Cancer Discov. 2(5):401-4. of TSC1 or TSC2 leads to mTOR activation. J 424. Chen L, Li Y, Lin JH (2005). Intraneural normalization. J Nucl Med. 56(3):379-85.
PMID:22588877 Neuropathol Exp Neurol. 63( 12): 1236-42. perineurioma in a child with Beckwith-Wiede- PMID:25655626
392. Cerase A, Vallone IM, Di Pietro G, Oliveri PM ID: 15624760 mann syndrome. J Pediatr Surg. 40(2):E12-4. 442. Chitoku S, Kawai S, Watabe Y, Nishitani
G, Miracco C, Venturi C (2009). Neuroradiologi- 407. Chandler JP, Yashar P, Laskin WB, Russell PMID:15750909 M, Fujimoto K, Otsuka H, et al. (1998). Intra-
cal follow-up of the growth of papillary tumor of EJ (2004). Intracranial chondrosarcoma: a case 425. Chen L, Voronovich Z, Clark K, Hands I, dural spinal hibernoma: case report. Surg
the pineal region: a case report. J Neurooncol. report and review of the literature. J Neuroon- Mannas J, Walsh M, et al. (2014). Predicting Neurol. 49(5):509-12, discussion 512-3.
95(3):433-5. PMID:19517065 col. 68(1):33-9. PMID:15174519 the likelihood of an isocitrate dehydrogenase 1 PMID:9586928
393. Cerda-Nicolas M, Lopez-Gines C, Gil-Ben- 408. Chang AH, Fuller GN, Debnam JM, or 2 mutation in diagnoses of infiltrative glioma. 443. Chittaranjan S, Chan S, Yang C, Yang KC,
so R, Donat J, Fernandez-Delgado R. Pellin A, Karis JP, Coons SW, Ross JS, et al. (2008). Neuro Oncol. 16(11):1478-83. PMID:24860178 Chen V, Moradian A, et al. (2014). Mutations
et al. (2006). Desmoplastic infantile gangliogli- MR imaging of papillary tumor of the pineal 426. Chen SC, Lin DS, Lee CC, Hung SC, Chen in CIC and IDH1 cooperatively regulate 2-hy-
oma. Morphological, immunohistochemical and region. AJNR Am J Neuroradiol. 29(1):187-9. YW, Hsu SP, et al. (2013). Rhabdoid glioblasto- droxyglutarate levels and cell clonogenicity.
genetic features. Histopathology. 48(5):617-21. PMID:17925365 ma: a recently recognized subtype of glioblasto- Oncotarget. 5(17)7960-79. PMID:25277207
PMID:16623795 409. Chang MW (2003). Updated classifi- ma. Acta Neurochir (Wien). 155(8):1443-8, 444. Chmielecki J, Crago AM, Rosenberg M,
394. Cervera-Pierot P, Varlet P, Chodkiewicz cation of hemangiomas and other vascular discussion 1448. PMID:23812963 O’Connor R, Walker SR, Ambrogio L, et al.
JP, Daumas-Duport C (1997). Dysembryopla- anomalies. Lymphat Res Biol. 1(4):259-65. 427. Chen SM, Chuang CC, Toh CH, Jung SM, (2013). Whole-exome sequencing identifies
stic neuroepithelial tumors located in the cau- PMID:15624554 Lui TN (2013). Solitary intracranial osteoma a recurrent NAB2-STAT6 fusion in solitary
date nucleus area: report of four cases. Neu- 410. Chang Q, Pang JC, Li KK, Poon WS, Zhou with attachment to the falx: a case report. World fibrous tumors. Nat Genet. 45(2):131-2.
rosurgery. 40(5):1065-9, discussion 1069-70. L, Ng HK (2005). Promoter hypermethylation J Surg Oncol. 11:221. PMID:24010982 PMID:23313954
PMID:9149266 profile of RASSF1A, FHIT, and sFRP1 in in- 428. Chen Y, Tachibana O, Oda M, Xu R, 445. Cho BK, Wang KC, Nam DH, Kim DG,
395. Cervoni L, Celli P, Caruso R, Gagliardi tracranial primitive neuroectodermal tumors. Hamada J, Yamashita J, et al. (2006). In- Jung HW, Kim HJ, et al. (1998). Pineal tumors:
FM, Cantore GP (1997). [Neurinomas and Hum Pathol. 36(12):1265-72. PMID:16311119 creased expression of aquaporin 1 in human experience with 48 cases over 10 years. Childs
362 References
NervSyst. 14(1-2):53-8. PMID:9548342 463. Claes A, Idema AJ, Wesseling P (2007), of 11 cases and literature review. Mayo Clin 494. Coons SW, Johnson PC, Scheithauer BW,
446. Cho HJ, Myung JK, Kim H, Park CK, Kim Diffuse glioma growth: a guerilla war. Acta Neu- Proc. 78(5):567-73. PMID:12744543 Yates AJ, Pearl DK (1997). Improving diagno-
SK, Chung CK, et al. (2015). Primary diffuse ropathol. 114(5):443-58. PMID:17805551 480. Colin C, Padovani L, Chappe C, Mercurio stic accuracy and interobserver concordance
leptomeningeal glioneuronal tumors. Brain Tu- 464. Clarenbach P, Kleihues P, Metzel E, Dich- S, Scavarda D, Loundou A, et al. (2013). Out- in the classification and grading of primary gli-
mor Pathol. 32(1 ):49-55. PMID:24770606 gans J (1979). Simultaneous clinical manifesta- come analysis of childhood pilocytic astrocyto- omas. Cancer. 79(7):1381-93. PMID:9083161
447. Cho Y, Gorina S, Jeffrey PD, Pavletich NP tion of subependymoma of the fourth ventricle mas: a retrospective study of 148 cases at a 495. Cooper ERA (1935). The relation of oli-
(1994). Crystal structure of a p53 tumor sup- in identical twins. Case report. J Neurosurg. single institution. Neuropathol Appl Neurobiol, godendrocytes and astrocytes in cerebral tu-
pressor-DNA complex: understanding tumori- 50(5):655-9. PMID:571009 39(6):693-705. PMID:23278243 mours. J Path Bad. 41:259-66.
genic mutations. Science. 265(5170):346-55. 465. Clark AJ, Sughrue ME, Ivan ME, Aranda D, 481. Colin C, Virard I, Baeza N, Tchoghandjian 496. Cooper LA, Gutman DA, Long Q, John-
PMID:8023157 Rutkowski MJ, Kane AJ, et al. (2010). Factors A, Fernandez C, Bouvier C, et al. (2007). Rele- son BA, Cholleti SR, Kurc T, et al. (2010). The
448. Cho YJ, Tsherniak A, Tamayo P, Santag- influencing overall survival rates for patients vance of combinatorial profiles of intermediate proneural molecular signature is enriched in
ata S, Ligon A, Greulich H, et al. (2011). Inte- with pineocytoma. J Neurooncol. 100(2):255- filaments and transcription factors for glioma oligodendrogliomas and predicts improved
grative genomic analysis of medulloblastoma 60. PMID:20461445 histogenesis. Neuropathol Appl Neurobiol. survival among diffuse gliomas. PLoS One.
identifies a molecular subgroup that drives poor 466. Clark GB, Henry JM, McKeever PE 33(4):431-9. PMID:17442061 5(9):e12548. PMID:20838435
clinical outcome. J Clin Oncol. 29(11 ):1424-30. (1985). Cerebral pilocytic astrocytoma. Cancer. 482. Collins VP, Jones DT, Giannini C (2015). 497. Copie-Bergman C, Wotherspoon AC, Nor-
PMID:21098324 56(5): 1128-33. PMID:4016701 Pilocytic astrocytoma: pathology, molecular ton AJ, Diss TC, Isaacson PG (1998). True his-
449. Choi C, Ganji SK, DeBerardinis RJ, Ha- 467. Clark VE, Erson-Omay EZ, Serin A, Yin mechanisms and markers. Acta Neuropathol. tiocytic lymphoma: a morphologic, immunohis-
tanpaa KJ, Rakheja D, Kovacs Z, et al. (2012). J, Cotney J, Ozduman K, et al. (2013). Geno- 129(6):775-88. PMID:25792358 tochemical, and molecular genetic study of
2-hydroxyglutarate detection by magnetic mic analysis of non-NF2 meningiomas reveals 483. Colnat-Coulbois S, Kremer S, Weinbreck 13 cases. Am J Surg Pathol. 22(11):1386-92.
resonance spectroscopy in IDH-mutated pa- mutations in TRAF7, KLF4, AKT1, and SMO. N, Pinelli C, Auque J (2008). Lipomatous PMID:9808131
tients with gliomas. Nat Med. 18(4):624-9. Science. 339(6123):1077-80. PMID:23348505 meningioma: report of 2 cases and review of 498. Cornejo KM, Hutchinson L, Cosar EF,
PMID:22281806 468. Clarke MJ, Foy AB, Wetjen N, Raffel C the literature. Surg Neurol. 69(4):398-402, di- Smith T, Tomaszewicz K, Dresser K, et al.
450. Choi JS, Nam DH, Ko YH, Seo JW, Choi (2006) . Imaging characteristics and growth of scussion 402. PMID:17825370 (2013). is it a primary or metastatic melanocytic
YL, Suh YL, et al. (2003). Primary central ner- subependymal giant cell astrocytomas. Neuro- 483A. Combs SE, Schulz-Ertner D, Debus J, neoplasm of the central nervous system?:
vous system lymphoma in Korea: comparison surg Focus. 20(1):E5. PMID:16459995 von Deimling A, Hartmann C (2011). Improved A molecular based approach. Pathol Int.
of B- and T-cell lymphomas. Am J Surg Pathol. 468A. Claus EB, Black PM, Bondy ML, Calvo- correlation of the neuropathologic classification 63(11):559-64. PMID:24274719
27(7):919-28. PMID:12826884 coressi L, Schildkraut JM, Wiemels JL, et al. according to adapted world health organization 499. Corti ME, Yampolsky C, Metta H, Valerga
451. Chou SM, Anderson JS (1991). Primary (2007) . Exogenous hormone use and meningi- classification and outcome after radiotherapy in M, Sevlever G, Capizzano A (2004). Oligo-
CNS malignant rhabdoid tumor (MRT): report of oma risk: what do we tell our patients? Cancer. patients with atypical and anaplastic meningio- dendroglioma in a patient with AIDS: case re-
two cases and review of literature. Clin Neuro- 110(3):471-6. PMID:17580362 mas. Int J Radiat Oncol Biol Phys. 81(5):1415- port and review of the literature. Rev Inst Med
pathol. 10(1):1-10. PMID:2015720 469. Claus EB, Calvocoressi L, Bondy ML, 21. PMID:20932661 Trap Sao Paulo. 46(4):195-7. PMID:15361970
452. Chow E, Jenkins JJ, Burger PC, Re- Schildkraut JM, Wiemels JL, Wrensch M (2011). 484. Comino-Mendez I, Gracia-Aznarez FJ, 500. Cosar M, Iplikcioglu AC, Bek S, Gokduman
ardon DA, Langston JW, Sanford RA, et al. Family and personal medical history and risk Schiavi F, Landa I, Leandro-Garcia LJ, Leton CA (2005). Intracranial falcine and convexity
(1999). Malignant evolution of choroid plexus of meningioma. J Neurosurg. 115(6):1072-7. R, et al. (2011). Exome sequencing identi- chondromas: two case reports. Br J Neurosurg.
papilloma. Pediatr Neurosurg. 31(3):127-30. PMID:21780859 fies MAX mutations as a cause of hereditary 19(3):241-3. PMID:16455525
PMID:10708353 470. Claus EB, Calvocoressi L, Bondy ML, pheochromocytoma. Nat Genet. 43(7):663-7. 501. Couce ME, Aker FV, Scheithauer BW
453. Chowdhary A, Spence AM, Sales L, Rosto- Schildkraut JM, Wiemels JL, Wrensch M PMID:21685915 (2000). Chordoid meningioma: a clinicopa-
mily RC, Rockhill JK, Silbergeld DL (2012). (2012). Dental x-rays and risk of meningioma. 485. Committee of Brain Tumor Registry of Ja- thologic study of 42 cases. Am J Surg Pathol.
Radiation associated tumors following thera- Cancer. 118(18):4530-7. PMID:22492363 pan (2003). Report of Brain Tumor Registry of 24(7):899-905. PMID:10895812
peutic cranial radiation. Surg Neurol Int. 3:48. 471. Claus EB, Calvocoressi L, Bondy ML, Japan (1969-1996). Neurol Med Chir (Tokyo). 502. Courts C, Montesinos-Rongen M, Brunn A,
PMID:22629485 Wrensch M, Wiemels JL, Schildkraut JM (2013). 43 Suppl:i-vii, 1-111. PMID:14705327 Bug S, Siemer D, Hans V, et al. (2008). Recur-
454. Christensen BC, Smith AA, Zheng S, Exogenous hormone use, reproductive factors, 485A. Committee of Brain Tumor Registry of rent inactivation of the PRDM1 gene in primary
Koestler DC, Houseman EA, Marsit CJ, et al. and risk of intracranial meningioma in females. Japan (2014). Report of Brain Tumor Registry central nervous system lymphoma. J Neuropa-
(2011). DNA methylation, isocitrate dehydro- J Neurosurg. 118(3):649-56. PMID:23101448 of Japan (2001-2004), Vol. 13. Neurol Med Chir thol Exp Neurol. 67(7):720-7. PMID:18596541
genase mutation, and survival in glioma. J Natl 472. Clifford SC, Lusher ME, Lindsey JC, (Tokyo)54:1-102. 503. Courville CB, Broussalian SL (1961). Pla-
Cancer Inst. 103(2):143-53. PMID:21163902 Langdon JA, Gilbertson RJ, Straughton D, et 486. Connor JM, Pirrit LA, Yates JR, Fryer AE, stic ependymomas of the lateral recess. Report
455. Christiaans I, Kenter SB, Brink HC, van Os al. (2006). WntA/Vingless pathway activation Ferguson-Smith MA (1987). Linkage of the tu- of eight verified cases. J Neurosurg. 18:792-9.
TA, Baas F, van den Munckhof P, et al. (2011). and chromosome 6 loss characterize a distinct berous sclerosis locus to a DNA polymorphism PMID:13881784
Germline SMARCB1 mutation and somatic NF2 molecular sub-group of medulloblastomas as- detected by v-abl. J Med Genet. 24(9):544-6. 504. Covington MF, Chin SS, Osborn AG (2011).
mutations in familial multiple meningiomas. J sociated with a favorable prognosis. Cell Cycle. PMID:2889832 Pituicytoma, spindle cell oncocytoma, and gra-
Med Genet. 48(2):93-7. PMID:20930055 5(22):2666-70. PMID:17172831 487. Constantini S, Softer D, Siegel T, Shalit MN nular cell tumor: clarification and meta-analysis
456. Christov C, Adle-Biassette H, Le Guerinel 473. Clynes D, Higgs DR, Gibbons RJ (2013). (1989). Paraganglioma of the thoracic spinal of the world literature since 1893. AJNR Am J
C, Natchev S, Gherardi RK (1998). Immunohis- The chromatin remodeller ATRX: a repeat of- cord with cerebrospinal fluid metastasis. Spine Neuroradiol. 32(11 ):2067-72. PMID:21960498
tochemical detection of vascular endothelial fender in human disease. Trends Biochem Sci. (Phila Pa 1976). 14(6):643-5. PMID:2749382 505. Crino PB, Mehta R, Vinters HV (2010).
growth factor (VEGF) in the vasculature of oli- 38(9):461-6. PMID:23916100 488. Conte D, Huh M, Goodall E, Delorme M, Pathogenesis of TSC in the brain. In: Tuberous
godendrogliomas. Neuropathol Appl Neurobiol. 474. Coakley KJ, Huston J 3rd, Scheithauer Parks RJ, Picketts DJ (2012). Loss of Atrx sen- sclerosis complex. Genes, clinical features, and
24(1):29-35. PMID:9549726 BW, Forbes G, Kelly PJ (1995). Pilocytic ast- sitizes cells to DNA damaging agents through therapeutics. Kwiatkowski DJ, Whittemore VH,
457. Chu LC, Eberhart CG, Grossman SA, Her- rocytomas: well-demarcated magnetic reso- p53-mediated death pathways. PLoS One. Thiele EA, eds. Wiley-Blackwell: Weinheim,
man JG (2006). Epigenetic silencing of multiple nance appearance despite frequent infiltration 7(12):e52167. PMID:23284920 Germany, pp. 161-185.
genes in primary CNS lymphoma. Int J Cancer. histologically. Mayo Clin Proc. 70(8):747-51. 489. Conti P, Mouchaty H, Spacca B, Bucco- 506. Crino PB, Trojanowski JQ, Dichter MA,
119(10):2487-91. PMID:16858686 PMID:7630212 liero AM, Conti R (2006). Thoracic extradural Eberwine J (1996). Embryonic neuronal mar-
458. Ciardiello F, Tortora G (2001). A novel 475. Cobbers JM, Wolter M, Reifenberger J, paragangliomas: a case report and review kers in tuberous sclerosis: single-cell mole-
approach in the treatment of cancer: targeting Ring GU, Jessen F, An HX, et al. (1998). Fre- of the literature. Spinal Cord. 44(2):120-5. cular pathology. Proc Natl Acad Sci U S A .
the epidermal growth factor receptor. Clin Can- quent inactivation of CDKN2A and rare mutati- PMID:16130022 93(24):14152-7. PMID:8943076
cer Res. 7(10):2958-70. PMID:11595683 on of TP53 in PCNSL. Brain Pathol. 8(2):263- 490. Conway JE, Chou D, Clatterbuck RE, 506A. Crocetti E, Trama A, Stiller C, Caldareila
459. Cimino PJ, Agarwal A, Dehner LP (2014). 76. PMID:9546285 Brem H, Long DM, Rigamonti D (2001). He- A, Soffietti R, Jaal J, et al. (2012). Epidemiology
Myxopapillary ependymoma in children: a study 476. Coca S, Moreno M, Martos JA, Rodriguez mangioblastomas of the central nervous system of glial and non-glial brain tumours in Europe.
of 11 cases and a comparison with the adult ex- J, Barcena A, Vaquero J (1994). Neurocytoma in von Hippel-Lindau syndrome and sporadic di- Eur J Cancer. 48(10):1532-42. PMID:22227039
perience. Pediatr Blood Cancer. 61(11):1969- of spinal cord. Acta Neuropathol. 87(5):537-40. sease. Neurosurgery. 48(1):55-62, discussion 507. Crotty TB, Scheithauer BW, Young WF Jr,
71. PMID:25066546 PMID:8059608 62-3. PMID:11152361 Davis DH, Shaw EG, Miller GM, et al. (1995).
460. Cimino PJ, Gonzalez-Cuyar LF, Perry A, 477. Coca S, Vaquero J, Escandon J, Moreno 491. Cook DJ, Christie SD, Macaulay RJ, Papillary craniopharyngioma: a clinicopa-
Dahiya S (2015). Lack of BRAF-V600E Muta- M, Peralba J, Rodriguez J (1992). Immunohisto- Rheaume DE, Holness RO (2004). Fourth ven- thological study of 48 cases. J Neurosurg.
tion in Papillary Tumor of the Pineal Region. chemical characterization of pineocytomas. Clin tricular neurocytoma: case report and review of 83(2):206-14. PMID:7616262
Neurosurgery. 77(4):621-8. PMID:26125673 Neuropathol. 11 (6):298-303. PMID:1473313 the literature. Can J Neurol Sci. 31 (4):558-64. 508. Cuccia V, Rodriguez F, Palma F, Zuccaro
461. Cinalli G, Zerah M, Carteret M, Doz F, Vi- 478. Cohen BH, Zeltzer PM, Boyett JM, Geyer PMID:15595267 G (2006). Pinealoblastomas in children. Childs
nikoff L, Lellouch-Tubiana A, et al. (1997). Sub- JR, Allen JC, Finlay JL, et al. (1995). Prognostic 492. Coons SW, Johnson PC (1993). Regional Nerv Syst. 22(6):577-85. PMID:16555075
dural sarcoma associated with chronic subdural factors and treatment results for supratentorial heterogeneity in the proliferative activity of hu- 509. Curatolo P, Moavero R (2012). mTOR
hematoma. Report of two cases and review primitive neuroectodermal tumors in children man gliomas as measured by the Ki-67 labeling Inhibitors in Tuberous Sclerosis Com-
of the literature. J Neurosurg. 86(3):553-7. using radiation and chemotherapy: a Childrens index. J Neuropathol Exp Neurol. 52(6):609-18. plex. Curr Neuropharmacol. 10(4):404-15.
PMID:9046316 Cancer Group randomized trial. J Clin Oncol. PMID:8229080 PMID:23730262
462. Ciriello G, Miller ML, Aksoy BA, Senba- 13(7):1687-96. PMID:7602359 493. Coons SW, Johnson PC, Pearl DK 510. Curless RG, Toledano SR, Ragheb J, Cle-
baoglu Y, Schultz N, Sander C (2013). Emer- 479. Cohen-Gadol AA, Pichelmann MA, Link (1997). The prognostic significance of Ki-67 veland WW, Falcone S (2002). Hematogenous
ging landscape of oncogenic signatures across MJ, Scheithauer BW, Krecke KN, Young WF Jr, labeling indices for oligodendrogliomas. Neu- brain metastasis in children. Pediatr Neurol.
human cancers. Nat Genet. 45(10):1127-33. et al. (2003). Granular cell tumor of the sellar rosurgery. 41 (4):878-84, discussion 884-5. 26(3):219-21. PMID:11955930
PMID:24071851 and suprasellar region: dinicopathologic study PMID:9316050 511. Curran EK, Sainani KL, Le GM, Propp
References 363
JM, Fisher PG (2009). Gender affects survival 114(4):681-8. PMID:15064624 humans and mice. Neuro Oncol. 12(3):233-42. Zakrzewski K, Liberski PP (1999). Cytogenetic
for medulloblastoma only in older children and 527. Darwish B, Arbuckle S, Kellie S, Besser PMID:20167811 changes in two cases of subependymal gi-
adults: a study from the Surveillance Epidemio- M, Chaseling R (2007). Desmoplastic infantile 543. De Jesus O, Rifkinson N (1995). Pleomor- ant-cell astrocytoma. Cancer Genet Cytogenet.
logy and End Results Registry. Pediatr Blood ganglioglioma/astrocytoma with cerebrospinal phic xanthoastrocytoma with invasion of the 109(1 ):29-33. PMID:9973956
Cancer. 52(1):60-4. PMID:19006250 metastasis. J Clin Neurosci. 14(5):498-501. tentorium and falx. Surg Neurol. 43(1 ):77-9. 561. Deckert M, Brunn A, Montesinos-Rongen
511 A. Custer B, Longstreth WT, Phillips LE, PMID:17386372 PMID:7701430 M, Terreni MR, Ponzoni M (2014). Primary lym-
Koepsell TD, Van Belle G (2006), Hormonal ex- 528. Darwish BS, Balakrishnan V, Maitra R 544. de Jong MC, Kors WA, de Graaf P, phoma of the central nervous system-a diag-
posures and the risk of intracranial meningioma (2002) . Intramedullary ancient schwannoma Castelijns JA, Kivela T, Moll AC (2014). Trila- nostic challenge. Hematol Oncol. 32(2):57-67.
in women: a population-based case-control stu- of the cervical spinal cord: case report and re- teral retinoblastoma: a systematic review and PMID:23949943
dy. BMC Cancer. 6:152. PMID:16759391 view of literature. J Clin Neurosci. 9(3):321-3. meta-analysis. Lancet Oncol. 15(10):1157-67. 562. Deckert M, Engert A, Bruck W, Ferreri AJ,
512. Cykowski MD, Wartchow EP, Mierau GW, PMID:12093146 PMID:25126964 Finke J, lllerhaus G, et al. (2011). Modern con-
Stolzenberg ED, Gumerlock MK, Fung KM 529. Dasgupta B, Dugan LL, Gutmann DH 545. de Kock L, Sabbaghian N, Druker H, We- cepts in the biology, diagnosis, differential diag-
(2012). Papillary tumor of the pineal region: ul- (2003) . The neurofibromatosis 1 gene product ber E, Hamel N, Miller S, et al. (2014). Germ- nosis and treatment of primary central nervous
trastructural study of a case. Ultrastruct Pathol. neurofibromin regulates pituitary adenylate line and somatic DICER1 mutations in pineob- system lymphoma. Leukemia. 25(12):1797-
36(1):68-77. PMID:22292738 cyclase-activating polypeptide-mediated signa- lastoma. Acta Neuropathol. 128(4):583-95. 807. PMID:21818113
513. D’Ambrosio N, Soohoo S, Warshall C, ling in astrocytes. J Neurosci. 23(26):8949-54. PMID:25022261 563. DeDavid M, Orlow SJ, Provost N, Mar-
Johnson A, Karimi S (2008). Craniofacial and PMID:14523097 546. de la Monte SM, Horowitz SA (1989). He- ghoob AA, Rao BK, Huang CL, et al. (1997). A
intracranial manifestations of langerhans cell 530. Daumas Duport C (1995). Patterns of tu- mangioblastomas: clinical and histopathological study of large congenital melanocytic nevi and
histiocytosis: report of findings in 100 pati- mor growth and problems associated with histo- factors correlated with recurrence. Neurosur- associated malignant melanomas: review of ca-
ents. AJR Am J Roentgenol. 191(2):589-97. logical typing of low-grade gliomas. In: Apuzzo gery. 25(5):695-8. PMID:2586723 ses in the New York University Registry and the
PMID:18647937 LJ, editor. Benign Cerebral Gliomas. Park Rid- 547. De Munnynck K, Van Gool S, Van Calen- world literature. J Am Acad Dermatol. 36(3 Pt
515. da Cruz Perez DE, Amanajas de Aguiar FC ge: AANS; pp. 125-47. bergh F, Demaerel P, Uyttebroeck A, Buyse G, 1):409-16. PMID:9091472
Jr, Leon JE, Graner E, Paes de Almeida O, Var- 531. Daumas-Duport C (1993). Dysembryo- et al. (2002). Desmoplastic infantile ganglioglio- 564. DeDavid M, Orlow SJ, Provost N, Mar-
gas PA (2006). Intraneural perineurioma of the plastic neuroepithelial tumours. Brain Pathol. ma: a potentially malignant tumor? Am J Surg ghoob AA, Rao BK, Wasti Q, et al. (1996).
tongue: a case report. J Oral Maxillofac Surg. 3(3):283-95. PMID:8293188 Pathol. 26(11):1515-22. PMID:12409729 Neurocutaneous melanosis: clinical features
64(7):1140-2. PMID:16781350 532. Daumas-Duport C (1995). Dysembryopla- 548. De Raedt T, Beert E, Pasmant E, Luscan of large congenital melanocytic nevi in pa-
516. Dabora SL, Jozwiak S, Franz DN, Roberts stic neuroepithelial tumours in epilepsy surgery. A, Brems H, Ortonne N, et al. (2014). PRC2 tients with manifest central nervous system
PS, Nieto A, Chung J, et al. (2001). Mutational In: Guerrini R, editor. Dysplasia of Cerebral loss amplifies Ras-driven transcription and melanosis. J Am Acad Dermatol. 35(4):529-38.
analysis in a cohort of 224 tuberous sclero- Cortex and Epilepsy. New York: Raven Press; confers sensitivity to BRD4-based therapies. PMID:8859278
sis patients indicates increased severity of pp. 125-47. Nature. 514(7521):247-51. PMID:25119042 565. Dedeurwaerdere F, Giannini C, Sciot R,
TSC2, compared with TSC1, disease in mul- 533. Daumas-Duport C, Scheithauer B, O’Fal- 549. De Raedt T, Brems H, Lopez-Correa C, Rubin BP, Perilongo G, Borghi L, et al. (2002).
tiple organs. Am J Hum Genet. 68(1):64-80. lon J, Kelly P (1988). Grading of astrocytomas. Vermeesch JR, Marynen P, Legius E (2004). Primary peripheral PNET/Ewing’s sarcoma
PMID:11112665 A simple and reproducible method. Cancer. Genomic organization and evolution of the NF1 of the dura: a clinicopathologic entity distinct
517. Dahia PL, Aguiar RC, Alberta J, Kum JB, 62(10):2152-65. PMID:3179928 microdeletion region. Genomics. 84(2):346-60. from central PNET, Mod Pathol. 15(6):673-8.
Caron S, Sill H, et al. (1999). PTEN is inversely 534. Daumas-Duport C, Scheithauer BW, Cho- PMID:15233998 PMID:12065782
correlated with the cell survival factor Akt/PKB dkiewicz JP, Laws ER Jr, Vedrenne C (1988). 550. De Raedt T, Brems H, Wolkenstein P, 566. Degen R, Ebner A, Lahl R, Leonhardt
and is inactivated via multiple mechanismsin Dysembryoplastic neuroepithelial tumor: a Vidaud D, Pilotti S, Perrone F, et al. (2003). S, Pannek HW, Tuxhorn I (2002). Various fin-
haematological malignancies. Hum Mol Genet. surgically curable tumor of young patients Elevated risk for MPNST in NF1 microdeletion dings in surgically treated epilepsy patients
8(2):185-93. PMID:9931326 with intractable partial seizures. Report of thir- patients. Am J Hum Genet. 72(5):1288-92. with dysembryoplastic neuroepithelial tumors
518. Dahiya S, Haydon DH, Alvarado D, Gur- ty-nine cases. Neurosurgery. 23(5):545-56. PMID:12660952 in comparison with those of patients with other
nett CA, Gutmann DH, Leonard JR (2013). PMID:3143922 551. de Ribaupierre S, Dorfmuller G, Bulteau C, low-grade brain tumors and other neuronal
BRAF(V600E) mutation is a negative prognosti- 535. Daumas-Duport C, Scheithauer BW, Kelly Fohlen M, Pinard JM, Chiron C, et al. (2007). migration disorders. Epilepsia. 43(11):1379-84.
cator in pediatric ganglioglioma. Acta Neuropa- PJ (1987). A histologic and cytologic method for Subependymal giant-cell astrocytomas in pedi- PMID:12423388
thol. 125(6):901-10. PMID:23609006 the spatial definition of gliomas. Mayo Clin Proc. atric tuberous sclerosis disease: when should 567. Dehghani F, Schachenmayr W, Laun
519. Dahiya S, Sarkar C, Hedley-Whyte ET, 62(6):435-49. PMID:2437411 we operate? Neurosurgery. 60(1):83-9, discus- A, Korf HW (1998). Prognostic implication of
Sharma MC, Zervas NT, Sridhar E, et al. (2005). 536. Daumas-Duport C, Varlet P (2003). sion 89-90. PMID:17228255 histopathological, immunohistochemical and
Spindle cell oncocytoma of the adenohypophy- [Dysembryoplastic neuroepithelial tumors]. 552. De Schepper S, Maertens O, Callens T, clinical features of oligodendrogliomas: a study
sis: report of two cases. Acta Neuropathol. Rev Neurol (Paris). 159(6-7 Pt 1):622-36. Naeyaert JM, Lambert J, Messiaen L (2008). of 89 cases. Acta Neuropathol. 95(5)493-504.
110(1):97-9. PMID:15973544 PMID:12910070 Somatic mutation analysis in NF1 cafe au PMID:9600596
520. Dahlback HS, Gorunova L, Micci F, Scheie 537. Daumas-Duport C, Varlet P, Bacha S, lait spots reveals two NF1 hits in the me- 568. Deisch JK, Patel R, Koral K, Cope-Yo-
D, Brandal P, Meling TR, et al. (2011). Molecu- Beuvon F, Cervera-Pierot P, Chodkiewicz JP lanocytes. J Invest Dermatol. 128(4):1050-3. koyama SD (2013). Juvenile xanthogranulomas
lar cytogenetic analysis of a gliosarcoma with (1999). Dysembryoplastic neuroepithelial tu- PMID:17914445 of the nervous system: A report of two cases
osseous metaplasia. Cytogenet Genome Res. mors: nonspecific histological forms - a study 553. De Tommasi A, Luzzi S, D’Urso PI, De and review of the literature. Neuropathology.
134(2):88-95. PMID:21555877 of 40 cases. J Neurooncol. 41(3):267-80. Tommasi C, Resta N, Ciappetta P (2008). 33(1):39-46. PMID:22640164
521. Dai C, Celestino JC, Okada Y, Louis DN, PMID:10359147 Molecular genetic analysis in a case of gan- 569. Del Bigio MR, Deck JH (1993). Rosenthal
Fuller GN, Holland EC (2001). PDGF autocrine 538. de Chadarevian JP, Montes JL, O'Gorman glioglioma: identification of a new mutation. fibers producing a granular cell appearance in
stimulation dedifferentiates cultured astrocytes AM, Freeman CR (1987). Maturation of cere- Neurosurgery. 63(5):976-80, discussion 980. a glioblastoma. Acta Neuropathol. 86(1)400-4.
and induces oligodendrogliomas and oligoast- bellar neuroblastoma into ganglioneuroma with PM ID: 19005389 PMID:8396834
rocytomas from neural progenitors and ast- melanosis. A histologic, immunocytochemical, 554. De Vos M, Hayward BE, Chariton R, Taylor 570. Del Valle L, Enam S, Lara C, Ortiz-Hidalgo
rocytes in vivo. Genes Dev. 15(15):1913-25. and ultrastructural study. Cancer. 59(1 ):69-76. GR, Glaser AW, Picton S, et al. (2006). PMS2 C, Katsetos CD, Khalili K (2002). Detection of
PMID:11485986 PMID:3539310 mutations in childhood cancer. J Natl Cancer JC polyomavirus DNA sequences and cellu-
522. Damodaran O, Robbins P, Knuckey N, 539. de Chadarevian JP, Pattisapu JV, Faerber Inst. 98(5):358-61. PMID:16507833 lar localization of T-antigen and agnoprotein
Bynevelt M, Wong G, Lee G (2014). Primary EN (1990). Desmoplastic cerebral astrocytoma 555. de Vries J, Scheremet R, Altmannsber- in oligodendrogliomas. Clin Cancer Res.
intracranial haemangiopericytoma: comparison of infancy Light microscopy immunocytoche- ger M, Michilli R, Lindemann A, Hinkelbein W 8(11):3332-40. PMID42429619
of survival outcomes and metastatic potential in mistry, and ultrastructure. Cancer. 66(1):173-9. (1994). Primary leiomyosarcoma of the spinal 571. Delnatte C, Sanlaville D, Mougenot JF,
WHO grade II and III variants. J Clin Neurosci. PMID:2354404 leptomeninges. J Neurooncol. 18(1):25-31. Vermeesch JR, Houdayer C, Blois MC, et al.
21(8):1310-4. PMID:24726230 540. de Cubas AA, Leandro-Garcia LJ, Schi- PMID:8057131 (2006). Contiguous gene deletion within chro-
523. Dang L, White DW, Gross S, Bennett avi F, Mancikova V, Comino-Mendez I, Ingla- 556. de Vries NA, Hulsman D, Akhtar W, de mosome arm 10q is associated with juvenile
BD, Bittinger MA, Driggers EM, et al. (2009). da-Perez L, et al. (2013). Integrative analysis Jong J, Miles DC, Blom M, etal. (2015). Prolon- polyposis of infancy, reflecting cooperation bet-
Cancer-associated IDH1 mutations produce of miRNA and mRNA expression profiles in ged Ezh2 Depletion in Glioblastoma Causes a ween the BMPR1A and PTEN tumor-suppres-
2-hydroxyglutarate. Nature. 462(7274):739-44. pheochromocytoma and paraganglioma identi- Robust Switch in Cell Fate Resulting in Tumor sor genes. Am J Hum Genet. 78(6)4066-74.
PMID:19935646 fies genotype-specific markers and potentially Progression. Cell Rep. PMID:25600873 PMID46685657
524. Dardick I, Hammar SP, Scheithauer BW regulated pathways. Endocr Relat Cancer. 557. DeAngelis LM (2001). Brain tumors. N 572. Demetriades AK, Al Hyassat S, Al-Sarraj
(1989). Ultrastructural spectrum of hemangi- 20(4):477-93. PMID:23660872 Engl J Med. 344(2):114-23. PMID:11150363 S, Bhangoo RS, Ashkan K (2013). Papillary
opericytoma: a comparative study of fetal, adult, 541. De Filippi P, Badulli C, Cuccia M, De 558. Dearnaley DP, A’Hem RP, Whittaker S, glioneuronal tumour: a review of the literature
and neoplastic pericytes. Ultrastruct Pathol. Silvestri A, Dametto E, Pasi A, et al. (2006). Bloom HJ (1990). Pineal and CNS germ cell with two illustrative cases. Br J Neurosurg.
13(2-3):111-54. PMID:2734855 Specific polymorphisms of cytokine genes tumors: Royal Marsden Hospital experience 27(3)401-4. PMID:23173837
525. Dario A, Cerati M, Taborelli M, Finzi G, are associated with different risks to develop 1962-1987. Int J Radiat Oncol Biol Phys. 573. Demuth T, Berens ME (2004). Mole-
Pozzi M, Dorizzi A (2000). Cytogenetic and ul- single-system or multi-system childhood Lan- 18(4):773-81. PMID:2323968 cular mechanisms of glioma cell migration
trastructural study of a pineocytoma case report. gerhans cell histiocytosis. Br J Haematol. 559. Deb P, Sharma MC, Gaikwad S, Gupta A, and invasion. J Neurooncol. 70(2):217-28.
J Neurooncol. 48(2):13M. PMID:11083076 132(6):784-7. PMID:16487180 Mehta VS, Sarkar C (2005). Cerebellopontine PMID45674479
526. Darrouzet V, Martel J, Enee V, Bebear JP, 542. de Groot JF, Fuller G, Kumar AJ, Piao Y, angle paraganglioma - report of a case and 574. Derlin T, Tornquist K, Munster S, Apo-
Guerin J (2004). Vestibular schwannoma sur- Eterovic K, Ji Y, et al. (2010). Tumor invasion review of literature. J Neurooncol, 74(1):65-9. stolova I, Hagel C, Friedrich RE, et al. (2013).
gery outcomes: our multidisciplinary experien- after treatment of glioblastoma with bevacizu- PMID:16078110 Comparative effectiveness of 18F-FDG PET/
ce in 400 cases over 17 years. Laryngoscope. mab: radiographic and pathologic correlation in 560. Debiec-Rychter M, Jesionek-Kupnicka D, CT versus whole-body MRI for detection of
364 References
malignant peripheral nerve sheath tumors Pathol. 22(6):869-70. PMID:23050874 611. Dunham C, Sugo E, Tobias V, Wills E, PMID:2009534
in neurofibromatosis type 1. Clin Nucl Med. 593. Dobbins SE, Broderick P, Melin B, Feych- Perry A (2007). Embryonal tumor with abundant 627. Ekstrand AJ, Sugawa N, James CD,
38(1 ):e19-25. PMID:23242059 ting M, Johansen C, Andersson U, et al. (2011). neuropil and true rosettes (ETANTR): report of a Collins VP (1992). Amplified and rearran-
575. Deshmukh H, Yu J, Shaik J, MacDonald Common variation at 10p12.31 near MLLT10 case with prominent neurocytic differentiation. J ged epidermal growth factor receptor genes
TJ, Perry A, Payton JE, et al. (2011). Identifi- influences meningioma risk. Nat Genet. Neurooncol. 84(1):91-8. PMID:17332950 in human glioblastomas reveal deletions of
cation of transcriptional regulatory networks 43(9):825-7. PMID:21804547 612. Dunham C, Yip S (2013). Cribriform neu- sequences encoding portions of the N- and/
specific to pilocytic astrocytoma. BMC Med 594. Doglioni C, Dell’Orto P, Coggi G, luzzo- roepithelial tumor or atypical teratoid/rhabdoid or C-terminal tails. Proc Natl Acad Sci U S A .
Genomics. 4:57. PMID:21745356 lino P, Bontempini L, Viale G (1987). Choroid tumor? J Neurosurg Pediatr. 11 (4):486-8. 89(10):4309-13. PMID:1584765
576. Desouza RM, Bodi I, Thomas N, Marsh H, plexus tumors. An immunocytochemical study PMID:23394355 628. Elefteriou F, Kolanczyk M, Schindeler
Crocker M (2010). Chordoid glioma: ten years with particular reference to the coexpression 613. Duo D, Gasverde S, Benech F, Zenga F, A, Viskochil DH, Hock JM, Schorry EK, et al.
of a low-grade tumor with high morbidity. Skull of intermediate filament proteins. Am J Pathol. Giordana MT (2003). MIB-1 immunoreactivity (2009). Skeletal abnormalities in neurofibro-
Base. 20(2):125-38. PMID:20808539 127(3):519-29. PMID:2438940 in craniopharyngiomas: a clinico-pathological matosis type 1: approaches to therapeutic op-
577. Dessauvagie BF, Wong G, Robbins PD 595. Dohrmann GJ, Farwell JR, Flannery JT analysis. Clin Neuropathol. 22(5):229-34. tions. Am J Med Genet A. 149A(10):2327-38.
(2015). Renal cell carcinoma to haemangiob- (1976). Glioblastoma multiforme in children. J PMID:14531547 PMID:19764036
lastoma metastasis: a rare manifestation of Neurosurg. 44(4):442-8. PMID:176331 614. Dumo CA, Aronson M, Tabori U, Malkin 629. Ellezam B, Theeler BJ, Luthra R, Adesina
Von Hippel-Lindau syndrome. J Clin Neurosci. 596. Dolecek TA, Propp JM, Stroup NE, Kruch- D, Gallinger S, Chan HS (2012). Oncologic AM, Aldape KD, Gilbert MR (2012). Recurrent
22(1 ):215-8. PMID:25088480 ko C (2012). CBTRUS statistical report: primary surveillance for subjects with biallelic mismatch PIK3CA mutations in rosette-forming glioneu-
578. Dewan R, Pemov A, Kim HJ, Morgan brain and central nervous system tumors diag- repair gene mutations: 10 year follow-up of a ronal tumor. Acta Neuropathol. 123(2):285-7.
KL, Vasquez RA, Chittiboina P, et al. (2015). nosed in the United States in 2005-2009. Neu- kindred. Pediatr Blood Cancer. 59(4):652-6. PMID:21997360
Evidence of polyclonality in neurofibromatosis ro Oncol. 14 Suppl 5:v1-49. PMID:23095881 PMID:22180144 630. Ellison DW (2010). Childhood medullob-
type 2-associated multilobulated vestibular 597. Donoho D, Zada G (2015). Imaging of 615. Durno CA, Sherman PM, Aronson M, Mal- lastoma: novel approaches to the classification
schwannomas. Neuro Oncol. 17(4):566-73. central neurocytomas. Neurosurg Clin N Am. kin D, Hawkins C, Bakry D, et al.; International of a heterogeneous disease. Acta Neuropathol.
PMID:25452392 26(1):11-9. PMID:25432179 BMMRD Consortium (2015). Phenotypic and 120(3):305-16. PMID:20652577
580. Dhimes P, Martinez-Gonzalez MA, Cara- 598. Donovan MJ, Yunis EJ, DeGirolami U, genotypic characterisation of biallelic mismatch 631. Ellison DW, Dalton J, Kocak M, Nichol-
cas E, Perez-Espejo G (1996). Ultrastructural Fletcher JA, Schofield DE (1994). Chromoso- repair deficiency (BMMR-D) syndrome. Eur J son SL, Fraga C, Neale G, et al. (2011). Me-
study of a perineurioma with ribosome-lamella me aberrations in choroid plexus papillomas. Cancer. 51(8):977-83. PMID:25883011 dulloblastoma: clinicopathological correlates
complexes. Ultrastruct Pathol. 20(2):167-72. Genes Chromosomes Cancer. 11 (4):267-70. 616. Eaton KW, Tooke LS, Wainwright LM, of SHH, WNT, and non-SHH/WNT molecular
PMID:8882362 PMID:7533531 Judkins AR, Biegel JA (2011). Spectrum of subgroups. Acta Neuropathol. 121(3):381-96.
581. Di Cristofano A, Pesce B, Cordon-Cardo 599. Donson AM, Kleinschmidt-DeMasters BK, SMARCB1/INI1 mutations in familial and spo- PMID:21267586
C, Pandolfi PP (1998). Pten is essential for em- Aisner DL, Bemis LT, Birks DK, Levy JM, et radic rhabdoid tumors. Pediatr Blood Cancer. 632. Ellison DW, Kocak M, Dalton J, Megahed
bryonic development and tumour suppression. al. (2014). Pediatric brainstem gangliogliomas 56(1)7-15. PMID:21108436 H, Lusher ME, Ryan SL, et al. (2011). Definition
Nat Genet. 19(4):348-55. PMID:9697695 show BRAF(V600E) mutation in a high percen- 617. Eberhart CG (2007). In search of the me- of disease-risk stratification groups in childhood
582. Di Rocco F, Carroll RS, Zhang J, Black tage of cases. Brain Pathol. 24(2):173-83. dulloblast: neural stem cells and embryonal medulloblastoma using combined clinical, pa-
PM (1998). Platelet-derived growth factor PMID:24238153 brain tumors . Neurosurg Clin N Am 18: 59-69, thologic, and molecular variables. J Clin Oncol.
and its receptor expression in human oligo- 600. Doskaliyev A, Yamasaki F, Kenjo M, Sh- viii-ix. PMID:17244554 29(11):1400-7. PMID:20921458
dendrogliomas. Neurosurgery. 42(2):341-6. restha P, Saito T, Hanaya R, et al. (2008). 618. Eberhart CG, Brat DJ, Cohen KJ, Bur- 633. Ellison DW, Kocak M, Figarella-Branger D,
PMID:9482185 Secondary anaplastic oligodendroglioma after ger PC (2000). Pediatric neuroblastic brain Felice G, Catherine G, Pietsch T, et al. (2011).
583. Di Rocco F, Sabatino G, Koutzoglou M, cranial irradiation: a case report. J Neurooncol. tumors containing abundant neuropil and true Histopathological grading of pediatric ependy-
Battaglia D, Caldarelli M, Tamburrini G (2004). 88(3):299-303. PMID:18373067 rosettes. Pediatr Dev Pathol. 3(4):346-52. moma: reproducibility and clinical relevance in
Neurocutaneous melanosis. Childs Nerv Syst. 601. Dougherty MJ, Santi M, Brose MS, Ma C, PMID:10890250 European trial cohorts. J Negat Results Bio-
20(1):23-8. PMID:14576958 Resnick AC, Sieved AJ, etal. (2010). Activating 619. Eberhart CG, Kepner JL, Goldthwaite PT, med. 10:7. PMID:21627842
584. Dias-Santagata D, Lam Q, Vernovsky mutations in BRAF characterize a spectrum Kun LE, Duffner PK, Friedman HS, et al. (2002). 634. Ellison DW, Onilude OE, Lindsey JC, Lus-
K, Vena N, Lennerz JK, Borger DR, et al. of pediatric low-grade gliomas. Neuro Oncol. Histopathologic grading of medulloblastomas: her ME, Weston CL, Taylor RE, et al.; United
(2011). BRAF V600E mutations are common 12(7):621-30. PMID:20156809 a Pediatric Oncology Group study. Cancer. Kingdom Children’s Cancer Study Group Brain
in pleomorphic xanthoastrocytoma: diagno- 602. Douglas-Akinwande AC, Payner TD, 94(2):552-60. PMID:11900240 Tumour Committee (2005). beta-catenin status
stic and therapeutic implications. PLoS One. Hattab EM (2009). Medulloblastoma mimi- 620. Eberhart CG, Kratz J, Wang Y, Summers predicts a favorable outcome in childhood me-
6(3):e17948. PMID',21479234 cking Lhermitte-Dudos disease on MRI and K, Stearns D, Cohen K, et al. (2004). Histopa- dulloblastoma: the United Kingdom Children’s
585. Diaz-Flores L, Alvarez-Argiielles H, Madrid CT. Clin Neurol Neurosurg. 111(6):536-9. thological and molecular prognostic markers Cancer Study Group Brain Tumour Committee.
JF, Varela H, Gonzalez MP, Gutierrez R (1997). PMID:19233547 in medulloblastoma: c-myc, N-myc, TrkC, J Clin Oncol. 23(31)7951-7. PMID:16258095
Perineurial cell tumor (perineurioma) with 603. Dragojevic S, Mehraein P, Bock HJ (1973). and anaplasia. J Neuropathol Exp Neurol. 635. Ellison DW, Zygmunt SC, Weller RO
granular cells. J Cutan Pathol. 24(9):575-9. [Lipoma of the temporal region with cortical 63(5):441-9. PMID:15198123 (1993). Neurocytoma/lipoma (neurolipocytoma)
PMID:9404856 malformation and epilepsy. Clinicopathological 621. Ebert C, von Haken M, Meyer-Puttlitz of the cerebellum. Neuropathol Appl Neurobiol.
586. Dim DC, Lingamfelter DC, Taboada EM, study (author's transl)]. Arch Psychiatr Nervenkr B, Wiestler OD, Reifenberger G, Pietsch T, 19(1):95-8. PMID:8474606
Fiorella RM (2006). Papillary glioneuronal tu- (1970). 217(4):335-42. PMID:4203636 et al. (1999). Molecular genetic analysis of 636. Elowe-Gruau E, Beltrand J, Brauner R,
mor: a case report and review of the literature. 604. Dratman MB (1979). Mechanism of thy- ependymal tumors. NF2 mutations and chro- Pinto G, Samara-Boustani D, Thalassinos C, et
Hum Pathol. 37(7):914-8. PMID:16784993 roxine action. N Engl J Med. 300(23):1336. mosome 22q loss occur preferentially in intra- al. (2013). Childhood craniopharyngioma: hypo-
587. Dinger A, Yener U, Ozek MM (2011). Hy- PMID:220535 medullary spinal ependymomas. Am J Pathol. thalamus-sparing surgery decreases the risk of
drocephalus in patients with neurofibromatosis 605. Dropcho EJ, Soong SJ (1996). The pro- 155(2):627-32. PMID:10433955 obesity. J Clin Endocrinol Metab. 98(6):2376-
type 1: MR imaging findings and the outcome gnostic impact of prior low grade histology in 622. Eckel-Passow JE, Lachance DH, Mo- 82. PMID:23633208
of endoscopic third ventriculostomy. AJNR Am patients with anaplastic gliomas: a case-control linaro AM, Walsh KM, Decker PA, Sicotte 637. Emory TS, Scheithauer BW, Hirose T,
J Neuroradiol. 32(4):643-6. PMID:21330395 study. Neurology. 47(3):684-90. PMID:8797465 H, et al. (2015). Glioma Groups Based on Wood M, Onofrio BM, Jenkins RB (1995). Intra-
588. Dinda AK, Sarkar C, Roy S (1990). 606. Ducatman BS, Scheithauer BW, Piepgras 1p/19q, IDH, and TERT Promoter Mutations neural perineurioma. A clonal neoplasm associ-
Rosenthal fibres: an immunohistochemical, DG, Reiman HM, llstrup DM (1986). Malignant in Tumors. N Engl J Med. 372(26):2499-508. ated with abnormalities of chromosome 22. Am
ultrastructural and immunoelectron micros- peripheral nerve sheath tumors. A clinicopatho- PMID:26061753 J Clin Pathol. 103(6):696-704. PMID7785653
copic study. Acta Neuropathol. 79(4):456-60. logic study of 120 cases. Cancer. 57(10):2006- 623. Eckhardt BP, Brandner S, Zollikofer CL, 638. En-Nafaa I, Latib R, Fikri M, Cisse A, El
PMID:2339597 21. PMID:3082508 Wentz KU (2004). Primary cerebral leiomyos- Kettani N, Chami I, et al. (2010). [Frontoparietal
589. Ding H, Shannon P, Lau N, Wu X, Roncari 607. Ducray F, Criniere E, Idbaih A, Mokhtari K, arcoma in a child. Pediatr Radiol. 34(6):495-8. paraganglioma: a case report]. J Radiol. 91(12
L, Baldwin RL, et al. (2003). Oligodendroglio- Marie Y, Paris S, et al. (2009). alpha-lntemexin PMID:15057493 Pt 1):1318-9. PMID:21242920
mas result from the expression of an activated expression identifies 1p19q codeleted gliomas. 624. Edwards A, Bermudez C, Piwonka G, Berr 639. Ene Cl, Morton RP, Ferreira M Jr, Sekhar
mutant epidermal growth factor receptor in a Neurology. 72(2):156-61. PMID:19139367 ML, Zamorano J, Larrain E, et al. (2002). Car- LN, Kim LJ (2015). Spontaneous Hemorrhage
RAS transgenic mouse astrocytoma model. 608. Ducray F, Idbaih A, de Reynies A, Bieche ney's syndrome: complex myxomas. Report of from Central Nervous System Hemangiob-
Cancer Res. 63(5):1106-13. PMID:12615729 I, Thillet J, Mokhtari K, et al. (2008). Anaplastic four cases and review of the literature. Cardio- lastomas. World Neurosurg. 83(6): 1180,e13-7.
590. Dirks PB, Harris L, Hoffman HJ, oligodendrogliomas with 1 p19q codeletion have vasc Surg. 10(3):264-75. PMID:12044436 PMID:25727302
Humphreys RP, Drake JM, Rutka JT (1996). a proneural gene expression profile. Mol Can- 625. Eigenbrod S, Roeber S, Thon N, Giese 640. Eng C (1997). Cowden Syndrome. J Genet
Supratentorial primitive neuroectodermal tu- cer. 7:41. PMID:18492260 A, Krieger A, Grasbon-Frodl E, et al. (2011). Couns. 6(2):181-92. PMID:26142096
mors in children. J Neurooncol. 29(1 ):75-84. 609. Duffell D, Farber L, Chou S, Hartmann JF, o-lntemexin in the diagnosis of oligodendro- 641. Eng C, Murday V, Seal S, Mohammed
PMID:8817418 Nelson E (1963). Electron microscopic observa- glial tumors and association with 1p/19q sta- S, Hodgson SV, Chaudary MA, et al. (1994).
591. Dirks PB, Jay V, Becker LE, Drake JM, tions on astrocytomas. Am J Pathol. 43:539-45. tus. J Neuropathol Exp Neurol. 70(11):970-8. Cowden syndrome and Lhermitte-Duclos di-
Humphreys RP, Hoffman HJ, et al. (1994). De- PMID:14068386 PMID:22002423 sease in a family: a single genetic syndrome
velopment of anaplastic changes in low-grade 610. DuffnerPK, Horowitz ME, KrischerJP, Bur- 626. Ekstrand AJ, James CD, Cavenee WK, with pleiotropy? J Med Genet. 31(6):458-61.
astrocytomas of childhood. Neurosurgery. ger PC, Cohen ME, Sanford RA, et al. (1999). Seliger B, Pettersson RF, Collins VP (1991). PMID:8071972
34(1 ):68-78. PMID:8121571 The treatment of malignant brain tumors in in- Genes for epidermal growth factor receptor, 642. Eng C, Peacocke M (1998). PTEN and
592. do Nascimento A, Maranha LA, Correda- fants and very young children: an update of the transforming growth factor alpha, and epider- inherited hamartoma-cancer syndromes. Nat
to RA, Araujo JC, Bleggi-Torres LF (2012). 33 Pediatric Oncology Group experience. Neuro mal growth factor and their expression in human Genet. 19(3):223. PMID:9662392
year-old woman with a large sellar tumor. Brain Oncol. 1(2):152-61. PMID:11554387 gliomas in vivo. Cancer Res. 51(8):2164-72. 643. Eng DY, DeMonte F, Ginsberg L, Fuller GN,
References 365
Jaeckle K (1997). Craniospinal dissemination of medulloblastoma. Br J Cancer. 64(5):959-61. Mohamed FB, Chen CY, Stein H (1997). Para- Oligodendroglial tumors: refinement of candida-
central neurocytoma. Report of two cases. J PMID:1931625 ganglioma of the cauda equina with associated te regions on chromosome arm 1p and correla-
Neurosurg. 86(3):547-52. PMID:9046315 658. Evans DG, Howard E, Giblin C, Clancy intramedullary cyst: MR findings. AJNR Am J tion of 1p/19q status with survival. Brain Pathol.
644. Eoli M, Menghi F, Bruzzone MG, De Simo- T, Spencer H, Huson SM, et al. (2010). Birth Neuroradiol. 18(8):1588-90. PMID:9296205 14(2):121-30. PMID:15193024
ne T, Valletta L, Polio B, et al. (2007). Methyla- incidence and prevalence of tumor-prone 673. Farwell JR, Dohrmann GJ, Flannery JT 687. Feng M, Carmichael JD, Bonert V, Ban-
tion of 06-methylguanine DNA methyltrans- syndromes: estimates from a UK family ge- (1984). Medulloblastoma in childhood: an epi- nykh S, Mamelak AN (2014). Surgical ma-
ferase and loss of heterozygosity on 19q and/ netic register service. Am J Med Genet A. demiological study. J Neurosurg. 61 (4):657-64. nagement of pituicytomas: case series and
or 17p are overlapping features of secondary 152A(2):327-32. PMID:20082463 PMID:6470775 comprehensive literature review. Pituitary.
glioblastomas with prolonged survival. Clin 659. Evans DG, Huson SM, Donnai D, Neary 674. Fassett DR, Pingree J, Kestle JR (2005). 17(5):399-413. PMID:24037647
Cancer Res. 13(9):2606-13. PMID:17473190 W, Blair V, Newton V, et al. (1992). A clinical The high incidence of tumor dissemination in 688. Fernandez C, Figarella-Branger D, Girard
645. Erdem-Eraslan L, Gravendeel LA, de Rooi study of type 2 neurofibromatosis. Q J Med. myxopapillary ependymoma in pediatric pa- N, Bouvier-Labit C, Gouvernet J, Paz Paredes
J, Eilers PH, Idbaih A, Spliet WG, et al. (2013). 84(304):603-18. PMID:1484939 tients. Report of five cases and review of the A, et al. (2003), Pilocytic astrocytomas in child-
Intrinsic molecular subtypes of glioma are prog- 660. Evans DG, Ladusans EJ, Rimmer S, Bur- literature. J Neurosurg. 102(1) Suppl:59-64. ren: prognostic factors-a retrospective study of
nostic and predict benefit from adjuvant procar- nell LD, Thakker N, Farndon PA (1993). Com- PMID:16206735 80 cases. Neurosurgery. 53(3):544-53, discus-
bazine, lomustine, and vincristine chemothera- plications of the naevoid basal cell carcinoma 675. Fassunke J, Majores M, Tresch A, Niehus- sion 554-5. PMID:12943571
py in combination with other prognostic factors syndrome: results of a population based study. mann P, Grate A, Schoch S, et al. (2008). Array 689. Fernandez C, Girard N, Paz Paredes A,
in anaplastic oligodendroglial brain tumors: a J Med Genet. 30(6):460-4. PMID:8326488 analysis of epilepsy-associated gangliogliomas Bouvier-Labit C, Lena G, Figarella-Branger D
report from EORTC study 26951. J Clin Oncol. 661. Evans DG, Mason S, Huson SM, Ponder reveals expression patterns related to aberrant (2003). The usefulness of MR imaging in the
31 (3):328-36. PMID:23269986 M, Harding AE, Strachan T (1997). Spinal and development of neuronal precursors. Brain. diagnosis of dysembryoplastic neuroepithelial
646. Erickson ML, Johnson R, Bannykh SI, cutaneous schwannomatosis is a variant form 131 (Pt 11 ):3034-50. PMID:18819986 tumor in children: a study of 14 cases. AJNR Am
de Lotbiniere A, Kim JH (2005). Malignant of type 2 neurofibromatosis: a clinical and mo- 676. Fauchon F, Hasselblatt M, Jouvet A, J Neuroradiol. 24(5):829-34. PMID:12748079
rhabdoid tumor in a pregnant adult female: lecular study. J Neurol Neurosurg Psychiatry. Champier J, Popovic M, Kirollos R, et al. (2013). 690. Fernandez-L A, Northcott PA, Dalton J,
literature review of central nervous system 62(4):361-6. PMID:9120449 Role of surgery, radiotherapy and chemothera- Fraga C, Ellison D, Angers S, et al. (2009).
rhabdoid tumors. J Neurooncol. 74(3):311-9. 662. Evans DG, Moran A, King A, Saeed S, py in papillary tumors of the pineal region: a YAP1 is amplified and up-regulated in hedge-
PMID:16132523 Gurusinghe N, Ramsden R (2005). Incidence multicenter study. J Neurooncol. 112(2):223- hog-associated medulloblastomas and medi-
647. Eriandson RA (1994). Paragangliomas. of vestibular schwannoma and neurofibro- 31. PMID:23314823 ates Sonic hedgehog-driven neural precursor
Diagnostic Transmission Electron Microscopy matosis 2 in the North West of England over 677. Fauchon F, Jouvet A, Paquis P, Saint-Pier- proliferation. Genes Dev. 23(23):2729-41.
of Tumors. Diagnostic Transmission Electron a 10-year period: higher incidence than pre- re G, Mottolese C, Ben Hassel M, et al. (2000). PMID:19952108
Microscopy of Tumors. New York: Raven Press; viously thought. Otol Neurotol. 26(1):93-7. Parenchymal pineal tumors: a clinicopathologi- 691. Femer RE, Hughes RA, Hall SM,
pp. 615-22. PMID:15699726 cal study of 76 cases. Int J Radiat Oncol Biol Upadhyaya M, Johnson MR (2004). Neuro-
648. Eriandson RA, Woodruff JM (1982). Peri- 663. Evans DG, O'Hara C, Wilding A, Ingham Phys. 46(4):959-68. PMID:10705018 fibromatous neuropathy in neurofibromato-
pheral nerve sheath tumors: an electron micros- SL, Howard E, Dawson J, et al. (2011). Morta- 677A. Faulkner C, Ellis HP, Shaw A, Penman sis 1 (NF1). J Med Genet. 41(11):837-41.
copic study of 43 cases. Cancer. 49(2):273-87. lity in neurofibromatosis Tin North West Eng- C, Palmer A, Wragg C, et al. (2015). BRAF PMID:15520408
PMID:7053827 land: an assessment of actuarial survival in a Fusion Analysis in Pilocytic Astrocytomas: 692. Ferreri AJ, Dell’Oro S, Capello D, Ponzoni
649. Emestus Rl, Schroder R, Stiitzer H, Klug region of the UK since 1989. Eur J Hum Genet. KIAA1549-BRAF 15-9 Fusions Are More Fre- M, luzzolino P, Rossi D, et al. (2004). Aberrant
N (1996). Prognostic relevance of localization 19(11):1187-91. PMID:21694737 quent in the Midline Than Within the Cerebel- methylation in the promoter region of the re-
and grading in intracranial ependymomas of 664. Evans DG, Wallace AJ, Wu CL, Trueman lum. J Neuropathol Exp Neurol. 74(9):867-72. duced folate carrier gene is a potential mecha-
childhood. Childs Nerv Syst. 12(9):522-6. L, Ramsden RT, Strachan T (1998). Somatic PMID:26222501 nism of resistance to methotrexate in primary
PMID:8906366 mosaicism: a common cause of classic disea- 678. Faulkner C, Palmer A, Williams H, Wragg central nervous system lymphomas. Br J Hae-
650. Ernestus Rl, Schroder R, Stiitzer H, Klug se in tumor-prone syndromes? Lessons from C, Haynes HR, White P, et al. (2014). EGFR matol. 126(5):657-64. PMID:15327516
N (1997). The clinical and prognostic relevance type 2 neurofibromatosis. Am J Hum Genet. and EGFRvlll analysis in glioblastoma as 693. Ferreri AJ, Reni M, Pasini F, Calderoni A,
of grading in intracranial ependymomas. Br J 63(3):727-36. PMID:9718334 therapeutic biomarkers. Br J Neurosurg. 1-7. Tirelli U, Pivnik A, et al. (2002). A multicenter
Neurosurg. 11(5):421-8. PMID:9474274 665. Fakhran S, Escott EJ (2008). Pineocytoma PMID:25141189 study of treatment of primary CNS lymphoma.
651. Errani C, Zhang L, Sung YS, Hajdu M, mimicking a pineal cyst on imaging: true diag- 679. Fauria-Robinson C, Nguyen J, Palacios Neurology. 58(10):1513-20. PMID:12034789
Singer S, Maki RG, et al. (2011). A novel nostic dilemma or a case of incomplete ima- E, Castillo-Jorge S (2014). Dysplastic cere- 694. Ferry JA, Harris NL, Picker LJ, Weinberg
WWTR1-CAMTA1 gene fusion is a consistent ging? AJNR Am J Neuroradiol. 29(1):159-63. bellar gangliocytoma Ihermitte-duclos disease DS, Rosales RK, Tapia J, et al. (1988). Intra-
abnormality in epithelioid hemangioendothelio- PMID:17925371 imaging and magnetic resonance spectros- vascular lymphomatosis (malignant angioen-
ma of different anatomic sites. Genes Chromo- 666. Fallon KB, Palmer CA, Roth KA, Nabors copy. J La State Med Soc. 166(5):193-6. dotheliomatosis). A B-cell neoplasm expres-
somes Cancer. 50(8):644-53. PMID:21584898 LB, Wang W, Carpenter M, et al. (2004). Pro- PMID:25369219 sing surface homing receptors. Mod Pathol.
652. Erson-Omay EZ, Qaglayan AO, Schultz gnostic value of 1p, 19q, 9p, 10q, and EG- 680. Favier J, Gimenez-Roqueplo AP (2010). 1 (6):444-52. PMID:3065781
N, Weinhold N, Omay SB, Ozduman K, et FR-FISH analyses in recurrent oligodendroglio- Pheochromocytomas: the (pseudo)-hypoxia 695. Fetsch JF, Miettinen M (1997). Sclerosing
al. (2015). Somatic POLE mutations cause mas. J Neuropathol Exp Neurol. 63(4):314-22. hypothesis. Best Pract Res Clin Endocrinol Me- perineurioma: a clinicopathologic study of 19
an ultramutated giant cell high-grade glioma PMID:15099021 tab. 24(6):957-68. PMID:21115164 cases of a distinctive soft tissue lesion with a
subtype with better prognosis. Neuro Oncol. 667. Fan Z, Li J, Du J, Zhang H, Shen Y, Wang 681. Feany MB, Anthony DC, Fletcher CD predilection for the fingers and palms of young
17(10):1356-64. PMID:25740784 CY, et al. (2008). A missense mutation in (1998). Nerve sheath tumours with hybrid fea- adults. Am J Surg Pathol. 21(12):1433-42.
653. Esteller M, Garcia-Foncillas J, Andion E, PTCH2 underlies dominantly inherited NBCCS tures of neurofibroma and schwannoma: a con- PMID:9414186
Goodman SN, Hidalgo OF, Vanaclocha V, et in a Chinese family. J Med Genet. 45(5):303-8. ceptual challenge. Histopathology. 32(5):405- 696. Fevre Montange M, Vasiljevic A, Bergemer
al. (2000). Inactivation of the DNA-repair gene PMID:18285427 10. PMID:9639114 Fouquet AM, Bernier M, Champier J, Chretien
MGMT and the clinical response of gliomas to 668. Fanburg-Smith JC, Auerbach A, Marwaha 682. Feigin IH, Gross SW (1955). Sarcoma ari- F, et al. (2012). Histopathologic and ultrastruc-
alkylating agents. N Engl J Med. 343(19):1350- JS, Wang Z, Rushing EJ (2010). Reappraisal sing in glioblastoma of the brain. Am J Pathol. tural features and claudin expression in papil-
4. PMID:11070098 of mesenchymal chondrosarcoma: novel mor- 31 (4):633-53. PMID:14388124 lary tumors of the pineal region: a multicenter
654. Esteller M, Hamilton SR, Burger PC, phologic observations of the hyaline cartilage 683. Feldman DS, Jordan C, Fonseca L (2010). analysis. Am J Surg Pathol. 36(6):916-28.
Baylin SB, Herman JG (1999). Inactivation of and endochondral ossification and beta-ca- Orthopaedic manifestations of neurofibromato- PMID:22588068
the DNA repair gene 06-methylguanine-DNA tenin, Sox9, and osteocalcin immunostaining sis type 1. J Am Acad Orthop Surg. 18(6):346- 697. Fevre Montange M, Vasiljevic A, Champier
methyltransferase by promoter hypermethylati- of 22 cases. Hum Pathol. 41 (5):653-62. 57. PMID:20511440 J, Jouvet A (2015). Papillary tumor of the pineal
on is a common event in primary human neopla- PMID:20138330 683A. Feliciano DM, Quon JL, Su T, Taylor region: Histopathological characterization and
sia. Cancer Res. 59(4):793-7. PMID:10029064 669. Fargen KM, Opalach KJ, Wakefield D, MM, Bordey A (2012). Postnatal neurogenesis review of the literature. Neurochirurgie. 61(2-
655. Euskirchen P, Haroche J, Emile JF, Bu- Jacob RP, Yachnis AT, Lister JR (2011). The generates heterotopias, olfactory micronodu- 3): 138-42 PMID:24556386
chert R, Vandersee S, Meisel A (2015). Com- central nervous system solitary fibrous tumor: les and cortical infiltration following single-cell 698. Fevre-Montange M, Champier J, Szathma-
plete remission of critical neurohistiocytosis by a review of clinical, imaging and pathologic fin- Tsc1 deletion. Hum Mol Genet. 21(4):799-810. ri A, Wierinckx A, Mottolese C, Guyotat J, et al.
vemurafenib. Neurol Neuroimmunol Neuroin- dings among all reported cases from 1996 to PMID:22068588 (2006). Microarray analysis reveals differential
flamm. 2(2):e78. PMID:25745636 2010. Clin Neurol Neurosurg. 113(9):703-10. 684. Felix I, Becker LE (1990-1991). Intracrani- gene expression patterns in tumors of the pine-
655A. Evans DG. Neurofibromatosis 2. 1998 PMID:21872387 al germ cell tumors in children: an immunohis- al region. J Neuropathol Exp Neurol. 65(7):675-
[Updated 2011 Aug 18], In: Pagon RA, Adam 670. Faria C, Miguens J, Antunes JL, Barroso tochemical and electron microscopic study. Pe- 84. PMID:16825954
MP, Ardinger HH, et al., editors. GeneReviews® C, Pimentel J, Martins MdoC, et al. (2008). diatr Neurosurg. 16(3):156-62. PMID:1966857 699. Fevre-Montange M, Hasselblatt M, Fi-
[Internet], Seattle (WA): University of Washing- Genetic alterations in a papillary glioneuron- 685. Fellah S, Caudal D, De Paula AM, Do- garella-Branger D, Chauveinc L, Champier J,
ton, Seattle; 1993-2016. Available from: http:// al tumor. J Neurosurg Pediatr. 1(1):99-102. ry-Lautrec P, Figarella-Branger D, Chinot O, et Saint-Pierre G, et al. (2006). Prognosis and
www.ncbi.nlm.nih.gov/books/NBK1201/ PMID:18352813 ai. (2013). Multimodal MR imaging (diffusion, histopathologic features in papillary tumors of
656. Evans DG, Birch JM, Ramsden RT 671. Famia B, Allen PK, Brown PD, Khatua perfusion, and spectroscopy): is it possible to the pineal region: a retrospective multicenter
(1999). Paediatric presentation of type 2 neu- S, Levine NB, Li J, et al. (2014). Clinical out- distinguish oligodendroglial tumor grade and study of 31 cases. J Neuropathol Exp Neurol.
rofibromatosis. Arch Dis Child. 81(6):496-9. comes and patterns of failure in pineoblasto- 1p/19q codeletion in the pretherapeutic diag- 65(10):1004-11. PMID:17021405
PMID: 10569966 ma: a 30-year, single-institution retrospective nosis? AJNR Am J Neuroradiol. 34(7):1326-33. 700. Fevre-Montange M, Jouvet A, Privat K,
657. Evans DG, Farndon PA, Burnell LD, Gat- review. World Neurosurg. 82(6):1232-41. PMID:23221948 Korf HW, Champier J, Reboul A, et al. (1998).
tamaneni HR, Birch JM (1991). The incidence PMID:25045788 686. Felsberg J, Erkwoh A, Sabel MC, Kirsch Immunohistochemical, ultrastructural, bioche-
of Gorlin syndrome in 173 consecutive cases of 672. Faro SH, Turtz AR, Koenigsberg RA, L, Fimmers R, Blaschke B, et ai. (2004). mical and in vitro studies of a pineocytoma.
366 References
Acta Neuropathol. 95(5):532-9. PMID:9600600 B, Sadetzki S (2011). Possible interaction bet- resolved through single-nucleus sequencing. 745. Fu YJ, Taniguchi Y, Takeuchi S, Shiga A,
701. Fevre-Montange M, Szathmari A, Cham- ween ionizing radiation, smoking, and gender Cancer Discov. 4(8):956-71. PMID:24893890 Okamoto K, Hirato J, et al. (2013). Cerebral
pier J, Mokhtari K, Chretien F, Coulon A, et al. in the causation of meningioma. Neuro Oncol. 732A. Franz DN, Belousova E, Sparagana S, astroblastoma in an adult: an immunohistoche-
(2008). Pineocytoma and pineal parenchymal 13(3):345-52. PMID:21339193 Bebin EM, Frost M, Kuperman R, et al. (2013). mical, ultrastructural and genetic study. Neuro-
tumors of intermediate differentiation presen- 717. Flint-Richter P, Sadetzki S (2007). Ge- Efficacy and safety of everolimus for sub- pathology. 33(3):312-9. PMID:22994361
ting cytologic pleomorphism: a multicenter stu- netic predisposition for the development of ependymal giant cell astrocytomas associated 746. Fu YS, Chen AT, Kay S, Young H (1974).
dy. Brain Pathol. 18(3):354-9. PMID18371183 radiation-associated meningioma: an epide- with tuberous sclerosis complex (EXIST-1): Is subependymoma (subependymal glomerate
702. Fevre-Montange M, Vasiljevic A, Frappaz miological study. Lancet Oncol. 8(5):403-10. a multicentre, randomised, placebo-control- astrocytoma) an astrocytoma or ependymo-
D, Champier J, Szathmari A, Aubriot Lorton MH, PMID:17466897 led phase 3 trial. Lancet. 381(9861)125-32. ma? A comparative ultrastructural and tissue
et al. (2012). Utility of Ki67 immunostaining in 718. Folpe AL (2014). Selected topics in the PMID:23158522 culture study. Cancer. 34(6)1992-2008.
the grading of pineal parenchymal tumours: a pathology of epithelioid soft tissue tumors. Mod 733. Franz DN, Belousova E, Sparagana S, PMID:4434329
multicentre study. Neuropathol Appl Neurobiol. Pathol. 27 Suppl 1:S64-79. PMID:24384854 Bebin EM, Frost M, Kuperman R, et al, (2014). 746A. Fujii K, Miyashita T (2014). Gorlin syn-
38(1 ):87-94. PMID:21696422 719. Folpe AL, Billings SD, McKenney JK, Everolimus for subependymal giant cell ast- drome (nevoid basal cell carcinoma syndro-
703. Figarella-Branger D, Civatte M, Bou- Walsh SV, Nusrat A, Weiss SW (2002). Ex- rocytoma in patients with tuberous sclerosis me): update and literature review. Pediatr Int.
vier-Labit C, Gouvernet J, Gambarelli D, Gentet pression of claudin-1, a recently described tight complex: 2-year open-label extension of the 56(5):667-74. PMID:25131638
JC, et al. (2000). Prognostic factors in intracra- junction-associated protein, distinguishes soft randomised EXIST-1 study. Lancet Oncol. 747. Fujii K, Ohashi H, Suzuki M, Hatsuse H,
nial ependymomas in children. J Neurosurg. tissue perineurioma from potential mimics. Am 15(13)1513-20. PMID:25456370 Shiohama T, Uchikawa H, et al. (2013), Fra-
93(4):605-13. PMID:11014538 J Surg Pathol. 26(12):1620-6. PMID:12459629 734. Frappaz D, Ricci AC, Kohler R, Bret P, meshift mutation in the PTCH2 gene can cause
704. Figarella-Branger D, Gambarelli D, Dollo 720. Font RL, Truong LD (1984). Melanotic Mottolese C (1999). Diffuse brain stem tumor in nevoid basal cell carcinoma syndrome. Fam
C, Devictor B, Perez-Castillo AM, Genitori L, et schwannoma of soft tissues. Electron-micros- an adolescent with multiple enchondromatosis Cancer. 12(4):611-4. PMID:23479190
al. (1991). Infratentorial ependymomas of child- copic observations and review of literature. Am (Ollier's disease). Childs Nerv Syst. 15(5):222- 748. Fujimaki T, Matsutani M, Funada N, Kiri-
hood. Correlation between histological features, J Surg Pathol. 8(2):129-38. PMID:6703189 5. PMID10392492 no T, Takakura K, Nakamura O, et al. (1994).
immunohistological phenotype, silver nucleolar 721. Fontebasso AM, Papillon-Cavanagh S, 735. Frattini V, Trifonov V, Chan JM, Castano CT and MRI features of intracranial germ
organizer region staining values and post-ope- Schwartzentruber J, Nikbakht H, Gerges N, Fi- A, Lia M, Abate F, et al. (2013). The integra- cell tumors. J Neurooncol. 19(3):217-26.
rative survival in 16 cases. Acta Neuropathol. set PO, et al. (2014). Recurrent somatic muta- ted landscape of driver genomic alterations PMID:7807172
82(3):208-16. PMID:1718129 tions in ACVR1 in pediatric midline high-gra- in glioblastoma. Nat Genet. 45(10)1141-9. 749. Fujimoto K, Ohnishi H, Tsujimoto M,
705. Figarella-Branger D, Pellissier JF, Dau- de astrocytoma. Nat Genet. 46(5):462-6. PMID:23917401 Hoshida T, Nakazato Y (2000). Dysembryo-
mas-Duport C, Delisle MB, Pasquier B, Parent PMID:24705250 736. Frebourg T, Barbier N, Yan YX, Garber JE, plastic neuroepithelial tumor of the cerebellum
M, et al. (1992). Central neurocytomas. Critical 722. Fontebasso AM, Schwartzentruber J, Dreyfus M, Fraumeni J Jr, et al. (1995). Germ- and brainstem. Case report. J Neurosurg.
evaluation of a small-cell neuronal tumor. Am J Khuong-Quang DA, Liu XY, Sturm D, Korshu- line p53 mutations in 15 families with Li-Frau- 93(3):487-9. PMID10969950
Surg Pathol. 16(2):97-109. PMID:1370756 nov A, et al. (2013). Mutations in SETD2 and meni syndrome. Am J Hum Genet. 56(3):608- 750. Fujisawa H, Kurrer M, Reis RM, Yonekawa
706. Figueroa ME, Abdel-Wahab O, Lu C, Ward genes affecting histone H3K36 methylation 15. PMID:7887414 Y, Kleihues P, Ohgaki H (1999). Acquisition of
PS, Patel J, Shih A, et al. (2010). Leukemic target hemispheric high-grade gliomas. Acta 737. Freilich RJ, Thompson SJ, Walker RW, the glioblastoma phenotype during astrocytoma
IDH1 and IDH2 mutations result in a hyper- Neuropathol. 125(5):659-69. PMID:23417712 Rosenblum MK (1995). Adenocarcinomat- progression is associated with loss of heterozy-
methylation phenotype, disrupt TET2 function, 723. Forest F, David A, Arrufat S, Pierron G, ous transformation of intracranial germ cell gosity on 10q25-qter. Am J Pathol. 155(2):387-
and impair hematopoietic differentiation. Can- Ranchere-Vince D, Stephan JL, et al. (2012). tumors. Am J Surg Pathol. 19(5):537-44. 94. PMID:10433932
cer Cell. 18(6):553-67. PMID:21130701 Conventional chondrosarcoma in a survivor PMID:7726363 751. Fujisawa H, Marukawa K, Hasegawa M,
707. Fine SW, McClain SA, Li M (2004). Im- of rhabdoid tumor: enlarging the spectrum of 738. Frenk E, Marazzi A (1984). Neurofibroma- Tohma Y, Hayashi Y, Uchiyama N, et al. (2002).
munohistochemical staining for calretinin is tumors associated with SMARCB1 germline tosis of von Recklinghausen: a quantitative stu- Genetic differences between neurocytoma
useful for differentiating schwannomas from mutations. Am J Surg Pathol. 36(12):1892-6. dy of the epidermal keratinocyte and melanocy- and dysembryoplastic neuroepithelial tumor
neurofibromas. Am J Clin Pathol. 122(4):552-9. PMID:23154773 te populations. J Invest Dermatol. 83(1):23-5. and oligodendroglial tumors. J Neurosurg.
PMID:15487453 724. Forshew T, Tatevossian RG, Lawson PMID:6203987 97(6)1350-5. PMID12507133
708. Fischer I, Gagner JP, Law M, Newcomb AR, Ma J, Neale G, Ogunkolade BW, et al. 739. Freudenstein D, Wagner A, Bornemann 752. Fujisawa H, Reis RM, Nakamura M, Co-
EW, Zagzag D (2005). Angiogenesis in gliomas: (2009). Activation of the ERK/MAPK pathway: A, Ernemann U, Bauer T, Duffner F (2004). Pri- lella S, Yonekawa Y, Kleihues P, et al. (2000).
biology and molecular pathophysiology Brain a signature genetic defect in posterior fossa pi- mary melanocytic lesions of the CNS: report of Loss of heterozygosity on chromosome 10 is
Pathol. 15(4):297-310. PMID:16389942 locytic astrocytomas. J Pathol. 218(2):172-81. five cases. Zentralbl Neurochir. 65(3)146-53. more extensive in primary (de novo) than in
709. Fisher PG, Breiter SN, Carson BS, Wha- PMID:19373855 PMID15306980 secondary glioblastomas. Lab Invest. 80(1):65-
ram MD, Williams JA, Weingart JD, et al. 725. Forsyth PA, Shaw EG, Scheithauer BW, 739A. Friedman JM. Neurofibromatosis 1.1998 72. PMID10653004
(2000). A clinicopathologic reappraisal of brain O’Fallon JR, Layton DD Jr, Katzmann JA [Updated 2014 Sep 4], In: Pagon RA.Adam MP, 753. Fujisawa H, Tohma Y, Muramatsu N, Kida
stem tumor classification. Identification of pi- (1993). Supratentorial pilocytic astrocytomas. A Ardinger HH, et al., editors. GeneReviews® [In- S, Kaizaki Y, Tamamura H (2012). Spindle cell
locystic astrocytoma and fibrillary astrocytoma clinicopathologic, prognostic, and flow cytomet- ternet], Seattle (WA): University of Washington, oncocytoma of the adenohypophysis with mar-
as distinct entities. Cancer. 89(7):1569-76. ric study of 51 patients. Cancer. 72(4):1335-42. Seattle; 1993-2016. Available from: http://www. ked hypervascularity. Case report. Neurol Med
PMID:11013373 PMID:8339223 ncbi.nlm.nih.gov/books/NBK1109/ Chir (Tokyo). 52(8):594-8. PMID:22976144
710. Fix SE, Nelson J, Schochet SS Jr (1989). 726. Foster RD, Williams ML, Barkovich AJ, 740. Friedman JM, Arbiser J, Epstein JA, 754. FukudaT.Akiyama N, Ikegami M.Takahas-
Focal leptomeningeal rhabdomyomatosis of Hoffman WY, Mathes SJ, Frieden IJ (2001). Gutmann DH, Huot SJ, Lin AE, et al. (2002). hi H, Sasaki A, Oka H, et al. (2010). Expression
the posterior fossa. Arch Pathol Lab Med. Giant congenital melanocytic nevi: the signifi- Cardiovascular disease in neurofibromatosis 1: of hydroxyindole-O-methyltransferase enzyme
113(8):872-3. PMID:2757487 cance of neurocutaneous melanosis in neuro- report of the NF1 Cardiovascular Task Force. in the human central nervous system and in
711. Flament-Durand J, Brion JP (1985). Tany- logically asymptomatic children. Plast Reconstr Genet Med. 4(3)105-11. PMID12180143 pineal parenchymal cell tumors. J Neuropathol
cytes: morphology and functions: a review. Int Surg. 107(4):933-41. PMID:11252085 741. Friedrich C, Warmuth-Metz M, von Bueren Exp Neurol. 69(5):498-510. PMID:20418777
Rev Cytol. 96:121-55. PMID:2416706 727. Fouladi M, Helton K, Dalton J, Gilger E, AO, Nowak J, Bison B, von Hoff K, et al. (2015). 755. Fukuda T, Yasumichi K, Suzuki T (2008).
712. Flamme I, Krieg M, Plate KH (1998). Gajjar A, Merchant T, et al. (2003). Clear cell Primitive neuroectodermal tumors of the brains- Immunohistochemistry of gliosarcoma with
Up-regulation of vascular endothelial growth ependymoma: a clinicopathologic and ra- tem in children treated according to the HIT liposarcomatous differentiation. Pathol Int.
factor in stromal cells of hemangioblastomas diographic analysis of 10 patients. Cancer. trials: clinical findings of a rare disease. J Neu- 58(6):396-401. PMID18477220
is correlated with up-regulation of the tran- 98(10):2232-44. PMID:14601094 rosurg Pediatr. 15(3):227-35. PMID:25555122 756. Fukunaga M (2001). Unusual malignant
scription factor HRF/HIF-2alpha. Am J Pathol. 728. Foulkes WD, Clarke BA, Hasselblatt 742. Fritchie KJ, Carver P, Sun Y, Batiouchko perineurioma of soft tissue. Virchows Arch.
153(1):25-9. PMID:9665461 M, Majewski J, Albrecht S, McCluggage WG G, Billings SD, Rubin BP, et al. (2012). Solitary 439(2):212-4. PMID11561764
713. Flannery T, Cawley D, Zulfiger A, Alderazi (2014). No small surprise - small cell carcinoma fibrous tumor: is there a molecular relationship 757. Fukuoka K, Sasaki A, Yanagisawa T, Su-
Y, Heffernan J, Brett F, et al. (2008). Familial of the ovary, hypercalcaemic type, is a malig- with cellular angiofibroma, spindle cell lipoma, zuki T, Wakiya K, Adachi J, et al. (2012). Pineal
occurrence of oligodendroglial tumours. Br J nant rhabdoid tumour. J Pathol. 233(3):209-14. and mammary-type myofibroblastoma? Am J parenchymal tumor of intermediate differenti-
Neurosurg. 22(3):436-8. PMID:18568735 PMID:24752781 Clin Pathol. 137(6):963-70. PMID:22586056 ation with marked elevation of MIB-1 labeling
713A. Flavahan WA, Drier Y, Liau BB, Gillespie 729. Fountas KN, Karampelas I, Nikolakakos 742A. Fritz A, Percy C, Jack A, Shanmugarat- index. Brain Tumor Pathol. 29(4):229-34.
SM, Venteicher AS, Stemmer-Rachamimov AO, LG, Troup EC, Robinson JS (2005). Primary nam K, Sobin L, Parkin DM, et al. (2000). Inter- PMID:22362162
et ai. (2016). Insulator dysfunction and oncoge- spinal cord oligodendroglioma: case report national Classification of Diseases for Oncology 758. Fukushima S, Otsuka A, Suzuki T, Yana-
ne activation in IDH mutant gliomas. Nature. and review of the literature. Childs Nerv Syst. (ICD-O). Third edition. World Health Organiza- gisawa T, Mishima K, Mukasa A, et al.; In-
529(7584):110-4. PMID:26700815 21(2):171-5. PMID:15138790 tion: Geneva. tracranial Germ Cell Tumor Genome Analysis
714. Fletcher CDM, Bridge JA, Hogendoorn 730. Fowler M, Simpson DA (1962). A malig- 743. Fruehwald-Pallamar J, Puchner SB, Consortium (iGCT Consortium) (2014). Mutual-
PCW, Mertens F (2013). WHO Classification nant melanin-forming tumour of the cerebellum. Rossi A, Garre ML, Cama A, Koelblinger C, ly exclusive mutations of KIT and RAS are as-
of Tumours of Soft Tissue and Bone. 4th ed. J Pathol Bacteriol. 84:307-11. PMID:13958991 et al. (2011). Magnetic resonance imaging sociated with KIT mRNA expression and chro-
Lyon: IARC. 731. Fox BD, Cheung VJ, Patel AJ, Suki D, spectrum of medulloblastoma. Neuroradiology. mosomal instability in primary intracranial pure
715. Fletcher CDM, Unni KK, Mertens F, edi- Rao G (2011). Epidemiology of metastatic brain 53(6):387-96. PMID:21279509 germinomas. Acta Neuropathol. 127(6):911-25.
tors. (2002). World Health Organization Classi- tumors. Neurosurg Clin N Am. 22(1):1-6, v. 744. Fryssira H, Leventopoulos G, Psoni S, PMID:24452629
fication of Tumours. Pathology and Genetics of PMID:21109143 Kitsiou-Tzeli S, Stavrianeas N, Kanavakis 759. Fukushima S, Yoshida A, Narita Y, Arita
Tumours of Soft Tissue and Bone. 3rd ed. Lyon: 732. Francis JM, Zhang CZ, Maire CL, Jung E (2008). Tumor development in three pati- H, Ohno M, Miyakita Y, et al. (2015). Multino-
IARC Press. J, Manzo VE, Adalsteinsson VA, et al. (2014). ents with Noonan syndrome. Eur J Pediatr. dular and vacuolating neuronal tumor of the
716. Flint-Richter P, Mandelzweig L, Oberman EGFR variant heterogeneity in glioblastoma 167(9)1025-31. PMID18057963 cerebrum. Brain Tumor Pathol. 32(2)131-6.
References 367
PMID:25146549 776. Gajjar A, Packer RJ, Foreman NK, Cohen 15(1):35-47. PMID:24314616 809. Geyer JR, Sposto R, Jennings M, Boyett
760. Fuld AD, Speck ME, Harris BT, Simmons K, Haas-Kogan D, Merchant TE; COG Brain 792. Gavrilovic IT, Posner JB (2005). Brain me- JM, Axtell RA, Breiger D, et al.; Children’s Can-
NE, Corless CL, Tsongalis GJ, et al. (2011). Tumor Committee (2013). Children’s Oncology tastases: epidemiology and pathophysiology. J cer Group (2005). Multiagent chemotherapy
Primary melanoma of the spinal cord: a case Group’s 2013 blueprint for research: central Neurooncol. 75(1):5-14. PMID:16215811 and deferred radiotherapy in infants with mali-
report, molecular footprint, and review of the nervous system tumors. Pediatr Blood Cancer. 793. Geddes JF, Thom M, Robinson SF, Re- gnant brain tumors: a report from the Children's
literature. J Clin Oncol. 29(17):e499-502. 60(6): 1022-6. PMID:23255213 vesz T (1996). Granular cell change in ast- Cancer Group. J Clin Oncol. 23(30)7621-31.
PMID:21444862 777. Gajjar A, Pfister SM, Taylor MD, Gilbert- rocytic tumors. Am J Surg Pathol. 20(1):55-63. PMID:16234523
761. Fulham MJ, Melisi JW, Nishimiya J, Dwyer son RJ (2014). Molecular insights into pediatric PMID:8540609 810. Geyer JR, Zeltzer PM, Boyett JM, Rorke
AJ, Di Chiro G (1993). Neuroimaging of juvenile brain tumors have the potential to transform 794. Gelabert-Gonzalez M (2005). Paragangli- LB, Stanley P, Albright AL, et al. (1994). Sur-
pilocytic astrocytomas: an enigma. Radiology. therapy. Clin Cancer Res. 20(22):5630-40. omas of the lumbar region. Report of two cases vival of infants with primitive neuroectodermal
189(1):221-5. PMID:8372197 PMID:25398846 and review of the literature. J Neurosurg Spine. tumors or malignant ependymomas of the CNS
762. Fuller C, Fouladi M, Gajjar A, Dalton J, 778. Galan SR, Kann PH (2013). Genetics and 2(3):354-65. PMID:15796363 treated with eight drugs in 1 day: a report from
Sanford RA, Helton KJ (2006). Chromosome molecular pathogenesis of pheochromocyto- 795. Gempt J, Baldawa SS, Weirich G, Del- the Childrens Cancer Group. J Clin Oncol.
17 abnormalities in pediatric neuroblastic tumor ma and paraganglioma. Clin Endocrinol (Oxf). bridge C, Hempel M, Lohse P, et al. (2013). 12(8):1607-15. PMID:8040673
with abundant neuropil and true rosettes. Am J 78(2):165-75. PMID:23061808 Recurrent multiple spinal paragangliomas as 811. Gherardi R, Baudrimont M, Nguyen JP,
Clin Pathol. 126(2):277-83. PMID:16891204 779. Galanis E, Buckner JC, Dinapoli RP, a manifestation of a metastatic composite pa- Gaston A, Cesaro P, Degos JD, et al. (1986).
763. Fuller CE, Perry A (2002). Fluorescence Scheithauer BW, Jenkins RB, Wang CH, et al. raganglioma-ganglioneuroblastoma. Acta Neu- Monstrocellular heavily lipidized malignant
in situ hybridization (FISH) in diagnostic and (1998). Clinical outcome of gliosarcoma compa- rochir (Wien). 155(7):1241-2. PMID:23532344 glioma. Acta Neuropathol. 69(1-2):28-32.
investigative neuropathology. Brain Pathol. red with glioblastoma multiforme: North Central 796. Gempt J, Ringel F, Oexle K, Delbridge PMID:3515829
12(1):67-86. PMID:11770903 Cancer Treatment Group results. J Neurosurg. C, Forschler A, Schlegel J, et al. (2012). Fa- 812. Gheyi V, Hui FK, Doppenberg EM, Todd W,
764. Fuller GN, Bigner SH (1992). Ampli- 89(3):425-30. PMID:9724117 milial pineocytoma. Acta Neurochir (Wien). Broaddus WC (2004). Glioblastoma multiforme
fied cellular oncogenes in neoplasms of the 780. Galli R, Binda E, Orfanelli U, Cipelletti B, 154(8):1413-6. PMID:22699425 causing calvarial destruction: an unusual ma-
human central nervous system. Mutat Res. Gritti A, De Vitis S, et al. (2004). Isolation and 797. George DH, Scheithauer BW, Aker FV, nifestation revisited. AJNR Am J Neuroradiol.
276(3):299-306. PMID:1374522 characterization of tumorigenic, stem-like neu- Kurtin PJ, Burger PC, Cameselle-Teijeiro J, et 25(9):1533-7. PMID:15502132
765. Fuller GN, Hess KR, Rhee CH, Yung WK, ral precursors from human glioblastoma. Can- al. (2003). Primary anaplastic large cell lympho- 813. Ghia AJ, Allen PK, Mahajan A, Penas-Pra-
Sawaya RA, Bruner JM, et al. (2002). Molecular cer Res. 64(19):7011-21. PMID:15466194 ma of the central nervous system: prognostic do M, McCutcheon IE, Brown PD (2013). In-
classification of human diffuse gliomas by mul- 781. Gallina P, Buccoliero AM, Mariotti F, effect of ALK-1 expression. Am J Surg Pathol. tracranial hemangiopericytoma and the role of
tidimensional scaling analysis of gene expres- Mennonna P, Di Lorenzo N (2006). Oncocytic 27(4):487-93. PMID:12657933 radiation therapy: a population based analysis.
sion profiles parallels morphology-based clas- meningiomas: Cases with benign histopatholo- 798. Gerson SL (2004). MGMT: its role in can- Neurosurgery. 72(2):203-9. PMID:23149953
sification, correlates with survival, and reveals gical features and a favorable clinical course. J cer aetiology and cancer therapeutics. Nat Rev 814. Ghia AJ, Chang EL, Allen PK, Mahajan A,
clinically-relevant novel glioma subsets. Brain Neurosurg. 105(5):736-8. PMID:17121136 Cancer. 4(4):296-307. PMID:15057289 Penas-Prado M, McCutcheon IE, et al. (2013).
Pathol. 12(1):108-16. PMID:11771519 782. Gao J, Aksoy BA, Dogrusoz U, Dresdner 799. Gerstner ER, Abrey LE, Schiff D, Ferra- Intracranial hemangiopericytoma: patterns of
766. Fung KM, Fang W, Norton RE, Torres N, G, Gross B, Sumer SO, et al. (2013). Integra- ri AJ, Lister A, Montoto S, et al. (2008). CNS failure and the role of radiation therapy. Neu-
Chu A, Langford LA (2003). Cerebellar central tive analysis of complex cancer genomics and Hodgkin lymphoma. Blood. 112(5):1658-61. rosurgery. 73(4):624-30, discussion 630-1.
liponeurocytoma. Ultrastruct Pathol. 27(2):109- clinical profiles using the cBioPortal. Sci Signal. PMID:18591379 PMID:23839520
14. PMID:12746202 6(269):pl1. PMID:23550210 800. Gessi M, Abdel Moneim Y, Hammes J, 815. Ghose A, Guha G, Kundu R, Tew J, Chau-
767. Furnari FB, Fluang HJ, Cavenee WK 783. Gao X, Zhang Y, Arrazola P, Hino O, Ko- Waha A, Pietsch T (2014). FGFR1 N546K dhary R (2014). CNS Hemangiopericytoma: A
(1998). The phosphoinositol phosphatase bayashi T, Yeung RS, et al. (2002). Tsc tumour mutation in a case of papillary glioneuronal tu- Systematic Review of 523 Patients. Am J Clin
activity of PTEN mediates a serum-sensitive suppressor proteins antagonize amino-acid- mor (PGNT). Acta Neuropathol. 127(6):935-6. Oncol. PMID:25350465
G1 growth arrest in glioma cells. Cancer Res. TOR signalling. Nat Cell Biol. 4(9):699-704. PMID:24777483 816. Giangaspero F, Cenacchi G, Losi L,
58(22):5002-8. PMID:9823298 PMID:12172555 801. Gessi M, Giangaspero F, Lauriola L, Gar- Cerasoli S, Bisceglia M, Burger PC (1997).
768. Furnari FB, Lin FI, Huang HS, Cavenee 784. Garcia DM, Fulling KH (1985), Juvenile pi- diman M, Scheithauer BW, Halliday W, et al. Extraventricular neoplasms with neurocyto-
WK (1997). Growth suppression of glioma cells locytic astrocytoma of the cerebrum in adults. A (2009). Embryonal tumors with abundant neu- ma features. A clinicopathological study of
by PTEN requires a functional phosphatase distinctive neoplasm with favorable prognosis. J ropil and true rosettes: a distinctive CNS primi- 11 cases. Am J Surg Pathol. 21(2):206-12.
catalytic domain. Proc Natl Acad Sci U S A . Neurosurg. 63(3):382-6. PMID:4020465 tive neuroectodermal tumor. Am J Surg Pathol. PMID:9042288
94(23):12479-84. PMID:9356475 785. Garcia-Lavandeira M, Saez C, Diaz-Rodri- 33(2):211-7. PMID:18987548 817. Giangaspero F, Cenacchi G, Roncaroli
769. Furtado A, Arantes M, Silva R, Romao H, guez E, Perez-Romero S, Senra A, Dieguez C, 802. Gessi M, Giangaspero F, Pietsch T F, Rigobello L, Manetto V, Gambacorta M, et
Resende M, Honavar M (2010). Comprehensi- etal. (2012). Craniopharyngiomas express em- (2003). Atypical teratoid/rhabdoid tumors and al. (1996). Medullocytoma (lipidized medul-
ve review of extraventricular neurocytoma with bryonic stem cell markers (SOX2, OCT4, KLF4, choroid plexus tumors: when genetics “sur- loblastoma). A cerebellar neoplasm of adults
report of two cases, and comparison with cen- and SOX9) as pituitary stem cells but do not prise” pathology. Brain Pathol. 13(3):409-14. with favorable prognosis. Am J Surg Pathol.
tral neurocytoma. Clin Neuropathol. 29(3):134- coexpress RET/GFRA3 receptors. J Clin En- PMID:12946029 20(6):656-64. PMID:8651344
40. PMID:20423686 docrinol Metab. 97(1 ):E80-7. PMID:22031517 803. Gessi M, Lambert SR, Lauriola L, Waha 818. Giangaspero F, Chieco P, Ceccarelli C,
770. Furuya K, Takanashi S, Ogawa A, Ta- 786. Gardiman MP, Fassan M, Orvieto E, A, Collins VP, Pietsch T (2012). Absence of Lisignoli G, Pozzuoli R, Gambacorta M, et al.
kahashi Y, Nakagomi T (2014). High-dose D'Avella D, Denaro L, Calderone M, et al. KIAA1549-BRAF fusion in rosette-forming glio- (1991). "Desmoplastic" versus “classic" me-
methotrexate monotherapy followed by radia- (2010). Diffuse leptomeningeal glioneuronal tu- neuronal tumors of the fourth ventricle (RGNT). dulloblastoma: comparison of DNA content,
tion for CD30-positive, anaplastic lymphoma mors: a new entity? Brain Pathol. 20(2):361-6. J Neurooncol. 110(1):21-5. PMID:22814862 histopathology and differentiation. Virchows
kinase-1-positive anaplastic large-cell lympho- PMID:19486008 804. Gessi M, Moneim YA, Hammes J, Go- Arch A Pathol Anat Histopathol. 418(3)207-14.
ma in the brain of a child. J Neurosurg Pediatr. 787. Garre ML, Cama A, Bagnasco F, Morana schzik T, Scholz M, Denkhaus D, et al. (2014). PMID:1900966
14(3):311-5. PMID:25014324 G, Giangaspero F, Brisigotti M, et al. (2009). FGFR1 mutations in Rosette-forming glioneu- 819. Giangaspero F, Guiducci A, Lenz FA,
771. Gabeau-Lacet D, Aghi M, Betensky RA, Medulloblastoma variants: age-dependent ronal tumors of the fourth ventricle. J Neuropa- Mastronardi L, Burger PC (1999). Meningioma
Barker FG, Loeffler JS, Louis DN (2009). Bone occurrence and relation to Gorlin syndrome-a thol Exp Neurol. 73(6)580^1. PMID:24806303 with meningioangiomatosis: a condition mimi-
involvement predicts poor outcome in atypical new clinical perspective. Clin Cancer Res. 805. Gessi M, Setty P, Bisceglia M, zur Muehlen cking invasive meningiomas in children and
meningioma. J Neurosurg. 111(3):464-71. 15(7):2463-71. PMID:19276247 A, Lauriola L, Waha A, et al. (2011). Supraten- young adults: report of two cases and review
PMID:19267533 788. Gasco J, Franklin B, Fuller GN, Salin- torial primitive neuroectodermal tumors of the of the literature. Am J Surg Pathol. 23(8)872-5.
772. Gadish T, Tulchinsky H, Deutsch AA, Ra- as P, Prabhu S (2009). Multifocal epithelioid central nervous system in adults: molecular and PMID:10435554
bau M (2005). Pinealoblastoma in a patient glioblastoma mimicking cerebral metastasis: histopathologic analysis of 12 cases. Am J Surg 820. Giangaspero F, Perilongo G, Fondelli MP,
with familial adenomatous polyposis: variant case report. Neurocirugia (Astur). 20(6):550-4. Pathol. 35(4):573-82. PMID:21378543 Brisigotti M, Carollo C, Burnelli R, et al. (1999).
of Turcot syndrome type 2? Report of a case PMID:19967320 806. Gessi M, von Bueren A, Treszl A, zur Medulloblastoma with extensive nodularity: a
and review of the literature. Dis Colon Rectum. 789. Gaspar LE, Mackenzie IR, Gilbert JJ, Miihlen A, Hartmann W, Warmuth-Metz M, et variant with favorable prognosis. J Neurosurg.
48(12):2343-6. PMID:16400511 Kaufmann JC, Fisher BF, Macdonald DR, et al. al. (2014). MYCN amplification predicts poor 91(6)971-7. PMID:10584843
773. Gaffney EF, Doorly T, Dinn JJ (1986). Ag- (1993). Primary cerebral fibrosarcomas. Clini- outcome for patients with supratentorial pri- 821. Giangaspero F, Rigobello L, Badiali M,
gressive oncocytic neuroendocrine tumour (‘on- copathologic study and review of the literature. mitive neuroectodermal tumors of the central Loda M, Andreini L, Basso G, et al. (1992). Lar-
cocytic paraganglioma’) of the cauda equina. Cancer. 72(11 ):3277-81. PMID:8242554 nervous system. Neuro Oncol. 16(7):924-32. ge-cell medulloblastomas. A distinct variant with
Histopathology. 10(3):311-9. PMID:2422107 790. Gaston-Massuet C, Andoniadou CL, Si- PMID:24470553 highly aggressive behavior. Am J Surg Pathol.
774. Gailani MR, Stahle-Backdahl M, Leffell gnore M, Jayakody SA, Charolidi N, Kyeyune 807. Gessi M, Waha A, Setty P, Waha A, 16(7)687-93. PMID:1530108
DJ, Glynn M, Zaphiropoulos PG, Pressman R, et al. (2011). Increased Wingless (Wnt) si- Pietsch T (2011). Analysis of KIAA1549-BRAF 822. Giangaspero F, Wellek S, Masuoka J, Ges-
C, et al. (1996). The role of the human homo- gnaling in pituitary progenitor/stem cells gives fusion status in a case of rosette-forming glio- si M, Kleihues P, Ohgaki H (2006). Stratification
logue of Drosophila patched in sporadic basal rise to pituitary tumors in mice and humans. neuronal tumor of the fourth ventricle (RGNT). of medulloblastoma on the basis of histopatho-
cell carcinomas. Nat Genet. 14(1):78-81. Proc Natl Acad Sci US A. 108(28):11482-7. Neuropathology. 31(6):654-7. PMID:21518014 logical grading. Acta Neuropathol. 112(1)5-12.
PMID:8782823 PMID:21636786 808. Gessi M, Zur Miihlen A, Hammes J, Waha PMID:16685513
775. Gajjar A, Bhargava R, Jenkins JJ, Heide- 791. Gatta G, Botta L, Rossi S, Aareleid T, A, Denkhaus D, Pietsch T (2013). Genome-wi- 823. Giannini C, Fratkin JD, Wyatt-Ashmead
man R, Sanford RA, Langston JW, et al. (1995). Bielska-Lasota M, Clavel J, et al.; EUROCARE de DNA copy number analysis of desmoplastic J, Aleff PC (2014). Rhabdoid-like meningioma
Low-grade astrocytoma with neuraxis dissemi- Working Group (2014). Childhood cancer survi- infantile astrocytomas and desmoplastic infan- with inclusions consisting of accumulations of
nation at diagnosis. J Neurosurg. 83(1):67-71. val in Europe 1999-2007: results of EUROCA- tile gangliogliomas. J Neuropathol Exp Neurol. complex interdigitating cell processes rather
PMID:7782852 RE-5-a population-based study. Lancet Oncol. 72(9):807-15. PMID:23965740 than intermediate filaments. Acta Neuropathol.
368 References
127(6):937-9. PMID:24691783 M, Tan PH, Agaimy A, et al. (2014). Succinate Acomparative study. J Neuropathol Exp Neurol. Chan J, Dreyfuss JM, Park PJ, et al. (2010).
824. Giannini C, Hebrink D, Scheithauer BW, dehydrogenase (SDH)-deficient renal carci- 31(1)84-71. PMID8060130 Genomic profiling reveals alternative genetic
Dei Tos AP, James CD (2001). Analysis of p53 noma: a morphologically distinct entity: a clini- 859. Goellner JR, Laws ER Jr, Soule EH, Oka- pathways of meningioma malignant progression
mutation and expression in pleomorphic xan- copathologic series of 36 tumors from 27 pa- zaki H (1978). Hemangiopericytoma of the dependent on the underlying NF2 status. Clin
thoastrocytoma. Neurogenetics. 3(3)459-62. tients. Am J Surg Pathol. 38(12):1588-602. meninges. Mayo Clinic experience. Am J Clin Cancer Res. 16(16)4155-64. PMID:20682713
PMID:11523567 PMID:25025441 Pathol. 70(3):375-80. PMID707404 878. Gozali AE, Britt B, Shane L, Gonzalez I,
825. Giannini C, Scheithauer BW, Burger PC, 842. Gimm O, Attie-Bitach T, Lees JA, Vekem- 860. Goerig M (1990). [Comments on the paper Gilles F, McComb JG, et al. (2012). Choroid
Brat DJ, Wollan PC, Lach B, et al. (1999). ans M, Eng C (2000). Expression of the PTEN by J.-P. Jantzen et al. An active charcoal filter plexus tumors; management, outcome, and
Pleomorphic xanthoastrocytoma: what do we tumour suppressor protein during human de- for removing volatile anesthetics]. Anaesthesist. association with the Li-Fraumeni syndrome:
really know about it? Cancer. 85(9):2033-45. velopment. Hum Mol Genet. 9(11):1633-9. 39(12)837-9. PMID:2073047 the Children’s Hospital Los Angeles (CHLA)
PMID:10223246 PMID:10861290 861. Gold JS, Antonescu CR, Hajdu C, Ferrone experience, 1991-2010. Pediatr Blood Cancer.
826. Giannini C, Scheithauer BW, Burger PC, 843. Giorgianni A, Pellegrino C, De Benedictis CR, Hussain M, Lewis JJ, et al. (2002). Clinico- 58(6):905-9. PMID:21990040
Christensen MR, Wollan PC, Sebo TJ, et al. A, MercuriA, Baruzzi F, Minotto R, et al. (2013). pathologic correlates of solitary fibrous tumors. 879. Graadt van Roggen JF, McMenamin ME,
(1999). Cellular proliferation in pilocytic and dif- Lhermitte-Duclos disease. A case report. Neu- Cancer. 94(4):1057-68. PMID:11920476 Belchis DA, Nielsen GP, Rosenberg AE, Flet-
fuse astrocytomas. J Neuropathol Exp Neurol. roradiol J. 26(6)855-60. PMID:24355184 862. Goldman JE, Corbin E (1991). Rosenthal cher CD (2001). Reticular perineurioma: a dis-
58(1 ):46-53. PMID:10068313 844. Gire J, Deveze A, Garcia S, Menelli C, fibers contain ubiquitinated alpha B-crystallin. tinctive variant of soft tissue perineurioma. Am
827. Giannini C, Scheithauer BW, Jenkins RB, Curto CL, Tardivet L, et al. (2008). [Paragan- Am J Pathol. 139(4):933-8. PMID:1656764 J Surg Pathol. 25(4)485-93. PMID:11257623
Erlandson RA, Perry A, Borell TJ, et al. (1997). glioma of the cerebellopontine angle: report of 863. Gomez MR (1991). Phenotypes of the 880. Grabb PA, Albright AL, Pang D (1992). Dis-
Soft-tissue perineurioma. Evidence for an ab- two cases]. Rev Laryngol Otol Rhinol (Bord). tuberous sclerosis complex with a revision of semination of supratentorial malignant gliomas
normality of chromosome 22, criteria for diag- 129(3):213-6. PMID:19694167 diagnostic criteria. Ann N Y Acad Sci. 615:1-7. via the cerebrospinal fluid in children. Neurosur-
nosis, and review of the literature. Am J Surg 845. Giulioni M, Galassi E, Zucchelli M, Volpi PMID:2039135 gery. 30(1)84-71. PMID4738457
Pathol. 21(2):164-73. PMID:9042282 L (2005). Seizure outcome of lesionectomy in 864. Gonzalez KD, Noltner KA, Buzin CH, Gu 882. Graham Dl, Lantos PL, editors. (2002).
828. Giannini C, Scheithauer BW, Lopes MB, glioneuronal tumors associated with epilepsy D, Wen-Fong CY, Nguyen VQ, et al. (2009). Greenfield’s Neuropathology. 7th ed. London:
Hirose T, Kros JM, VandenBerg SR (2002). in children. J Neurosurg. 102(3) Suppl:288-93. Beyond Li Fraumeni Syndrome: clinical charac- Arnold.
Immunophenotype of pleomorphic xanthoast- PMID:15881752 teristics of families with p53 germline mutations. 883. Grajkowska W, Kotulska K, Jurkiewicz E,
rocytoma. Am J Surg Pathol. 26(4):479-85. 846. Gjerris F, Agerlin N, Borgesen SE, Buhl L, J Clin Oncol. 27(8):1250-6. PMID:19204208 Roszkowski M, Daszkiewicz P, Jozwiak S, et
PMID:11914626 Haase J, Klinken L, et al. (1998). Epidemiology 865. Gonzalez-Aguilar A, Idbaih A, Boisselier al. (2011). Subependymal giant cell astrocyto-
829. Giannini C, Scheithauer BW, Steinberg J, and prognosis in children treated for intracranial B, Habbita N, Rossetto M, Laurenge A, et al. mas with atypical histological features mimi-
Cosgrove TJ (1998). Intraventricular perineurio- tumours in Denmark 1960-1984. Childs Nerv (2012). Recurrent mutations of MYD88 and cking malignant gliomas. Folia Neuropathol.
ma: case report. Neurosurgery. 43(6):1478-81, Syst. 14(7):302-11. PMID:9726580 TBL1XR1 in primary central nervous system 49(1)39-46. PMID:21455842
discussion 1481-2. PMID:9848865 847. Gjerris F, Klinken L (1978). Long-term lymphomas. Clin Cancer Res. 18(19)8203-11. 884. Grammel D, Warmuth-Metz M, von Bueren
830. Giannini C, Scheithauer BW, Weaver AL, prognosis in children with benign cerebellar PMID:22837180 AO, Kool M, Pietsch T, Kretzschmar HA, et al.
Burger PC, Kros JM, Mork S, et al. (2001). astrocytoma. J Neurosurg. 49(2):179-84. 866. Gonzalez-Campora R, Weller RO (1998). (2012). Sonic hedgehog-associated medullob-
Oligodendrogliomas: reproducibility and pro- PMID871072 Lipidized mature neuroectodermal tumour lastoma arising from the cochlear nuclei of the
gnostic value of histologic diagnosis and gra- 848. Gleissner B, Chamberlain MC (2006). of the cerebellum with myoid differentiation. brainstem. Acta Neuropathol. 123(4)601-14.
ding. J Neuropathol Exp Neurol. 60(3):248-62. Neoplastic meningitis. Lancet Neurol. 5(5)443- Neuropathol Appl Neurobiol. 24(5)397-402. PMID:22349907
PMID:11245209 52. PMID:16632315 PMID:9821171 885. Grant JW, Steart PV, Aguzzi A, Jones
831. Gibson P, Tong Y, Robinson G, Thompson 849. Glick R, Baker C, Husain S, Hays A, 867. Goodrich LV, Milenkovic L, Higgins KM, DB, Gallagher PJ (1989). Gliosarcoma: an
MC, Currie DS, Eden C, et al. (2010). Subty- Hibshoosh H (1997). Primary melanocytomas Scott MP (1997). Altered neural cell fates and immunohistochemical study. Acta Neuropathol.
pes of medulloblastoma have distinct develop- of the spinal cord: a report of seven cases. Clin medulloblastoma in mouse patched mutants. 79(3)305-9. PMID:2609937
mental origins. Nature. 468(7327): 1095-9. Neuropathol. 16(3):127-32. PMID:9197936 Science. 277(5329): 1109-13. PMID:9262482 886. Gravendeel LA, Kouwenhoven MC, Ge-
PMID:21150899 850. Glasker S, Bender BU, Apel TW, Natt E, 868. Goodrich LV, Scott MP (1998). Hedgehog vaert O, de Rooi JJ, Stubbs AP, Duijm JE, et
832. Gielen GH, Gessi M, Buttarelli FR, Baldi van Velthoven V, Scheremet R, et al. (1999). and patched in neural development and disea- al. (2009). Intrinsic gene expression profiles
C, Hammes J, zur Muehlen A, et al. (2015). Ge- The impact of molecular genetic analysis of the se. Neuron. 21(6):1243-57. PMID:9883719 of gliomas are a better predictor of survival
netic Analysis of Diffuse High-Grade Astrocyto- VHL gene in patients with haemangioblastomas 869. Gorlin RJ (1987). Nevoid basal-cell than histology. Cancer Res. 69(23):9065-72.
mas in Infancy Defines a Novel Molecular Enti- of the central nervous system. J Neurol Neuro- carcinoma syndrome. Medicine (Baltimore). PMID:19920198
ty. Brain Pathol. 25(4):409-17 PMID:25231549 surg Psychiatry. 67(6):758-62. PMID:10567493 66(2):98-113. PMID3547011 887. Griffin CA, Burger P, Morsberger L, Yo-
833. Gielen GH, Gessi M, Hammes J, Kramm 851. Glasker S, Bender BU, Apel TW, van 870. Gorovets D, Kannan K, Shen R, Kastenhu- nescu R, Swierczynski S, Weingart JD, et al.
CM, Waha A, Pietsch T (2013). H3F3A K27M Velthoven V, Mulligan LM, Zentner J, et al. ber ER, Islamdoust N, Campos C, et al. (2012). (2006). Identification of der(1;19)(q10;p10) in
mutation in pediatric CNS tumors: a marker for (2001). Reconsideration of biallelic inactivation IDH mutation and neuroglial developmental five oligodendrogliomas suggests mechanism
diffuse high-grade astrocytomas. Am J Clin Pa- of the VHL tumour suppressor gene in heman- features define clinically distinct subclasses of of concurrent 1p and 19q loss. J Neuropathol
thol. 139(3):345-9. PMID:23429371 gioblastomas of the central nervous system, lower grade diffuse astrocytic glioma. Clin Can- Exp Neurol. 65(10):988-94. PMID47021403
834. Giese A, Bjerkvig R, Berens ME, Westphal J Neurol Neurosurg Psychiatry. 70(5)844-8. cer Res. 18(9):2490-501. PMID:22415316 888. Grill J, Avet-Loiseau H, Lellouch-Tubiana
M (2003). Cost of migration: invasion of mali- PMID:11309459 871. Gorski GK, McMorrow LE, Donaldson A, Sevenet N, Terrier-Lacombe MJ, Venuat
gnant gliomas and implications for treatment. 852. Glasker S, Berlis A, Pagenstecher A, Vou- MH, Freed M (1992). Multiple chromosomal AM, et al. (2002). Comparative genomic hybri-
J Clin Oncol. 21(8):1624-36. PMID:12697889 gioukas VI, Van Velthoven V (2005). Characte- abnormalities in a case of craniopharyngio- dization detects specific cytogenetic abnorma-
835. Giese A, Loo MA, Tran N, Haskett D, rization of hemangioblastomas of spinal nerves. ma. Cancer Genet Cytogenet. 60(2):212-3. lities in pediatric ependymomas and choroid
Coons SW, Berens ME (1996). Dichotomy of Neurosurgery. 56(3)803-9, discussion 503-9. PMID:1606570 plexus papillomas. Cancer Genet Cytogenet.
astrocytoma migration and proliferation. Int J PMID:15730575 872. Goschzik T, Gessi M, Denkhaus D, Pietsch 136(2)421-5. PMID42237235
Cancer. 67(2):275-82. PMID:8760599 853. Glasker S, Kruger MT, Klingler JH, Wlodar- T (2014). PTEN mutations and activation of the 888A. Grimm T, Teglund S, Tackels D, Sangior-
836. Gil-Gouveia R, Cristino N, Farias JP, ski M, Klompen J, Schatlo B, et al. (2013). He- PI3K/Akt/mTOR signaling pathway in papillary gi E, Gurrieri F, Schwartz C, etal. (2001). Geno-
Trindade A, Ruivo NS, Pimentel J (2004). Ple- mangioblastomas and neurogenic polyglobulia. tumors of the pineal region. J Neuropathol Exp mic organization and embryonic expression of
omorphic xanthoastrocytoma of the cerebel- Neurosurgery. 72(6):930-5, discussion 935. Neurol. 73(8)747-51. PMID:25003235 Suppressor of Fused, a candidate gene for the
lum: illustrated review. Acta Neurochir (Wien). PMID:23407287 873. Gossage L, Eisen T, Maher ER (2015)1 split-hand/split-foot malformation type 3. FEBS
146(11):1241-4. PMID:15455217 854. Glasker S, Li J, Xia JB, Okamoto H, Zeng VHL, the story of a tumour suppressor gene. Lett. 505(1)43-7. PMID41557033
837. Gilbert MR, Dignam JJ, Armstrong TS, W, Lonser RR, et al. (2006). Hemangioblasto- Nat Rev Cancer. 15(1)85-64. PMID:25533676 889. Grois N, Fahrner B, Arceci RJ, Henter Jl,
Wefel JS, Blumenthal DT, Vogelbaum MA, et al. mas share protein expression with embryonal 874. Goto J, Talos DM, Klein P, Qin W, Che- McClain K, Lassmann H, Nanduri V, Prosch
(2014). A randomized trial of bevacizumab for hemangioblast progenitor cell. Cancer Res. kaluk Yl, Anderl S, et al. (2011). Regulable H, Prayer D, (2010). Central nervous system
newly diagnosed glioblastoma. N Engl J Med. 66(8):4167-72. PMID:16618738 neural progenitor-specific Tsc1 loss yields giant disease in Langerhans cell histiocytosis . J
370(8):699-708. PMID:24552317 855. Glasker S, Van Velthoven V (2005). Risk of cells with organellar dysfunction in a model of Pediatr 156:873-81,881.e1. PMID:20434166
838. Gilbert MR, Wang M, Aldape KD, Stupp R, hemorrhage in hemangioblastomas of the cen- tuberous sclerosis complex. Proc Natl Acad Sci 890. Grosse G, Lindner G, Matthies HJ (1976).
Hegi ME, Jaeckle KA, et al. (2013). Dose-dense tral nervous system. Neurosurgery. 57(1)71-6, U SA. 108(45):E1070-9. PMID:22025691 [Effect of orotic acid on the in vitro cultured ner-
temozolomide for newly diagnosed glioblasto- discussion 71-6. PMID:15987542 875. Gould VE, Rorke LB, Jansson DS, Mo- ve tissue]. Z Mikrosk Anat Forsch. 90(3)499-
ma: a randomized phase III clinical trial. J Clin 856. Godfraind C (2009). Classification and lenaar WM, Trojanowski JQ, Lee VM, et al. 506. PMID: 1088565
Oncol. 31(32):4085-91. PMID:24101040 controversies in pathology of ependymo- (1990). Primitive neuroectodermal tumors of 891. Filbin MG, Dabral SK, Pazyra-Murphy MF,
839. Gilbertson RJ, Ellison DW (2008). The mas. Childs Nerv Syst. 25(10):1185-93. the central nervous system express neuroen- Ramkissoon S, Kung AL, Pak E, et al. (2013).
origins of medulloblastoma subtypes. Annu Rev PMID:19212775 docrine markers and may express all classes of Coordinate activation of Shh and PI3K signa-
Pathol. 3:341-65. PMID:18039127 857. Godfraind C, Kaczmarska JM, Kocak intermediate filaments. Hum Pathol. 21(3):245- ling in PTEN-deficient glioblastoma: new thera-
840. Gill AJ, Benn DE, Chou A, Clarkson A, M, Dalton J, Wright KD, Sanford RA, et al. 52. PMID:2155868 peutic opportunities. Nat Med. 19(11)4518-23.
Muljono A, Meyer-Rochow GY, et al. (2010). Im- (2012). Distinct disease-risk groups in pedia- 876. Goutagny S, Nault JC, Mallet M, Henin D, PMID:24076665
munohistochemistry for SDHB triages genetic tric supratentorial and posterior fossa epen- Rossi JZ, Kalamarides M (2014). High inciden- 892. Gu J, Tamura M, Yamada KM (1998).
testing of SDHB, SDHC, and SDHD in parag- dymomas. Acta Neuropathol. 124(2):247-57. ce of activating TERT promoter mutations in Tumor suppressor PTEN inhibits integrin- and
anglioma-pheochromocytoma syndromes. Hum PMID:22526017 meningiomas undergoing malignant progressi- growth factor-mediated mitogen-activated pro-
Pathol. 41 (6):805-14. PMID:20236688 858. Goebel HH, Cravioto H (1972). Ultrastruc- on. Brain Pathol. 24(2):184-9. PMID:24261697 tein (MAP) kinase signaling pathways. J Cell
841. Gill AJ, Hes O, Papathomas T, Sedivcova ture of human and experimental ependymomas. 877. Goutagny S, Yang HW, Zucman-Rossi J, Biol. 143(5)4375-83. PMID:9832564
References 369
893. Guan H, Huang Y, Wen W, Xu M, Zan astrocytoma. Genome Res. 23(3):431-9. 925. Hainaut P, Olivier M, Wiman K (2013).p53 G, Piotrowski A, Hellstrom AR, Mantripragada
Q, Zhang Z (2011). Primary central nervous PMID:23222849 in the Clinics. New York: Springer. K, et al. (2007). Comprehensive genetic and
system extranodal NK/T-cell lymphoma, nasal 910. Gutmann DH, Parada LF, Silva AJ, Ratner 926. Hair LS, Symmans F, Powers JM, Carmel epigenetic analysis of sporadic meningioma for
type: case report and review of the literature. N (2012). Neurofibromatosis type 1: modeling P (1992). Immunohistochemistry and prolifera- macro-mutations on 22q and micro-mutations
J Neurooncol. 103(2):387-91. PMID:20845062 CNS dysfunction. J Neurosci. 32(41 ):14087- tive activity in Lhermitte-Duclos disease. Acta within the NF2 locus. BMC Genomics. 8:16.
894. Gucer H, Mete 0 (2014). Endobronchial 93. PMID:23055477 Neuropathol. 84(5):570-3. PMID:1462769 PMID:17222329
gangliocytic paraganglioma: not all keratin-po- 911. Gutmann DH, Wood DL, Collins FS 927. Hajnsek S, Paladino J, Gadze ZP, Nan- 943. Hao C, Beguinot F, Condorelli G, Trencia
sitive endobronchial neuroendocrine neoplas- (1991). Identification of the neurofibromatosis kovic S, Mrak G, Lupret V (2013). Clinical A, Van Meir EG, Yong VW, et al. (2001). Induc-
ms are pulmonary carcinoids. Endocr Pathol. type 1 gene product. Proc Natl Acad Sci U S A . and neurophysiological changes in patients tion and intracellular regulation of tumor necro-
25(3):356-8. PMID:23912549 88(21 ):9658-62. PMID:1946382 with pineal region expansions. Coll Antropol. sis factor-related apoptosis-inducing ligand
895. Guermazi A, De Kerviler E, Zagdanski 912. Gyure KA, Morrison AL (2000). Cytokeratin 37(1):35-40. PMID:23697248 (TRAIL) mediated apotosis in human malig-
AM, Frija J (2000). Diagnostic imaging of cho- 7 and 20 expression in choroid plexus tumors: 928. Haliloglu G, Jobard F, Oguz KK, Anlar B, nant glioma cells. Cancer Res, 61(3):1162-70.
roid plexus disease. Clin Radiol. 55(7):503-16. utility in differentiating these neoplasms from Akalan N, Coskun T, et al. (2008). L-2-hydroxy- PMID:11221847
PMID:10924373 metastatic carcinomas. Mod Pathol. 13(6):638- glutaric aciduria and brain tumors in children 944. Hardee ME, Zagzag D (2012). Mechanis-
896. Guesmi H, Houtteville JP, Courtheoux P, 43. PMID:10874668 with mutations in the L2HGDH gene: neuroima- ms of glioma-associated neovascularization.
Derlon JM, Chapon F (1999). [Dysembryopla- 913. Gyure KA, Prayson RA (1997). Subepen- ging findings. Neuropediatrics. 39(2):119-22. Am J Pathol. 181(4):1126-41. PMID:22858156
stic neuroepithelial tumors. Report of 8 cases dymal giant cell astrocytoma: a dinicopatholo- PMID:18671189 945. Harder A, Wesemann M, Hagel C, Schit-
including two with unusual localization], Neuro- gic study with HMB45 and MIB-1 immunohis- 929. Haller F, Bieg M, Moskalev EA, Barthel- tenhelm J, Fischer S, Tatagiba M, et al. (2012).
chirurgie. 45(3)490-200. PMID:10567958 tochemical analysis. Mod Pathol. 10(4):313-7. melJ S, Geddert H, Boltze C, et al. (2015). Hybrid neurofibroma/schwannoma is over-
897. Gunny RS, Hayward RD, Phipps KP, Har- PMID:9110292 Recurrent mutations within the amino-terminal represented among schwannomatosis and
ding BN, Saunders DE (2005). Spontaneous 914. Gotze S, Wolter M, Reifenberger G, Muller region of p-catenin are probable key molecular neurofibromatosis patients. Am J Surg Pathol.
regression of residual low-grade cerebellar pi- O, Sievers S (2010). Frequent promoter hyper- driver events in sinonasal hemangiopericytoma. 36(5):702-9. PMID:22446939
locytic astrocytomas in children. Pediatr Radiol. methylation of Wnt pathway inhibitor genes in Am J Pathol. 185(2):563-71. PMID:25482924 946. Haroche J, Charlotte F, Arnaud L, von
35(11):1086-91. PMID:16047140 malignant astrocytic gliomas. Int J Cancer. 930. Haller F, Moskalev EA, Faucz FR, Bart- Deimling A, Helias-Rodzewicz Z, Hervier B, et
898. Guppy KH, Akins PT, Moes GS, Prados 126(11):2584-93. PMID:19847810 helmeli S, Wiemann S, Bieg M, et al. (2014). al. (2012). High prevalence of BRAF V600E
MD (2009). Spinal cord oligodendroglioma with 915. Haapasalo H, Isola J, Sallinen P, Kalimo Aberrant DNA hypermethylation of SDHC: a mutations in Erdheim-Chester disease but not
1p and 19q deletions presenting with cerebral H, Helin H, Rantala I (1993). Aberrant p53 ex- novel mechanism of tumor development in Car- in other non-Langerhans cell histiocytoses.
oligodendrogliomatosis. J Neurosurg Spine. pression in astrocytic neoplasms of the brain: ney triad. Endocr Relat Cancer. 21(4):567-77. Blood. 120(13):2700-3. PMID:22879539
10(6):557-63. PMID:19558288 association with proliferation. Am J Pathol. PMID:24859990 947. Haroche J, Cohen-Aubart F, Emile JF,
899. Gurney JG, Smith MA, Bunin GR CNS and 142(5): 1347-51. PMID:7684193 931. Hailing KC, Scheithauer BW, Hailing AC, Maksud P, Drier A, Toledano D, et al. (2015).
miscellaneous intracranial and intraspinal neo- 916. Haas JE, Palmer NF, Weinberg AG, Beck- Nascimento AG, Ziesmer SC, Roche PC, et Reproducible and sustained efficacy of tar-
plasms. In: Ries LAG, Smith MA, Gurney JG, with JB (1981). Ultrastructure of malignant rh- al. (1996). p53 expression in neurofibroma geted therapy with vemurafenib in patients
Linet M, Tamra T, Young JL, Bunin GR, editors abdoid tumor of the kidney. A distinctive renal and malignant peripheral nerve sheath tumor. with BRAF(V600E)-mutated Erdheim-Ches-
(1995).Cancer incidence and survival among tumor of children. Hum Pathol. 12(7):646-57. An immunohistochemical study of sporadic ter disease. J Clin Oncol. 33(5):411-8.
children and adolescents United States SEER PMID:7275104 and NF1-associated tumors. Am J Clin Pathol. PMID:25422482
Program 1975-1995. NIH Pub no. 99-4649 917. Haberler C, Jarius C, Lang S, Rossler K, 106(3):282-8. PMID:8816583 948. Harris CP, Townsend JJ, Brockmeyer
Bethesda, MD: National Cancer Institute. Gruber A, Hainfellner JA, et al. (2002). Fibrous 932. Hama S, Arita K, Nishisaka T, Fukuha- DL, Heilbrun MP (1991). Cerebral granular
900. Gusella JF, Ramesh V, MacCollin M, Ja- meningeal tumours with extensive non-cal- ra T, Tominaga A, Sugiyama K, et al. (2002). cell tumor occurring with glioblastoma multi-
coby LB (1996). Neurofibromatosis 2: loss of cifying collagenous whorls and glial fibrillary Changes in the epithelium of Rathke cleft cyst forme: case report. Surg Neurol. 36(3):202-6.
merlin's protective spell. Curr Opin Genet Dev. acidic protein expression: the whorling-sclero- associated with inflammation. J Neurosurg. PMID:1652163
6(1 ):87-92. PMID:8791482 sing variant of meningioma. Neuropathol Appl 96(2):209-16. PMID:11838792 949. Harter DH, Omeis I, Forman S, Braun A
901. Gusella JF, Ramesh V, MacCollin M, Ja- Neurobiol. 28(1 ):42-7. PMID:11849562 933. Hamasaki T, Yamada K, Kuratsu J (2013). (2006). Endoscopic resection of an intraventri-
coby LB (1999). Merlin: the neurofibromatosis 918. Haberler C, Laggner U, Slave I, Czech Seizures as a presenting symptom in neurosur- cular dysembryoplastic neuroepithelial tumor
2 tumor suppressor. Biochim Biophys Acta. T, Ambros IM, Ambros PF, et al. (2006). Im- gical patients: a retrospective single-institution of the septum pellucidum. Pediatr Neurosurg.
1423(2):M29-36. PMID:10214350 munohistochemical analysis of INI1 protein in analysis. Clin Neurol Neurosurg. 115(11):2336- 42(2):105-7. PMID:16465080
902. Gutenberg A, Brandis A, Hong B, Guna- malignant pediatric CNS tumors: Lack of INI1 40. PMID:24011499 950. Hartmann C, Hentschel B, Simon M, West-
wan B, Enders C, Schaefer IM, et al. (2011). in atypical teratoid/rhabdoid tumors and in a 934. Hamazaki S, Nakashima H, Matsumoto phal M, Schackert G, Tonn JC, et al.; German
Common molecular cytogenetic pathway in pa- fraction of primitive neuroectodermal tumors K, Taguchi K, Okada S (2001). Metastasis of Glioma Network (2013). Long-term survival in
pillary tumors of the pineal region (PTPR). Brain without rhabdoid phenotype. Am J Surg Pathol. renal cell carcinoma to central nervous system primary glioblastoma with versus without iso-
Pathol. 21 (6):672-7. PMID:21470326 30(11 ):1462-8. PMID:17063089 hemangioblastoma in two patients with von Hip- citrate dehydrogenase mutations. Clin Cancer
903. Guthrie BL, Ebersold MJ, Scheithauer BW, 919. Haddad SF, Hitchon PW, Godersky JC pel-Lindau disease. Pathol Int. 51(12):948-53. Res. 19(18):5146-57. PMID:23918605
Shaw EG (1989). Meningeal hemangiopericyto- (1991). Idiopathic and glucocorticoid-induced PMID:11844068 951. Hartmann C, Hentschel B, Tatagiba
ma: histopathological features, treatment, and spinal epidural lipomatosis. J Neurosurg. 935. Hamilton JD, Rapp M, Schneiderhan T, M, Schramm J, Schnell O, Seidel C, et al.;
long-term follow-up of 44 cases. Neurosurgery. 74(1):38-42. PMID:1984504 Sabel M, Hayman A, Scherer A, et al. (2014). German Glioma Network (2011). Molecular
25(4):514-22. PMID:2797389 920. Haddad SF, Moore SA, Schelper RL, Glioblastoma multiforme metastasis outside the markers in low-grade gliomas: predictive or
904. Gutman DA, Cooper LA, Hwang SN, Hol- Goeken JA (1992). Vascular smooth muscle CNS: three case reports and possible mecha- prognostic? Clin Cancer Res. 17(13):4588-99.
der CA, Gao J, Aurora TD, et al. (2013). MR hyperplasia underlies the formation of glomeru- nisms of escape. J Clin Oncol. 32(22):e80-4. PMID:21558404
imaging predictors of molecular profile and sur- loid vascular structures of glioblastoma multifor- PMID:24567434 952. Hartmann C, Hentschel B, Wick W, Capper
vival: multi-institutional study of the TCGA gli- me. J Neuropathol Exp Neurol. 51 (5):488-92. 936. Hamilton RL, Pollack IF (1997). The mo- D, Felsberg J, Simon M, et al. (2010). Patients
oblastoma data set. Radiology. 267(2):560-9. PMID:1381413 lecular biology of ependymomas. Brain Pathol. with IDH1 wild type anaplastic astrocytomas
PMID:23392431 921. Hadfield KD, Newman WG, Bowers NL, 7(2):807-22. PMID:9161731 exhibit worse prognosis than IDH1-mutated
905. Gutmann DH, Aylsworth A, Carey JC, Korf Wallace A, Bolger C, Colley A, et al. (2008). 937. Hamilton SR, Liu B, Parsons RE, Papad- glioblastomas, and IDH1 mutation status ac-
B, Marks J, Pyeritz RE, et al. (1997). The diag- Molecular characterisation of SMARCB1 and opoulos N, Jen J, Powell SM, et al. (1995). The counts for the unfavorable prognostic effect
nostic evaluation and multidisciplinary manage- NF2 in familial and sporadic schwannomatosis. molecular basis of Turcot’s syndrome. N Engl J of higher age: implications for classification of
ment of neurofibromatosis 1 and neurofibromat- J Med Genet. 45(6):332-9. PMID:18285426 Med. 332(13):839-47. PMID:7661930 gliomas. Acta Neuropathol. 120(6)707-18.
osis 2. JAMA. 278(1):51-7. PMID:9207339 922. Hadfield KD, Smith MJ, Urquhart JE, 938. Han L, Niu H, Wang J, Wan F, Shu K, Ke PMID:21088844
906. Gutmann DH, Collins FS (1993). The Wallace AJ, Bowers NL, King AT, et al. (2010). C, et al. (2013). Extraventricular neurocytoma in 953. Hartmann C, Meyer J, Balss J, Capper
neurofibromatosis type 1 gene and its protein Rates of loss of heterozygosity and mitotic re- pediatric populations: A case report and review D, Mueller W, Christians A, et al. (2009). Type
product, neurofibromin. Neuron. 10(3):335-43. combination in NF2 schwannomas, sporadic of the literature. Oncol Lett. 6(5)4397-405. and frequency of IDH1 and IDH2 mutations
PMID:8461130 vestibular schwannomas and schwannomato- PMID:24179531 are related to astrocytic and oligodendroglial
907. Gutmann DH, Donahoe J, Perry A, Lemke sis schwannomas. Oncogene. 29(47):6216-21. 939. Han SJ, Yang I, Otero JJ, Ahn BJ, Tihan T, differentiation and age: a study of 1,010 diffu-
N, Gorse K, Kittiniyom K, et al. (2000). Loss of PMID:20729918 McDermott MW, et al. (2010). Secondary glios- se gliomas. Acta Neuropathol. 118(4)469-74.
DAL-1, a protein 4.1-related tumor suppressor, 923. Hagel C, Stemmer-Rachamimov AO, Bor- arcoma after diagnosis of glioblastoma: clinical PMID49554337
is an important early event in the pathogenesis nemann A, Schuhmann M, Nagel C, Huson S, experience with 30 consecutive patients. J Neu- 954. Hartmann C, Siebems J, Gehlhaar C, Si-
of meningiomas. Hum Mol Genet. 9(10)4495- et al. (2012). Clinical presentation, immunohis- rosurg. 112(5):990-6. PMID:19817543 mon M, Paulus W, von Deimling A (2006). NF2
500. PMID:10888600 tochemistry and electron microscopy indicate 940. Hannan F, Ho I, Tong JJ, Zhu Y, Nurnberg mutations in secretory and other rare variants
908. Gutmann DH, James CD, Poyhonen M, neurofibromatosis type 2-associated gliomas P, Zhong Y (2006). Effect of neurofibromatosis of meningiomas. Brain Pathol. 16(1):15-9.
Louis DN, Ferner R, Guha A, et al. (2003). to be spinal ependymomas. Neuropathology. type I mutations on a novel pathway for ade- PMID46612978
Molecular analysis of astrocytomas presenting 32(6):611-6. PMID:22394059 nylyl cyclase activation requiring neurofibromin 955. Hartmann C, Xu X, Bartels G, Holtkamp N,
after age 10 in individuals with NF1. Neurology. 924. Hahn H, Wicking C, Zaphiropoulous PG, and Ras. Hum Mol Genet. 15(7): 1087-98. Gonzales IA, Tallen G, et al. (2004). Pdgfr-alpha
61(10):1397-400. PMID:14638962 Gailani MR, Shanley S, Chidambaram A, et PMID:16513807 in 1p/19q LOH oligodendrogliomas. Int J Can-
909. Gutmann DH, McLellan MD, Hussain I, al. (1996). Mutations of the human homolog 941. Hanssen AM, Fryns JP (1995). Cow- cer. 112(6)4081-2. PMID45386438
Wallis JW, Fulton LL, Fulton RS, et al. (2013). of Drosophila patched in the nevoid basal cell den syndrome. J Med Genet. 32(2)417-9. 956. Hashimoto T, Sasagawa I, Ishigooka M,
Somatic neurofibromatosis type 1 (NF1) inac- carcinoma syndrome. Cell. 85(6):841-51. PMID:7760320 Kubota Y, Nakada T, Fujita T, et al. (1995).
tivation characterizes NF1-associated pilocytic PMID:8681379 942. Hansson CM, Buckley PG, Grigelioniene Down's syndrome associated with intracranial
370 References
germinoma and testicular embryonal carcino- growth factors and receptors in capillary he- extragonadal germ cell tumor. Cancer Genet progressive, therapeutically targetable disease.
ma. Urol Int. 55(2):120-2. PMID:8533196 mangioblastomas and hemangiopericytomas. Cytogenet. 57(1):41-6. PMID:1756483 Cancer Cell. 27(1):72-84. PMID:25533335
957. Hasselblatt M, Bliimcke I, Jeibmann A, Am J Pathol. 148(3):763-75. PMID:8774132 988. Helseth A, Helseth E, Unsgaard G (1989). 1004. Hiniker A, Hagenkord JM, Powers MP,
Rickert CH, Jouvet A, van de Nes JA, et al. 972. Hayasaka K, Nihashi T, Takebayashi Primary meningeal melanoma. Acta Oncol. Aghi MK, Prados MD, Perry A (2013). Gliosar-
(2006). Immunohistochemical profile and chro- S, Bundoh M (2008). FDG PET in Lhermit- 28(1):103-4. PMID:2706127 coma arising from an oligodendroglioma (oli-
mosomal imbalances in papillary tumours of te-Duclos disease. Clin Nud Med. 33(1):52-4. 989. Hemminki K, Kyyronen P, Vaittinen P gosarcoma). Clin Neuropathol. 32(3):165-70.
the pineal region. Neuropathol Appl Neurobiol. PMID:18097262 (1999). Parental age as a risk factor of child- PMID23254140
32(3):278-83. PMID:16640646 973. Hayashi K, Ohara N, Jeon HJ, Akagi S, Ta- hood leukemia and brain cancer in offspring. 1005. Hinkes BG, von Hoff K, Deinlein F, War-
958. Hasselblatt M, Bohm C, Tatenhorst L, kahashi K, Akagi T, et al. (1993). Gliosarcoma Epidemiology. 10(3)271-5. PMID:10230837 muth-Metz M, Soerensen N, Timmermann B, et
Dinh V, Newrzella D, Keyvani K, et al. (2006). with features of chondroblastic osteosarcoma. 990. Hemminki K, Liu X, Forsti A, Ji J, Sundquist al. (2007). Childhood pineoblastoma: experien-
Identification of novel diagnostic markers for Cancer. 72(3):850-5. PMID:8334639 J, Sundquist K (2013). Subsequent brain tu- ces from the prospective multicenter trials HIT-
choroid plexus tumors: a microarray-based 974. Hayostek CJ, Shaw EG, Scheithauer B, mors in patients with autoimmune disease. SKK87, HIT-SKK92 and HIT91. J Neurooncol.
approach. Am J Surg Pathol. 30(1 ):66-74. O'Fallon JR, Weiland TL, Schomberg PJ, et al. Neuro Oncol. 15(9):1142-50. PMID:23757294 81(2)217-23. PMID:16941074
PMID:16330944 (1993). Astrocytomas of the cerebellum. A com- 991. Hennessy MJ, Elwes RD, Rabe-Hesketh 1006. Hirbe AC, Gutmann DH (2014). Neuro-
959. Hasselblatt M, Gesk S, Oyen F, Rossi parative dinicopathologic study of pilocytic and S, Binnie CD, Polkey CE (2001). Prognostic fibromatosis type 1: a multidisciplinary appro-
S, Viscardi E, Giangaspero F, et al. (2011). diffuse astrocytomas. Cancer. 72(3):856-69. factors in the surgical treatment of medically ach to care. Lancet Neurol. 13(8):834-43.
Nonsense mutation and inactivation of SMAR- PMID:8334640 intractable epilepsy associated with mesial tem- PMID25030515
CA4 (BRG1) in an atypical teratoid/rhabdoid 975. He J, Mokhtari K, Sanson M, Marie Y, Ku- poral sclerosis. Acta Neurol Scand. 103(6):344- 1007. Hirose T, Giannini C, Scheithauer BW
tumor showing retained SMARCB1 (INI1) jas M, Huguet S, et al. (2001). Glioblastomas 50. PMID:11421846 (2001). Ultrastructural features of pleomorphic
expression. Am J Surg Pathol. 35(6):933-5. with an oligodendroglial component: a patholo- 992. Henske EP, Wessner LL, Golden J, Scheit- xanthoastrocytoma: a comparative study with
PMID:21566516 gical and molecular study. J Neuropathol Exp hauer BW, Vortmeyer AO, Zhuang Z, et al. glioblastoma multiforme. Ultrastruct Pathol.
960. Hasselblatt M, Jeibmann A, Guerry M, Neurol. 60(9):863-71. PMID:11556543 (1997). Loss of tuberin in both subependymal 25(6):469-78. PMID:11783911
Senner V, Paulus W, McLendon RE (2008). 976. He MX, Wang JJ (2011). Rhabdoid gli- giant cell astrocytomas and angiomyolipomas 1008. Hirose T, Scheithauer BW (1998). Mixed
Choroid plexus papilloma with neuropil-li- oblastoma: case report and literature review. supports a two-hit model for the pathogenesis dysembryoplastic neuroepithelial tumor and
ke islands. Am J Surg Pathol. 32(1):162-6. Neuropathology. 31(4):421-6. PMID:21092062 of tuberous sclerosis tumors. Am J Pathol. ganglioglioma. Acta Neuropathol. 95(6):649-
PMID:18162784 977. Heaphy CM, de Wilde RF, Jiao Y, Klein AP, 151 (6):1639-47. PMID:9403714 54. PMID:9650758
961. Hasselblatt M, Muhlisch J, Wrede B, Kal- Edil BH, Shi C, et al. (2011). Altered telomeres 993. Henson JW, Schnitker BL, Correa KM, von 1009. Hirose T, Scheithauer BW, Lopes MB,
linger B, Jeibmann A, Peters O, et al. (2009). in tumors with ATRX and DAXX mutations. Deimling A, Fassbender F, Xu HJ, et al. (1994). Gerber HA, Altermatt HJ, Hukee MJ, et al.
Aberrant MGMT (06-methylguanine-DNA Science. 333(6041 ):425. PMID:21719641 The retinoblastoma gene is involved in malig- (1995). Tuber and subependymal giant cell as-
methyltransferase) promoter methylation 978. Heath JA, Ng J, Beshay V, Coleman nant progression of astrocytomas. Ann Neurol. trocytoma associated with tuberous sclerosis:
in choroid plexus tumors. J Neurooncol. L, Lo P, Amor DJ (2013). Anaplastic oligo- 36(5):714-21. PMID:7979217 an immunohistochemical, ultrastructural, and
91(2):151-5. PMID:18795231 dendroglioma in an adolescent with Lynch 994. Herpers MJ, Budka H (1984). Glial fibrillary immunoelectron and microscopic study. Acta
962. Hasselblatt M, Nagel I, Oyen F, Bartelheim syndrome. Pediatr Blood Cancer. 60(6):E13-5. acidic protein (GFAP) in oligodendroglial tu- Neuropathol. 90(4):387-99. PMID:8546029
K, Russell RB, Schuller U, et al. (2014). SMAR- PMID:23255519 mors: gliofibrillary oligodendroglioma and tran- 1010. Hirose T, Scheithauer BW, Lopes MB,
CA4-mutated atypical teratoid/rhabdoid tumors 979. Hebert-Blouin MN, Scheithauer BW, Amra- sitional oligoastrocytoma as subtypes of oligo- Gerber HA, Altermatt HJ, VandenBerg SR
are associated with inherited germline altera- mi KK, Durham SR, Spinner RJ (2012). Fibro- dendroglioma. Acta Neuropathol. 64(4):265-72. (1997) . Ganglioglioma: an ultrastructural
tions and poor prognosis. Acta Neuropathol. matosis: a potential sequela of neuromuscular PMID:6391068 and immunohistochemical study. Cancer.
128(3):453-6. PMID:25060813 choristoma. J Neurosurg. 116(2):399-408. 995. Herpers MJ, Ramaekers FC, Aldeweireldt 79(5):989-1003. PMID:9041162
963. Hasselblatt M, Nolte KW, Paulus W PMID:21819193 J, Moesker O, Slooff J (1986). Co-expression 1011. Hirose T, Scheithauer BW, Sano T
(2004). Angiomatous meningioma: a clinicopa- 980. Heegaard S, Sommer HM, Broholm H, of glial fibrillary acidic protein- and vimen- (1998) . Perineurial malignant peripheral nerve
thologic study of 38 cases. Am J Surg Pathol. Broendstrup O (1995). Proliferating cell nuc- tin-type intermediate filaments in human ast- sheath tumor (MPNST): a dinicopathologic, im-
28(3):390-3. PMID:15104303 lear antigen and Ki-67 immunohistochemistry rocytomas. Acta Neuropathol. 70(3-4):333-9. munohistochemical, and ultrastructural study of
964. Hasselblatt M, Oyen F, Gesk S, Kordes U, of oligodendrogliomas with special referen- PMID:3020864 seven cases. Am J Surg Pathol. 22(11):1368-
Wrede B, Bergmann M, et al. (2009). Cribriform ce to prognosis. Cancer. 76(10):1809-13. 996. Herregodts P, Vloeberghs M, Schmedding 78. PMID:9808129
neuroepithelial tumor (CRINET): a nonrhabdoid PMID:8625052 E, Goossens A, Stadnik T, D’Haens J (1991). 1012. Hirose T, Tani T, Shimada T, Ishizawa K,
ventricular tumor with INI1 loss and relatively 981. Heesters M, Molenaar W, Go GK (2003). Solitary dorsal intramedullary schwannoma. Shimada S, Sano T (2003). Immunohistochemi-
favorable prognosis. J Neuropathol Exp Neurol. Radiotherapy in supratentorial gliomas. A study Case report. J Neurosurg. 74(5):816-20. cal demonstration of EMA/Glut1 -positive peri-
68(12):1249-55. PMID:19915490 of 821 cases. Strahlenther Onkol. 179(9):606- PMID:2013780 neurial cells and CD34-positive fibroblastic cells
965. Hasselblatt M, Paulus W (2003). Sensiti- 14. PMID:14628126 997. Herrick MK, Rubinstein LJ (1979). The in peripheral nerve sheath tumors. Mod Pathol.
vity and specificity of epithelial membrane an- 982. Hegi ME, Diserens AC, Gorlia T, Hamou cytological differentiating potential of pineal 16(4)293-8. PMID:12692193
tigen staining patterns in ependymomas. Acta MF, de Tribolet N, Weller M, et al. (2005). parenchymal neoplasms (true pinealomas). A 1013. Hiroyuki M, Ogino J, Takahashi A, Hase-
Neuropathol. 106(4):385-8. PMID:12898159 MGMT gene silencing and benefit from te- clinicopathological study of 28 tumours . Brain gawa T, Wakabayashi T (2015). Rhabdoid gli-
965A. Hasselblatt M, Riesmeier B, Lechtape mozolomide in glioblastoma. N Engl J Med. 102:289-320. PMID:88244 oblastoma: an aggressive variaty of astrocytic
B, Brentrup A, Stummer W, Albert FK, et al. 352( 10):997-1003. PMID:15758010 998. Hertzler DA 2nd, DePowell JJ, Stevenson tumor. Nagoya J Med Sci. 77(1-2):321-8.
(2011). BRAF-KIAA1549 fusion transcripts are 983. Hegi ME, Janzer RC, Lambiv WL, Gorlia T, CB, Mangano FT (2010). Tethered cord syn- PMID25797998
less frequent in pilocytic astrocytomas diag- Kouwenhoven MC, Hartmann C, et al.; Europe- drome: a review of the literature from embryo- 1014. Hitotsumatsu T, Iwaki T, Kitamoto T, Mi-
nosed in adults. Neuropathol Appl Neurobiol. an Organisation for Research and Treatment of logy to adult presentation. Neurosurg Focus. zoguchi M, Suzuki SO, Hamada Y, etal. (1997).
37(7):803-6. PMID:21696415 Cancer Brain Tumour and Radiation Oncology 29(1):E1. PMID:20593997 Expression of neurofibromatosis 2 protein in
966. Hasselblatt M, Sepehrnia A, von Falken- Groups; National Cancer Institute of Canada 999. Herva R, Serlo W, Laitinen J, Becker LE human brain tumors: an immunohistochemi-
hausen M, Paulus W (2003). Intracranial follicu- Clinical Trials Group (2012). Presence of an (1996). Intraventricular rhabdomyosarcoma cal study. Acta Neuropathol. 93(3)225-32.
lar dendritic cell sarcoma. Case report. J Neuro- oligodendroglioma-like component in newly after resection of hyperplastic choroid plexus. PMID:9083553
surg. 99(6):1089-90. PMID:14705740 diagnosed glioblastoma identifies a pathoge- Acta Neuropathol. 92(2):213-6. PMID:8841669 1015. Hjalmars U, Kulldorff M, Wahlqvist Y,
967. Hassoun J, Gambarelli D, Grisoli F, Pellet netically heterogeneous subgroup and lacks 1000. Hewer E, Beck J, Murek M, Kappeler A, Lannering B (1999). Increased incidence ra-
W, Salamon G, Pellissier JF, et al. (1982). Cent- prognostic value: central pathology review of Vassella E, Vajtai I (2014). Polymorphous oligo- tes but no space-time clustering of childhood
ral neurocytoma. An electron-microscopic study the EORTC_26981/NCIC_CE.3 trial. Acta Neu- dendroglioma of Zulch revisited: a genetically astrocytoma in Sweden, 1973-1992: a popu-
of two cases. Acta Neuropathol. 56(2):151-6. ropathol. 123(6):841-52. PMID:22249618 heterogeneous group of anaplastic gliomas lation-based study of pediatric brain tumors.
PMID:7064664 984. Heim S, Beschorner R, Mittelbronn M, including tumors of bona fide oligodendroglial Cancer. 85(9)2077-90. PMID:10223251
968. Hassoun J, Gambarelli D, Peragut JC, Keyvani K, Riemenschneider MJ, Vajtai I, et differentiation. Neuropathology. 34(4):323-32. 1016. Ho DM, Hsu CY, Wong TT, Ting LT, Ch-
Toga M (1983). Specific ultrastructural mar- al. (2014). Increased mitotic and proliferative PMID:24444336 iang H (2000). Atypical teratoid/rhabdoid tumor
kers of human pinealomas. A study of four activity are associated with worse prognosis in 1001. Hijiya N, Hudson MM, Lensing S, Za- of the central nervous system: a comparative
cases. Acta Neuropathol. 62(1-2):31-40. papillary tumors of the pineal region. Am J Surg cher M, Onciu M, Behm FG, et al. (2007). study with primitive neuroectodermal tumor/me-
PMID:6318505 Pathol. 38(1):106-10. PMID:24121176 Cumulative incidence of secondary neoplasms dulloblastoma. Acta Neuropathol. 99(5):482-8.
969. Hassoun J, Soylemezoglu F, Gambarelli 985. Heim S, Coras R, Ganslandt O, Kufeld M, as a first event after childhood acute lympho- PMID:10805090
D, Figarella-Branger D, von Ammon K, Kleihues Blümcke I, Paulus W, et al. (2013). Papillary tu- blastic leukemia. JAMA. 297(11):1207-15. 1017. Ho DM, Liu HC (1992). Primary intracra-
P (1993). Central neurocytoma: a synopsis of mor of the pineal region with anaplastic small PMID:17374815 nial germ cell tumor. Pathologic study of 51 pa-
clinical and histological features. Brain Pathol. cell component. J Neurooncol. 115(1):127-30. 1002. Hilden JM, Meerbaum S, Burger P, Finlay tients. Cancer. 70(6):1577-84. PMID:1325276
3(3):297-306. PMID:8293189 PMID:23817812 J, Janss A, Scheithauer BW, et al. (2004). Cen- 1018. Ho KL (1990). Intercellular septate-like
970. Hatton BA, Villavicencio EH, Tsuchiya KD, 986. Heim S, Sill M, Jones DT, Vasiljevic A, tral nervous system atypical teratoid/rhabdoid junction of neoplastic cells in myxopapillary
Pritchard Jl, Ditzler S, Pullar B, et al. (2008). Jouvet A, Fevre-Montange M, et al. (2015). tumor: results of therapy in children enrolled ependymoma of the filum terminale. Acta Neu-
The Smo/Smo model: hedgehog-induced me- Papillary tumor of the pineal region: A distinct in a registry, J Clin Oncol. 22(14)2877-84. ropathol. 79(4):432-7. PMID2339595
dulloblastoma with 90% incidence and lepto- molecular entity. Brain Pathol. PMID:26113311 PMID:15254056 1019. Ho KL (1990). Microtubular aggregates
meninges! spread. Cancer Res. 68(6):1768-76. 987. Heimdal K, Evensen SA, Fossa SD, 1003. Hill RM, Kuijper S, Lindsey JC, Pe- within rough endoplasmic reticulum in myxopa-
PMID:18339857 Hirscberg H, Langholm R, Bragger A, et al. trie K, Schwalbe EC, Barker K, et al. (2015). pillary ependymoma of the filum terminale. Arch
971. Hatva E, Bohling T, Jaaskelainen J, Per- (1991). Karyotyping of a hematologic neoplasia Combined MYC and P53 defects emerge at Pathol Lab Med. 114(9):956-60. PMID2390011
sia) MG, Haltia M, Alitalo K (1996). Vascular developing shortly after treatment for cerebral medulloblastoma relapse and define rapidly 1020. Ho YS, Wei CH, Tsai MD, Wai YY (1992).
References 371
Intracerebral malignant fibrous histiocytoma: 1036. Horbinski C, Hobbs J, Cieply K, Dacic S, Mutations in the SMAD4/DPC4 gene in juve- 1069. Husemann K, Wolter M, Biischges R,
case report and review of the literature. Neuro- Hamilton RL (2011). EGFR expression strati- nile polyposis. Science. 280(5366):1086-8. Bostrom J, Sabel M, Reifenberger G (1999).
surgery. 31(3):567-71. PMID:1328926 fies oligodendroglioma behavior. Am J Pathol. PMID:9582123 Identification of two distinct deleted regions on
1021. Hoang MP, Amirkhan RH (2003). Inhibin 179(4):1638-44. PMID:21839716 1054. Hoyt WF, Baghdassarian SA (1969). the short arm of chromosome 1 and rare muta-
alpha distinguishes hemangioblastoma from 1037. Horbinski C, Kofler J, Yeaney G, Came- Optic glioma of childhood. Natural history and tion of the CDKN2C gene from 1p32 in oligo-
clear cell renal cell carcinoma. Am J Surg Pa- lo-Piragua S, Venneti S, Louis DN, et al. (2011). rationale for conservative management. Br J dendroglial tumors. J Neuropathol Exp Neurol.
thol. 27(8):1152-6. PMID.12883249 Isocitrate dehydrogenase 1 analysis differenti- Ophthalmol. 53(12):793-8. PMID:5386369 58(10):1041-50. PMID:10515227
1022. Hoang-Xuan K, Capelle L, Kujas M, ates gangliogliomas from infiltrative gliomas. 1055. Hruban RH, Shiu MH, Senie RT, Woo- 1070. Hussain N, Curran A, Pilling D, Mallu-
Taillibert S, Duffau H, Lejeune J, et al. (2004). Brain Pathol. 21(5):564-74. PMID:21314850 druff JM (1990). Malignant peripheral nerve ci CL, Ladusans EJ, Alfirevic Z, et al. (2006).
Temozolomide as initial treatment for adults 1038. Horiguchi H, Hirose T, Kannuki S, Na- sheath tumors of the buttock and lower extremi- Congenital subependymal giant cell astrocyto-
with low-grade oligodendrogliomas or oligoast- gahiro S, Sano T (1998). Gliosarcoma: an ty. Astudy of 43 cases. Cancer. 66(6):1253-65. ma diagnosed on fetal MRI. Arch Dis Child.
rocytomas and correlation with chromosome immunohistochemical, ultrastructural and flu- PMID:2119249 91(6):520. PMID:16714726
1p deletions. J Clin Oncol. 22(15):3133-8. orescence in situ hybridization study. Pathol Int. 1056. Hsu DW, Louis DN, Efird JT, Hed- 1071. Husseini L, Saleh A, Reifenberger G,
PMID:15284265 48(8):595-602. PMID:9736406 ley-Whyte ET (1997). Use of MIB-1 (Ki-67) Hartung HP, Kieseier BC (2012). Inflammatory
1023. Hobbs J, Nikiforova MN, Fardo DW, Bor- 1039. Horiguchi H, Hirose T, Sano T, Nagahiro immunoreactivity in differentiating grade II and demyelinating brain lesions heralding primary
toluzzi S, Cieply K, Hamilton RL, et al. (2012). S, Seki K, Fujimoto N, et al. (2000). Meningi- grade III gliomas. J Neuropathol Exp Neurol. CNS lymphoma. Can J Neurol Sci. 39(1):6-10.
Paradoxical relationship between the degree oma with granulofilamentous inclusions. Ultra- 56(8):857-65. PMID:9258255 PMID:22384490
of EGFR amplification and outcome in gliob- struct Pathol. 24(4):267-71. PMID:11013967 1057. Huang H, Mahler-Araujo BM, Sankila 1072. Huttenlocher PR, Heydemann PT (1984).
lastomas. Am J Surg Pathol. 36(8):1186-93. 1040. Hornick JL, Bundock EA, Fletcher CD A, Chimelli L, Yonekawa Y, Kleihues P, et al. Fine structure of cortical tubers in tuberous sc-
PMID:22472960 (2009). Hybrid schwannoma/perineurioma: (2000). APC mutations in sporadic medul- lerosis: a Golgi study. Ann Neurol. 16(5):595-
1024. Hoefnagel LD, van der Groep P, van de clinicopathologic analysis of 42 distinctive be- loblastomas. Am J Pathol. 156(2):433-7. 602. PMID:6508241
Vijver MJ, Boers JE, Wesseling P, Wesseling nign nerve sheath tumors. Am J Surg Pathol. PMID:10666372 1073. Hutter S, Piro RM, Reuss DE, Hovestadt
J, et al.; Dutch Distant Breast Cancer Metas- 33(10): 1554-61. PMID:19623031 1058. Huang H, Reis R, Yonekawa Y, Lopes V, Sahm F, Farschtschi S, et al. (2014). Whole
tases Consortium (2013). Discordance in ERa, 1041. Hornick JL, Fletcher CD (2005). Intes- JM, Kleihues P, Ohgaki H (1999). Identificati- exome sequencing reveals that the majority of
PR and HER2 receptor status across different tinal perineuriomas: clinicopathologic defini- on in human brain tumors of DNA sequences schwannomatosis cases remain unexplained
distant breast cancer metastases within the tion of a new anatomic subset in a series of specific for SV40 large T antigen. Brain Pathol. after excluding SMARCB1 and LZTR1 germline
same patient. Ann Oncol. 24(12):3017-23. 10 cases. Am J Surg Pathol. 29(7):859-65. 9(1 ):33-42. PMID:9989448 variants. Acta Neuropathol. 128(3):449-52.
PMID:24114857 P MID: 15958849 1058A. Huang J, Grotzer MA, Watanabe T, PMID:25008767
1025. Hoffman HJ, Otsubo H, Hendrick EB, 1042. Hornick JL, Fletcher CD (2005). Soft tis- Hewer E, Pietsch T, Rutkowski S, et al. (2008). 1074. Huynh DP, Mautner V, Baser ME, Stav-
Humphreys RP, Drake JM, Becker LE, et al. sue perineurioma: clinicopathologic analysis of Mutations in the Nijmegen breakage syndrome rou D, Pulst SM (1997). Immunohistochemical
(1991). Intracranial germ-cell tumors in child- 81 cases including those with atypical histolo- gene in medulloblastomas. Clin Cancer Res. detection of schwannomin and neurofibromin
ren. J Neurosurg. 74(4):545-51. PMID:1848284 gic features. Am J Surg Pathol. 29(7):845-58. 14(13):4053-8. PMID:18593981 in vestibular schwannomas, ependymomas
1026. Hoffman LM, Donson AM, Nakachi I, P MID: 15958848 1059. Huang JG, Kavar B, Smith PD (2007). and meningiomas. J Neuropathol Exp Neurol.
Griesinger AM, Birks DK, Amani V, et al. (2014). 1043. Hornick JL, Jaffe ES, Fletcher CD (2004). Intradural extramedullary spinal spread of oli- 56(4):382-90. PMID:9100669
Molecular sub-group-specific immunopheno- Extranodal histiocytic sarcoma: clinicopatho- goastrocytoma. J Clin Neurosci. 14(9):879-82. 1075. Hyman SL, Arthur Shores E, North KN
typic changes are associated with outcome in logic analysis of 14 cases of a rare epithelioid PMID:17582770 (2006). Learning disabilities in children with
recurrent posterior fossa ependymoma. Acta malignancy. Am J Surg Pathol. 28(9):1133-44. 1060. Huang MC, Kubo O, Tajika Y, Takakura neurofibromatosis type 1: subtypes, cognitive
Neuropathol. 127(5):731-45. PMID:24240813 PMID:15316312 K (1996). A clinico-immunohistochemical stu- profile, and attention-deficit-hyperactivity dis-
1027. Hofman S, Heeg M, Klein JP, Krikke AP 1044. Horstmann S, Perry A, Reifenberger G, dy of giant cell glioblastoma. Noshuyo Byori. order. Dev Med Child Neurol. 48(12):973-7.
(1998) . Simultaneous occurrence of a supra- Giangaspero F, Huang H, Hara A, et al. (2004). 13(1):11-6. PMID:8916121 PMID:17109785
and an infratentorial glioma in a patient with Genetic and expression profiles of cerebellar 1061. Hufnagel TJ, Kim JH, True LD, Manueli- 1076. Hiitt-Cabezas M, Karajannis MA, Zagzag
Ollier's disease: more evidence for non-me- liponeurocytomas. Brain Pathol. 14(3):281-9. dis EE (1989). Immunohistochemistry of capil- D, Shah S, Horkayne-Szakaly I, Rushing EJ,
sodermal tumor predisposition in multiple en- P MID: 15446583 lary hemangioblastoma. Immunoperoxidase-la- et al. (2013). Activation of mTORC1/mTORC2
chondromatosis. Skeletal Radiol. 27(12):688- 1045. Horten BC, Rubinstein LJ (1976). Pri- beled antibody staining resolves the differential signaling in pediatric low-grade glioma and
91. PMID:9921931 mary cerebral neuroblastoma. A clinicopatho- diagnosis with metastatic renal cell carcinoma, pilocytic astrocytoma reveals mTOR as a the-
1028. Hofmann BM, Kreutzer J, Saeger W, logical study of 35 cases. Brain. 99(4):735-56. but does not explain the histogenesis of the rapeutic target. Neuro Oncol. 15(12):1604-14.
Buchfelder M, Bliimcke I, Fahlbusch R, et al. PMID:1030655 capillary hemangioblastoma. Am J Surg Pathol. PMID:24203892
(2006). Nuclear beta-catenin accumulation as 1046. Hoshino T, Wilson BC, Ellis WG (1975). 13(3):207-16. PMID:2465700 1077. Holsken A, Kreutzer J, Hofmann BM, Hans
reliable marker for the differentiation between Gemistocytic astrocytes in gliomas. An auto- 1062. Hulsebos TJ, Kenter S, Siebers-Renelt V, Oppel F, Buchfelder M, et al. (2009). Target
cystic craniopharyngiomas and rathke cleft radiographic study. J Neuropathol Exp Neurol. U, Hans V, Wesseling P, Flucke U (2014). SM- gene activation of the Wnt signaling pathway
cysts: a clinico-pathologic approach. Am J Surg 34(3):263-81. PMID:167133 ARCB1 involvement in the development of lei- in nuclear beta-catenin accumulating cells of
Pathol. 30(12):1595-603. PMID:17122517 1047. Hosokawa Y, Tsuchihashi Y, Okabe H, omyoma in a patient with schwannomatosis. Am adamantinomatous craniopharyngiomas. Brain
1029. Hoischen A, Ehrler M, Fassunke J, Simon Toyama M, Namura K, Kuga M, et al. (1991). J Surg Pathol. 38(3):421-5. PMID:24525513 Pathol. 19(3):357-64. PMID:18540944
M, Baudis M, Landwehr C, et al. (2008). Com- Pleomorphic xanthoastrocytoma. Ultrastructu- 1063. Hulsebos TJ, Kenter S, Verhagen Wl, 1078. Ichimura K, Pearson DM, Kocialkowski S,
prehensive characterization of genomic aber- ral, immunohistochemical, and DNA cytofluo- Baas F, Flucke U, Wesseling P (2014). Prema- Backlund LM, Chan R, Jones DT, et al. (2009).
rations in gangliogliomas by CGH, array-ba- rometric study of a case. Cancer. 68(4):853-9. ture termination of SMARCB1 translation may IDH1 mutations are present in the majority of
sed CGH and interphase FISH. Brain Pathol. PMID:1855184 be followed by reinitiation in schwannomato- common adult gliomas but rare in primary
18(3):326-37. PMID:18371186 1048. Hou Z, Wu Z, Zhang J, Zhang L, Tian sis-associated schwannomas, but results in glioblastomas. Neuro Oncol. 11(4):341-7.
1030. Holash J, Maisonpierre PC, Compton R, Liu B, et al. (2013). Clinical features and absence of SMARCB1 expression in rhabdoid P MID: 19435942
D, Boland P, Alexander CR, Zagzag D, et al. management of intracranial subependymo- tumors. Acta Neuropathol. 128(3):439-48. 1079. Ichimura K, Schmidt EE, Miyakawa A,
(1999) . Vessel cooption, regression, and growth mas in children. J Clin Neurosci. 20(1):84-8. PMID:24740647 Goike HM, Collins VP (1998). Distinct patterns
in tumors mediated by angiopoietins and VEGF. PMID:23117139 1064. Hulsebos TJ, Plomp AS, Wolterman RA, of deletion on 10p and 10q suggest involvement
Science. 284(5422):1994-8. PMID:10373119 1049. Hovestadt V, Remke M, Kool M, Pietsch Robanus-Maandag EC, Baas F, Wesseling P of multiple tumor suppressor genes in the de-
1031. Homma T, Fukushima T, Vaccarella S, T, Northcott PA, Fischer R, et al. (2013). Robust (2007). Germline mutation of INI1/SMARCB1 velopment of astrocytic gliomas of different ma-
Yonekawa Y, Di Patre PL, Franceschi S, et al. molecular subgrouping and copy-number pro- in familial schwannomatosis. Am J Hum Genet. lignancy grades. Genes Chromosomes Cancer.
(2006). Correlation among pathology, geno- filing of medulloblastoma from small amounts 80(4):805-10. PMID:17357086 22(1):9-15. PMID:9591629
type, and patient outcomes in glioblastoma. of archival tumour material using high-density 1065. Hung KL, Wu CM, Huang JS, How SW 1080. Iczkowski KA, Butler SL, Shanks JH,
J Neuropathol Exp Neurol. 65(9):846-54. DNA methylation arrays. Acta Neuropathol. (1990). Familial medulloblastoma in siblings: Hossain D, Schall A, Meiers I, et al. (2008).
PMID:16957578 125(6):913-6. PMID:23670100 report in one family and review of the literature. Trials of new germ cell immunohistochemi-
1032. Honan WP, Anderson M, Carey MP, Wil- 1050. Howard BM, Hofstetter C, Wagner PL, Surg Neurol. 33(5):341-6. PMID:2184531 cal stains in 93 extragonadal and metastatic
liams B (1987). Familial subependymomas. Br J Muskin ET, Lavi E, Boockvar JA (2009). Trans- 1066. Husain AN, Leestma JE (1986). Cerebral germ cell tumors. Hum Pathol. 39(2):275-81.
Neurosurg. 1(3):317-21. PMID:3268127 formation of a low-grade pineal parenchymal tu- astroblastoma: immunohistochemical and ultra- PMID:18045648
1033. Honavar M, Janota I (1994). 73 cases mour to secondary pineoblastoma. Neuropathol structural features. Case report. J Neurosurg. 1081. Ida CM, Rodriguez FJ, Burger PC, Ca-
of dysembryoplastic neuroepithelial tumour: Appl Neurobiol. 35(2):214-7. PMID:19284482 64(4):657-61. PMID:3950749 ron AA, Jenkins SM, Spears GM, et al. (2015).
the range of histological appearances. Brain 1051. Howard JE, Dwivedi RC, Masterson L, 1067. Huse JT, Diamond EL, Wang L, Rosen- Pleomorphic Xanthoastrocytoma: Natural His-
Pathol. 4:428. Jani P (2015). Langerhans cell sarcoma: a sys- blum MK (2015). Mixed glioma with molecular tory and Long-Term Follow-Up. Brain Pathol.
1034. Horbinski C (2013). To BRAF or not tematic review. Cancer Treat Rev. 41 (4):320- features of composite oligodendroglioma and 25(5):575-86 PMID:25318587
to BRAF: is that even a question anymo- 31. PMID:25805533 astrocytoma: a true "oligoastrocytoma”? Acta 1082. Ida CM, Vrana JA, Rodriguez FJ, Jen-
re? J Neuropathol Exp Neurol. 72(1):2-7. 1052. Howe JR, Ringold JC, Summers RW, Neuropathol. 129(1):151-3. PMID:25359109 toft ME, Caron AA, Jenkins SM, et al. (2013).
PMID:23242278 Mitros FA, Nishimura DY, Stone EM (1998), 1068. Huse JT, Edgar M, Halliday J, Mikolaenko Immunohistochemistry is highly sensitive and
1035. Horbinski C, Dacic S, McLendon RE, Cie- A gene for familial juvenile polyposis maps I, Lavi E, Rosenblum MK (2013). Multinodular specific for detection of BRAF V600E mutation
ply K, Datto M, Brat DJ, et al. (2009). Chordoid to chromosome 18q21.1. Am J Hum Genet. and vacuolating neuronal tumors of the ce- in pleomorphic xanthoastrocytoma. Acta Neuro-
glioma: a case report and molecular characte- 62(5):1129-36. PMID:9545410 rebrum: 10 cases of a distinctive seizure-as- pathol Commun. 1:20. PMID:24252190
rization of five cases. Brain Pathol. 19(3):439- 1053. Howe JR, Roth S, Ringold JC, Summers sociated lesion. Brain Pathol. 23(5):515-24. 1083. Idbaih A, Criniere E, Marie Y, Rousseau
48. PMID:18652591 RW, Jarvinen HJ, Sistonen P, et al, (1998). PMID:23324039 A, Mokhtari K, Kujas M, et al. (2008). Gene
372 References
amplification is a poor prognostic factor in Absence of p53 gene mutations in a tumor 1115. Jacoby LB, Jones D, Davis K, Kronn large B-cell lymphoma of the elderly: a clini-
anaplastic oligodendrogliomas. Neuro Oncol. panel representative of pilocytic astrocytoma D, Short MP, Gusella J, et al. (1997). Mole- copathologic study of five cases. Brain Tumor
10(4):540-7. PMID:18544654 diversity using a p53 functional assay. Int J cular analysis of the NF2 tumor-suppressor Pathol. 31(4):265-73. PMID:24399201
1084. Idbaih A, Ducray F, Dehais C, Courdy Cancer. 76(6):797-800. PMID:9626343 gene in schwannomatosis. Am J Hum Genet. 1132. Jansen M, Mohapatra G, Betensky
C, Carpentier C, de Bernard S, et al.; POLA 1099. Ishizawa K, Kan-nuki S, Kumagai H, Ko- 61 (6): 1293-302. PMID:9399891 RA, Keohane C, Louis DN (2012). Gain of
Network (2012). SNP array analysis reveals mori T, Hirose T (2002). Lipomatous primitive 1116. Jacoby LB, MacCollin M, Barone R, chromosome arm 1q in atypical meningioma
novel genomic abnormalities including copy neuroectodermal tumor with a glioblastoma Ramesh V, Gusella JF (1996). Frequency and correlates with shorter progression-free survi-
neutral loss of heterozygosity in anaplastic component: a case report. Acta Neuropathol. distribution of NF2 mutations in schwannomas. val. Neuropathol Appl Neurobiol. 38(2):213-9.
oligodendrogliomas. PLoS One. 7(10):e45950. 103(2):193-8. PMID:11810187 Genes Chromosomes Cancer. 17(1 ):45-55. PMID:21988727
PMID:23071531 1100. Ishizawa K, Komori T, Hirose T (2005). PMID:8889506 1133. Janson K, Nedzi LA, David O, Schorin M,
1085. Idbaih A, Mokhtari K, Emile JF Galanaud Stromal cells in hemangioblastoma: neuroecto- 1117. Jacoby LB, MacCollin M, Louis DN, Walsh JW, Bhattacharjee M, et al. (2006). Pre-
D, Belaid H, de Bernard S, et al. (2014). Dra- dermal differentiation and morphological simila- Mohney T, Rubio MP, Pulaski K, et al. (1994). disposition to atypical teratoid/rhabdoid tumor
matic response of a BRAF V600E-mutated pri- rities to ependymoma. Pathol Int. 55(7):377-85. Exon scanning for mutation of the NF2 gene in due to an inherited INI1 mutation. Pediatr Blood
mary CNS histiocytic sarcoma to vemurafenib. PMID:15982211 schwannomas. Hum Mol Genet. 3(3):413-9. Cancer. 47(3):279-84. PMID:16261613
Neurology. 83(16):1478-80. PMID:25209580 1101. Ishizawa K, Komori T, Shimada S, Hirose PMID:8012353 1134. Janssen D, Harms D (2005). Juvenile
1086. Ikeda J, Sawamura Y, van Meir EG T (2008). Olig2 and CD99 are useful negative 1118. Jacoby LB, Pulaski K, Rouleau GA, xanthogranuloma in childhood and adolescen-
(1998). Pineoblastoma presenting in familial markers for the diagnosis of brain tumors. Clin Martuza RL (1990). Clonal analysis of human ce: a clinicopathologic study of 129 patients
adenomatous polyposis (FAP): random asso- Neuropathol. 27(3):118-28. PMID:18552083 meningiomas and schwannomas. Cancer Res. from the kiel pediatric tumor registry. Am J Surg
ciation, FAP variant or Turcot syndrome? Br J 1102. Ishizawa T, Komori T, Shibahara J, Ishiza- 50(21 ):6783-6. PMID:2208143 Pathol. 29(1 ):21-8. PMID:15613853
Neurosurg. 12(6):576-8. PMID:10070471 wa K, Adachi J, Nishikawa R, et al. (2006). Pa- 1119. Jacques TS, Eldridge C, Patel A, Saleem 1135. Janz C, Buhl R (2014). Astroblastoma:
1087. Ikezaki K, Matsushima T, Inoue T, Yokoya- pillary glioneuronal tumor with minigemistocytic NM, Powell M, Kitchen ND, et al. (2006). Mixed report of two cases with unexpected clinical be-
ma N, Kaneko Y, Fukui M (1993). Correlation of components and increased proliferative activity. glioneuronal tumour of the fourth ventricle with havior and review of the literature. Clin Neurol
microanatomical localization with postoperative Hum Pathol. 37(5):627-30. PMID:16647962 prominent rosette formation. Neuropathol Appl Neurosurg. 125:114-24. PMID:25108699
survival in posterior fossa ependymomas. Neu- 1103. Ismat FA, Xu J, Lu MM, Epstein JA Neurobiol. 32(2):217-20. PMID:16599951 1136. Japp AS, Gessi M, Messing-Junger M,
rosurgery. 32(1 ):38-44. PMID:8421555 (2006). The neurofibromin GAP-related do- 1120. Jacques TS, Valentine A, Bradford R, Denkhaus D, Zur Miihlen A, Wolff JE, et al.
1088. Ikota H, Tanaka Y, Yokoo H, Nakazato main rescues endothelial but not neural McLaughlin JE (2004). December 2003: a (2015). High-resolution genomic analysis does
Y (2011). Clinicopathological and immunohis- crest development in Nf1 mice. J Clin Invest. 70-year-old woman with a recurrent meningeal not qualify atypical plexus papilloma as a se-
tochemical study of 20 choroid plexus tumors: 116(9):2378-84. PMID:16906226 mass. Recurrent meningioma with rhabdomyo- parate entity among choroid plexus tumors.
their histological diversity and the expression of 1104. Italiano A, Sung YS, Zhang L, Singer S, sarcomatous differentiation. Brain Pathol. J Neuropathol Exp Neurol. 74(2):110-20.
markers useful for differentiation from metas- Maki RG, Coindre JM, et al. (2012). High pre- 14(2):229-30. PMID:15193039 PMID:25575132
tatic cancer. Brain Tumor Pathol. 28(3):215-21. valence of CIC fusion with double-homeobox 1121. Jaeckle KA, Decker PA, Ballman KV, 1137. Jaros E, Perry RH, Adam L, Kelly PJ,
PM1D:21394517 (DUX4) transcription factors in EWSR1-negati- Flynn PJ, Giannini C, Scheithauer BW, et al. Crawford PJ, Kalbag RM, et al. (1992). Prog-
1089. Ilhan I, Berberoglu S, Kutluay L, Maden ve undifferentiated small blue round cell sarco- (2011). Transformation of low grade glioma nostic implications of p53 protein, epidermal
HA (1998). Subcutaneous sacrococcygeal mas. Genes Chromosomes Cancer. 51(3):207- and correlation with outcome: an NCCTG da- growth factor receptor, and Ki-67 labelling in
myxopapillary ependymoma. Med Pediatr On- 18. PMID:22072439 tabase analysis. J Neurooncol. 104(1):253-9. brain tumours. Br J Cancer. 66(2):373-85.
col. 30(2):81-4. PMID:9403014 1105. Ito T, Kanno H, Sato K, Oikawa M, Ozaki PMID:21153680 PMID:1503912
1090. Imperiale A, Moussallieh FM, Roche P, Y, Nakamura H, et al. (2014). Clinicopathologic 1122. Jaffe ES, Harris NL, Vardiman JW, Cam- 1138. Jarrell ST, Vortmeyer AO, Linehan WM,
Battini S, Cicek AE, Sebag F, et al. (2015). Me- study of pineal parenchymal tumors of interme- po E, Arber DA, editors. (2010). Hematopatho- Oldfield EH, Lonser RR (2006). Metastases
tabolome profiling by HRMAS NMR spectrosco- diate differentiation. World Neurosurg. 81(5- logy. 1st Philadelphia. Saunders/ Elsevier. to hemangioblastomas in von Hippel-Lindau
py of pheochromocytomas and paragangliomas 6):783-9. PMID:23396072 1123. Jahnke K, Korfel A, Komm J, Bechrakis disease. J Neurosurg. 105(2):256-63.
detects SDH deficiency: clinical and pathophy- 1106. Iwaki T, Fukui M, Kondo A, Matsushima NE, Stein H, Thiel E, et al. (2006). Intraocular PMID:17219831
siological implications. Neoplasia. 17(1):55-65. T, Takeshita I (1987). Epithelial properties of lymphoma 2000-2005: results of a retrospecti- 1139. Javahery RJ, Davidson L, Fangusaro
PMID:25622899 pleomorphic xanthoastrocytomas determined ve multicentre trial. Graefes Arch Clin Exp Opht- J, Finlay JL, Gonzalez-Gomez I, McComb JG
1091. Inatomi Y, Ito T, Nagae K, Yamada Y, in ultrastructural and immunohistochemical halmol. 244(6):663-9. PMID:16228920 (2009). Aggressive variant of a papillary glio-
Kiyomatsu M, Nakano-Nakamura M, et al. studies. Acta Neuropathol. 74(2):142-50. 1124. Jahnke K, Thiel E, Martus P, Herrlinger neuronal tumor. Report of 2 cases, J Neurosurg
(2014). Hybrid perineurioma-neurofibroma in PMID:3673505 U, Weller M, Fischer L, et al.; German Primary Pediatr. 3(1):46-52. PMID:19119904
a patient with neurofibromatosis type 1, cli- 1107. Iwamoto FM, DeAngelis LM, Abrey LE Central Nervous System Lymphoma Study 1140. Jay V, Edwards V, Squire J, Rutka
nically mimicking malignant peripheral nerve (2006). Primary dural lymphomas: a clinico- Group (2006). Relapse of primary central J (1993). Astroblastoma: report of a case
sheath tumor. Eur J Dermatol. 24(3):412-3. pathologic study of treatment and outcome nervous system lymphoma: clinical features, with ultrastructural, cell kinetic, and cytoge-
PMID:24751814 in eight patients. Neurology. 66(11):1763-5. outcome and prognostic factors. J Neurooncol. netic analysis. Pediatr Pathol. 13(3):323-32.
1092. Ingham PW (1998). The patched gene in PMID:16769960 80(2):159-65. PMID:16699873 PMID:8516227
development and cancer. Curr Opin Genet Dev. 1108. Iwashita T, Enjoji M (1987). Plexiform 1125. Jahnke K, Thiel E, Schilling A, Herrlin- 1141. Jay V, Squire J, Becker LE, Humphreys
8(1):88-94. PMID:9529611 neurilemmoma: a clinicopathological and im- ger U, Weller M, Coupland SE, et al. (2005). R (1994). Malignant transformation in a gan-
1093. Ingold B, Wild PJ, Nocito A, Amin MB, munohistochemical analysis of 23 tumours from Low-grade primary central nervous system glioglioma with anaplastic neuronal and ast-
Storz M, Heppner FL, et al. (2008). Renal cell 20 patients. Virchows Arch A Pathol Anat Histo- lymphoma in immunocompetent patients. Br J rocytic components. Report of a case with flow
carcinoma marker reliably discriminates central pathol. 411 (4):305-9. PMID:3114942 Haematol. 128(5):616-24. PMID:15725082 cytometric and cytogenetic analysis. Cancer.
nervous system haemangioblastoma from brain 1109. Iwata H, Mori Y, Takagi H, Shirahashi K, 1126. Jain A, Amin AG, Jain P, Burger P, Jal- 73(11):2862-8. PMID:8194028
metastases of renal cell carcinoma. Histopatho- Shinoda J, Shimokawa K, et al. (2004). Medi- lo Gl, Lim M, et al. (2012). Subependymoma: 1142. Jay V, Squire J, Blaser S, Hoffman HJ,
logy. 52(6):674-81. PMID:18393979 astinal growing teratoma syndrome after cispla- clinical features and surgical outcomes. Neurol Hwang P (1997). Intracranial and spinal metas-
1094. Inoue Y, Nemoto Y, Murata R, Tashiro T, tin-based chemotherapy and radiotherapy for Res. 34(7):677-84. PMID:22747714 tases from a ganglioglioma with unusual cyto-
Shakudo M, Kohno K, et al. (1998). CT and MR intracranial germinoma. J Thorac Cardiovasc 1127. Jain RK, Carmeliet P (2012). Snapshot: genetic abnormalities in a patient with complex
imaging of cerebral tuberous sclerosis. Brain Surg. 127(1 ):291-3. PMID:14752454 Tumor angiogenesis. Cell. 149(6): 1408-1408. partial seizures. Childs Nerv Syst. 13(10):550-
Dev. 20(4):209-21. PMID:9661965 1110. Jacks T, Shih TS, Schmitt EM, Bronson e1.PMID:22682256 5. PMID:9403205
1095. Cairncross G, Berkey B, Shaw E, Jenkins RT, Bernards A, Weinberg RA(1994). Tumour 1128. Jakacki Rl, Burger PC, Kocak M, Bo- 1143. Jeffs GJ, Lee GY, Wong GT (2003). Fun-
R, Scheithauer B, Brachman D, et al,; Interg- predisposition in mice heterozygous for a tar- yett JM, Goldwein J, Mehta M, et al. (2015). ctioning paraganglioma of the thoracic spine:
roup Radiation Therapy Oncology Group Trial geted mutation in Nf1. Nat Genet. 7(3):353-61. Outcome and prognostic factors for children case report. Neurosurgery. 53(4):992-4, dis-
9402 (2006). Phase III trial of chemotherapy PMID:7920653 with supratentorial primitive neuroectodermal cussion 994-5. PMID:14519233
plus radiotherapy compared with radiotherapy 1111. Jackson CG (2001). Glomus tympanicum tumors treated with carboplatin during radio- 1144. Jehi L, Yardi R, Chagin K, Tassi L, Russo
alone for pure and mixed anaplastic oligo- and glomus jugulare tumors . Otolaryngol Clin therapy: a report from the Children’s Oncology GL, Worrell G, et al. (2015). Development and
dendroglioma: Intergroup Radiation Therapy North Am 34:941-70, vii. PMID:11557448 Group. Pediatr Blood Cancer. 62(5):776-83. validation of nomograms to provide individuali-
Oncology Group Trial 9402. J Clin Oncol. 1112. Jackson M, Hassiotou F, NowakA(2015). PMID:25704363 sed predictions of seizure outcomes after epi-
24(18):2707-14. PMID:16782910 Glioblastoma stem-like cells: at the root of tu- 1129. Jakobiec FA, Kool M, Stagner AM, Pfister lepsy surgery: a retrospective analysis. Lancet
1096. Ironside JW, Jefferson AA, Royds JA, mor recurrence and a therapeutic target. Car- SM, Eagle RC, Praia AD, et al. (2015). Intrao- Neurol. 14(3):283-90. PMID:25638640
Taylor CB, Timperley WR (1984). Carcinoid cinogenesis. 36(2):177-85. PMID:25504149 cular Medulloepitheliomas and Embryonal Tu- 1145. Jeibmann A, Eikmeier K, Linge A, Kool
tumour arising in a recurrent intradural spi- 1113. Jacob K, Albrecht S, Sollier C, Faury D, mors With Multilayered Rosettes of the Brain: M, Koos B, Schulz J, et al. (2014). Identi-
nal teratoma. Neuropathol Appl Neurobiol. Sader E, Montpetit A, et al. (2009). Duplication Comparative Roles of LIN28A and C19MC. fication of genes involved in the biology of
10(6):479-89. PMID:6084821 of 7q34 is specific to juvenile pilocytic astrocyto- Am J Ophthalmol. 159(6):1065-1074.e1. atypical teratoid/rhabdoid tumours using Dro-
1097. Ishida M, Hotta M, Tsukamura A, Taga mas and a hallmark of cerebellar and optic pa- PMID:25748578 sophila melanogaster. Nat Commun. 5:4005,
T, Kato H, Ohta S, et al. (2010). Malignant thway tumours. Br J Cancer. 101(4):722-33. 1130. Jallo Gl, Zagzag D, Epstein F (1996). PMID:24892285
transformation in craniopharyngioma after PMID:19603027 Intramedullary subependymoma of the 1146. Jeibmann A, Hasselblatt M, Gerss J,
radiation therapy: a case report and review 1114. Jacobs JJ, Rosenberg AE (1989). Ex- spinal cord. Neurosurgery. 38(2):251-7. Wrede B, Egensperger R, Beschorner R, et
of the literature. Clin Neuropathol. 29(1):2-8. tracranial skeletal metastasis from a pinea- PMID:8869051 al. (2006). Prognostic implications of atypical
PMID:20040326 loblastoma. A case report and review of the 1131. Jamal SE, Li S, Bajaj R, Wang Z, Kenyon histologic features in choroid plexus papilloma.
1098. Ishii N, Sawamura Y, Tada M, Daub DM, literature. Clin Orthop Relat Res. (247):256-60. L, Glass J, et al. (2014). Primary central ner- J Neuropathol Exp Neurol. 65(11):1069-73.
Janzer RC, Meagher-Villemure M, et al. (1998). PMID:2676297 vous system Epstein-Barr virus-positive diffuse PMID:17086103
References 373
1147. Jeibmann A, Wrede B, Peters 0, Wolff JE, M, Schramm J, Wiestler OD, et al. (2001). al. (2015). Cross-reactivity of the BRAF VE1 an- leiomyomatosis). Zentralbl Pathol. 140(2):195-
Paulus W, Hasselblatt M (2007). Malignant pro- Comparative analysis of the NF2, TP53, PTEN, tibody with epitopes in axonemal dyneins leads 200. PMID7947627
gression in choroid plexus papillomas. J Neu- KRAS, NRAS and HRAS genes in sporadic and to staining of cilia. Mod Pathol. 28(4):596-606. 1196. Janisch W, Staneczek W (1989). [Pri-
rosurg. 107(3) Suppl:199-202. PMID:17918524 radiation-induced human meningiomas. Int J PMID:25412847 mary tumors of the choroid plexus. Frequency,
1148. Jellinger K (2009). Metastatic oligo- Cancer. 94(2):218-21. PMID:11668501 1181. Jordanova ES, Riemersma SA, Philip- localization and age], Zentralbl Allg Pathol.
dendrogliomas: a review of the literature and 1165. Johannsson O, Ostermeyer EA, Hakans- po K, Giphad-Gassler M, Schuuring E, Kluin 135(3):235-40. PMID:2773602
case report. Acta Neurochir (Wien). 151(8):987. son S, Friedman LS, Johansson U, Sellberg G, PM (2002). Hemizygous deletions in the HLA 1197. Jaaskelainen J (1986). Seemingly com-
PMID: 19424658 etal. (1996). Founding BRCA1 mutations in he- region account for loss of heterozygosity in plete removal of histologically benign intracra-
1149. Jellinger K, Bock F, Brenner H (1988). reditary breast and ovarian cancer in southern the majority of diffuse large B-cell lymphomas nial meningioma: late recurrence rate and
Meningeal melanocytoma. Report of a case and Sweden. Am J Hum Genet. 58(3):441-50. of the testis and the central nervous system. factors predicting recurrence in 657 patients. A
review of the literature. Acta Neurochir (Wien). PMID:8644702 Genes Chromosomes Cancer. 35(1):38-48. multivariate analysis. Surg Neurol. 26(5):461-9.
94(1-2):78-87. PMID:3051898 1166. Goldblum JR, Weiss SW, Folpe AL PMID:12203788 PMID:3764651
1150. Jenevein EP (1964). A neurohypophyseal (2013). Enzinger and Weiss's Soft Tissue Tu- 1182. Joseph NM, Mosher JT, Buchstal- 1198. Jaaskelainen J, Paetau A, Pyykko I,
tumor originating from pituicytes. Am J Clin Pa- mors. 6th ed. Philadelphia: Elsevier Saunders. ler J, Snider P, McKeever PE, Lim M, et al. Blomstedt G, Palva T, Troupp H (1994). Interfa-
thol. 41:522-6. PMID:14165459 1167. Johnson BE, Mazor T, Hong C, Barnes (2008). The loss of Nf1 transiently promotes ce between the facial nerve and large acoustic
1151. Jenkins RB, Blair H, Ballman KV, Giannini M, Aihara K, McLean CY, et al. (2014). Mutatio- self-renewal but not tumorigenesis by neural neurinomas. Immunohistochemical study of the
C, Arusell RM, Law M, et al. (2006). A t(1;19) nal analysis reveals the origin and therapy-dri- crest stem cells. Cancer Cell. 13(2):129-40. cleavage plane in NF2 and non-NF2 cases. J
(q10;p10) mediates the combined deletions of ven evolution of recurrent glioma. Science. PMID:18242513 Neurosurg. 80(3):541-7. PMID:8113868
1p and 19q and predicts a better prognosis of 343(6167):189-93. PMID:24336570 1183. Joseph NM, Phillips J, Dahiya S, M Fe- 1199. Kacerovska D, Michal M, Kuroda N,
patients with oligodendroglioma. Cancer Res. 1168. Johnson MW, Eberhart CG, Perry A, licella M, Tihan T, Brat DJ, et al. (2013). Diag- Tanaka A, Sima R, Denisjuk N, et al. (2013).
66(20):9852-61. PMID:17047046 Tihan T, Cohen KJ, Rosenblum MK, et al. nostic implications of IDH1-R132H and OLIG2 Hybrid peripheral nerve sheath tumors, inclu-
1152. Jenkins RB, Xiao Y, Sicotte H, Decker (2010). Spectrum of pilomyxoid astrocytomas: expression patterns in rare and challenging gli- ding a malignant variant in type 1 neurofibro-
PA, Kollmeyer TM, Hansen HM, et al. (2012). intermediate pilomyxoid tumors. Am J Surg Pa- oblastoma variants. Mod Pathol. 26(3):315-26. matosis. Am J Dermatopathol. 35(6):641-9.
A low-frequency variant at 8q24.21 is strongly thol. 34(12):1783-91. PMID:21107083 PMID:23041832 PMID:23676318
associated with risk of oligodendroglial tumors 1169. Johnson MW, Emelin JK, Park SH, Vin- 1184. Jouvet A, Fauchon F, Liberski P, 1200. Kachhara R, Bhattacharya RN, Nair S,
and astrocytomas with IDH1 or IDH2 mutation. ters HV (1999). Co-localization of TSC1 and Saint-Pierre G, Didier-Bazes M, Heitzmann Radhakrishnan W (2003). Liponeurocytoma
Nat Genet. 44(10):1122-5. PMID:22922872 TSC2 gene products in tubers of patients with A, et al. (2003). Papillary tumor of the pine- of the cerebellum-a case report. Neurol India.
1153. Jenkinson MD, Bosma JJ, Du Plessis D, tuberous sclerosis. Brain Pathol. 9(1):45-54. al region. Am J Surg Pathol. 27(4):505-12. 51(2):274-6. PMID:14571027
Ohgaki H, Kleihues P, Warnke P, et al. (2003). PMID:9989450 PMID:12657936 1201. Kadonaga JN, Frieden IJ (1991). Neu-
Cerebellar liponeurocytoma with an unusually 1170. Johnson MW, Kerfoot C, Bushnell T, Li 1185. Jouvet A, Fevre-Montange M, Besanqon rocutaneous melanosis: definition and review
aggressive clinical course: case report. Neu- M, Vinters HV (2001). Hamartin and tuberin R, Derrington E, Saint-Pierre G, Belin MF, et al. of the literature. J Am Acad Dermatol. 24(5 Pt
rosurgery. 53(6): 1425-7, discussion 1428. expression in human tissues. Mod Pathol. (1994). Structural and ultrastructural characteri- 1)747-55. PMID:1869648
PMID:14633310 14(3):202-10. PMID:11266527 stics of human pineal gland, and pineal paren- 1202. Kaido T, Sasaoka Y, Hashimoto H, Taira
1154. Jennings MT, Gelman R, Hochberg F 1171. Johnson RA, Wright KD, Poppleton H, chymal tumors. Acta Neuropathol. 88(4):334- K (2003). De novo germinoma in the brain in
(1985). Intracranial germ-cell tumors: natu- Mohankumar KM, Finkelstein D, Pounds SB, 48. PMID:7839826 association with Klinefelter's syndrome: case
ral history and pathogenesis. J Neurosurg. et al. (2010). Cross-species genomics matches 1186. Jouvet A, Lellouch-Tubiana A, Boddaed report and review of the literature. Surg Neurol.
63(2):155-67. PMID:2991485 driver mutations and cell compartments to mo- N, Zerah M, Champier J, Fevre-Montange M 60(6):553-8, discussion 559. PMID:14670679
1155. Jensen RL, Caamano E, Jensen EM, del ependymoma. Nature. 466(7306):632-6. (2005). Fourth ventricle neurocytoma with li- 1203. Kakita A, Inenaga C, Kameyama S,
Couldwell WT (2006). Development of contrast PMID:20639864 pomatous and ependymal differentiation. Acta Masuda H, Ueno T, Honma J, et al. (2005).
enhancement after long-term observation of a 1172. Johnson RL, Rothman AL, Xie J, Neuropathol. 109(3):346-51. PMID:15627205 Cerebral lipoma and the underlying cortex of
dysembryoplastic neuroepithelial tumor. J Neu- Goodrich LV, Bare JW, Bonifas JM, et al. 1187. Jouvet A, Saint-Pierre G, Fauchon F, the temporal lobe: pathological features asso-
rooncol. 78(1):59-62. PMID:16314940 (1996). Human homolog of patched, a candi- Privat K, Bouffet E, Ruchoux MM, et al. (2000). ciated with the malformation. Acta Neuropathol.
1156. Jentoft M, Giannini C, Rossi S, Mota date gene for the basal cell nevus syndrome. Pineal parenchymal tumors: a correlation of 109(3):339-45. PMID:15622498
R, Jenkins RB, Rodriguez FJ (2011). Oligo- Science. 272(5268):1668-71. PMID:8658145 histological features with prognosis in 66 cases. 1204. Kalamarides M, Niwa-Kawakita M, Leblo-
dendroglial tumors with marked desmoplasia: 1173. Johnston DL, Keene DL, Lafay-Cousin Brain Pathol. 10(1):49-60. PMID:10668895 is H, Abramowski V, Perricaudet M, Janin A, et
clinicopathologic and molecular features of L, Steinbok P, Sung L, Carret AS, et al. (2008). 1188. Jozwiak J, Jozwiak S, Skopinski P al. (2002). NF2 gene inactivation in arachnoidal
7 cases. Am J Surg Pathol. 35(6):845-52. Supratentorial primitive neuroectodermal tu- (2005). Immunohistochemical and microscopic cells is rate-limiting for meningioma develop-
PMID:21552114 mors: a Canadian pediatric brain tumor con- studies on giant cells in tuberous sclerosis. His- ment in the mouse. Genes Dev. 16(9):1060-5.
1157. Jeong JY, Suh YL, Hong SW (2014). Aty- sortium report. J Neurooncol. 86(1):101-8. tol Histopathol. 20(4):1321-6. PMID:16136513 PMID:12000789
pical teratoid/rhabdoid tumor arising in pleomor- PMID:17619825 1189. Juco J, Horvath E, Smyth H, Rotondo F, 1205. Kalamarides M, Stemmer-Rachamimov
phic xanthoastrocytoma: a case report. Neuro- 1174. Jones AC, Shyamsundar MM, Thomas Kovacs K (2007). Hemangiopericytoma of the AO, Niwa-Kawakita M, Chareyre F, Taranchon
pathology. 34(4):398-405. PMID:25268025 MW, Maynard J, Idziaszczyk S, Tomkins S, et sella mimicking pituitary adenoma: case repod E, Han ZY, et al. (2011). Identification of a
1159. Jeuken JW, Sprenger SH, Gilhuis J, al. (1999). Comprehensive mutation analysis of and review of the literature. Clin Neuropathol. progenitor cell of origin capable of generating
Teepen HL, Grotenhuis AJ, Wesseling P (2002). TSC1 and TSC2-and phenotypic correlations in 26(6):288-93. PMID:18232595 diverse meningioma histological subtypes. On-
Correlation between localization, age, and chro- 150 families with tuberous sclerosis. Am J Hum 1190. Judkins AR, Burger PC, Hamilton RL, cogene. 30(20):2333-44. PMID:21242963
mosomal imbalances in ependymal tumours as Genet. 64(5):1305-15. PMID:10205261 Kleinschmidt-DeMasters B, Perry A, Pomeroy 1206. Kaloshi G, Alikaj V, Rroji A, Vreto G, Petre-
detected by CGH. J Pathol. 197(2):238-44. 1175. Jones C, Baker SJ (2014). Unique SL, et al. (2005). INI1 protein expression dis- la M (2013). Visual and auditory hallucinations
PMID:12015749 genetic and epigenetic mechanisms driving tinguishes atypical teratoid/rhabdoid tumor from revealing cerebellar extraventricular neurocyto-
1159A. Jhawar BS, Fuchs CS, Colditz GA, paediatric diffuse high-grade glioma. Nat Rev choroid plexus carcinoma. J Neuropathol Exp ma: uncommon presentation for uncommon
Stampfer MJ (2003). Sex steroid hormone ex- Cancer. 14(10):14. PMID:25230881 Neurol. 64(5):391-7. PMID:15892296 tumor in uncommon location. Gen Hosp Psychi-
posures and risk for meningioma. J Neurosurg. 1176. Jones DT, Hutter B, Jager N, Korshunov 1191. Judkins AR, Ellison DW (2010). Epen- atry. 35(6):680.e1 -3. PMID:24199787
99(5):848-53. PMID:14609164 A, Kool M, Wamatz HJ, et al.; International dymoblastoma: dear, damned, distracting dia- 1207. Kalyan-Raman UP, Olivero WC (1987).
1160. Jiao Y, Killela PJ, Reitman ZJ, Rasheed Cancer Genome Consortium PedBrain Tumor gnosis, farewell!*. Brain Pathol. 20(1):133-9. Ganglioglioma: a correlative clinicopathological
AB, Heaphy CM, de Wilde RF, et al. (2012). Fre- Project (2013). Recurrent somatic alterations PMID:19120373 and radiological study of ten surgically treated
quent ATRX, CIC, FUBP1 and IDH1 mutations of FGFR1 and NTRK2 in pilocytic astrocytoma. 1192. Judkins AR, Mauger J, Ht A, Rorke cases with follow-up. Neurosurgery. 20(3):428-
refine the classification of malignant gliomas. Nat Genet. 45(8):927-32. PMID:23817572 LB, Biegel JA (2004). Immunohistochemi- 33. PMID:3574619
Oncotarget. 3(7):709-22. PMID:22869205 1177. Jones DT, Ichimura K, Liu L, Pearson cal analysis of hSNF5/INI1 in pediatric CNS 1208. Kambham N, Chang Y, Matsushima AY
1161. Jimsheleishvili S, Alshareef AT, Papadi- DM, Plant K, Collins VP (2006). Genomic ana- neoplasms. Am J Surg Pathol. 28(5):644-50. (1998). Primary low-grade B-cell lymphoma of
mitriou K, Bregy A, Shah AH, Graham RM, et lysis of pilocytic astrocytomas at 0.97 Mb re- PMID:15105654 mucosa-associated lymphoid tissue (MALT)
al. (2014). Extracranial glioblastoma in trans- solution shows an increasing tendency toward 1192A. Jung KW, Ha J, Lee SH, Won YJ, Yoo H arising in dura. Clin Neuropathol. 17(6):311-7.
plant recipients. J Cancer Res Clin Oncol. chromosomal copy number change with age. (2013). An updated nationwide epidemiology of PMID:9832258
140(5):801-7. PMID:24595597 J Neuropathol Exp Neurol. 65(11):1049-58. primary brain tumors in republic of Korea. Brain 1209. Kamoshima Y, Sawamura Y, Sugiyama
1162. Jo VY, Fletcher CD (2015). Epithelioid PMID:17086101 Tumor Res Treat. 1(1):16-23. PMID:24904884 T, Yamaguchi S, Houkin K, Kubota K (2011).
malignant peripheral nerve sheath tumor: clini- 1178. Jones DT, Kocialkowski S, Liu L, Pe- 1193. Jung SM, Kuo TT (2005). Immunoreacti- Primary central nervous system mucosa-as-
copathologic analysis of 63 cases. Am J Surg arson DM, Backlund LM, Ichimura K, et al. vity of CD10 and inhibin alpha in differentiating sociated lymphoid tissue lymphoma-case re-
Pathol. 39(5):673-82. PMID:25602794 (2008). Tandem duplication producing a novel hemangioblastoma of central nervous system port. Neurol Med Chir (Tokyo). 51(7):527-30.
1163. Jozwiak S, Kwiatkowski D, Kotulska K, oncogenic BRAF fusion gene defines the ma- from metastatic clear cell renal cell carcinoma. PMID:21785250
Larysz-Brysz M, Lewin-Kowalik J, Grajkowska jority of pilocytic astrocytomas. Cancer Res. Mod Pathol. 18(6)788-94. PMID:15578072 1210. Kanamori M, Kumabe T, Saito R, Yamas-
W, et al. (2004). Tuberin and hamartin expressi- 68(21 ):8673-7. PMID:18974108 1194. Jurco S 3rd, Nadji M, Harvey DG, Parker hita Y, Sonoda Y, Ariga H, et al. (2009). Optimal
on is reduced in the majority of subependymal 1179. Jones H, Stead PV, Weller RO (1991). JC Jr, Font RL, Morales AR (1982). Hemangi- treatment strategy for intracranial germ cell tu-
giant cell astrocytomas in tuberous sclerosis Spindle-cell glioblastoma or gliosarcoma? oblastomas: histogenesis of the stromal cell mors: a single institution analysis. J Neurosurg
complex consistent with a two-hit model of Neuropathol Appl Neurobiol. 17(3):177-87. studied by immunocytochemistry. Hum Pathol. Pediatr. 4(6):506-14. PMID:19951035
pathogenesis. J Child Neurol. 19(2):102-6. PMID:1653908 13(1):13-8. PMID:6176519 1211. Kandenwein JA, Bostroem A, Feuss
PMID:15072102 1180. Jones RT, Abedalthagafi MS, Brahman- 1195. Janisch W, Janda J, Link I M, Pietsch T, Simon M (2011). Surgical ma-
1164. Joachim T, Ram Z, Rappaport ZH, Simon dam M, Greenfield EA, Hoang MP, Louis DN, et (1994). [Primary diffuse leptomeningeal nagement of intracranial subependymomas.
374 References
Acta Neurochir (Wien). 153(7):1469-75. Kramm CM, Wolff JE (2009). Anaplastic gang- 1243. Keith J, Lownie S, Ang LC (2006). 1260. Khalid L, Carone M, Dumrongpisutikul N,
PMID:21499782 lioglioma in children. J Neurooncol. 92(2)157- Co-existence of paraganglioma and myxopa- Intrapiromkul J, Bonekamp D, Barker PB, et al.
1212. Kandt RS, Haines JL, Smith M, Northrup 63. PMID19043777 pillary ependymoma of the cauda equina. Acta (2012). Imaging characteristics of oligodendro-
H, Gardner RJ, Short MP, et al. (1992). Lin- 1228. Karremann M, Rausche U, Fleischhack Neuropathol. 111(6):617-8. PMID:16718356 gliomas that predict grade. AJNR Am J Neuro-
kage of an important gene locus for tuberous G, Nathrath M, Pietsch T, Kramm CM, et al. 1244. Kelleher T, Aquilina K, Keohane C, radiol. 33(5):852-7. PMID:22268087
sclerosis to a chromosome 16 marker for poly- (2010). Clinical and epidemiological characte- O’Sullivan MG (2005). Intramedullary capillary 1261. Khanani MF, Hawkins C, Shroff M,
cystic kidney disease. Nat Genet. 2(1):37-41. ristics of pediatric gliosarcomas. J Neurooncol. haemangioma. Br J Neurosurg. 19(4):345-8. Dirks P, Capra M, Burger PC, et al. (2006).
PMID:1303246 97(2):257-65. PMID19806321 PMID:16455542 Pilomyxoid astrocytoma in a patient with neuro-
1213. Kane AJ, Sughrue ME, Rutkowski MJ, 1229. Karremann M, Rausche U, Roth D, Kuhn 1245. Kelsey KT, Wrensch M, Zuo ZF, Miike fibromatosis. Pediatr Blood Cancer. 46(3):377-
Aranda D, Mills SA, Lehil M, et al. (2012). Atypia A, Pietsch T, Gielen GH, et al. (2013). Cere- R, Wiencke JK (1997). A population-based 80. PMID:15800886
predicting prognosis for intracranial extraventri- bellar location may predict an unfavourable case-control study of the CYP2D6 and GSTT1 1262. Khanna M, Siraj F, Chopra P, Bhalla S,
cular neurocytomas. J Neurosurg. 116(2):349- prognosis in paediatric high-grade glioma. Br J polymorphisms and malignant brain tumors. Roy S (2011). Gliosarcoma with prominent
54. PM ID:22054208 Cancer. 109(4):844-51. PMID:23868007 Pharmacogenetics. 7(6):463-8. PMID:9429231 smooth muscle component (gliomyosarcoma):
1214. Kane AJ, Sughrue ME, Rutkowski MJ, 1230. Kasashima S, Oda Y, Nozaki J, Shirasaki 1246. Kepes JJ (1978). Transitional cell tumor a report of 10 cases. Indian J Pathol Microbiol.
Shangari G, Fang S, McDermott MW, et al. M, Nakanishi I (2000). A case of atypical gra- of the pituitary gland developing from a Rathke’s 54(1 ):51-4. PMID:21393877
(2011). Anatomic location is a risk factor for nular cell tumor of the neurohypophysis. Pathol cleft cyst. Cancer. 41(1):337-43. PMID:626939 1263. Khuong-Quang DA, Buczkowicz P, Ra-
atypical and malignant meningiomas. Cancer. Int. 50(7):568-73. PMID:10886742 1247. Kepes JJ (1987). Astrocytomas: old and kopoulos P, Liu XY, Fontebasso AM, Bouffet
117(6):1272-8. PMID:21381014 1231. Kato K, Nakatani Y, Kanno H, Inayama newly recognized variants, their spectrum of E, et al. (2012). K27M mutation in histone
1215. Kannan K, Inagaki A, Silber J, Gorovets Y, Ijiri R, Nagahara N, et al. (2004). Possible morphology and antigen expression. Can J H3.3 defines clinically and biologically distinct
D, Zhang J, Kastenhuber ER, et al. (2012). linkage between specific histological structures Neurol Sci. 14(2):109-21. PMID:3607613 subgroups of pediatric diffuse intrinsic pontine
Whole-exome sequencing identifies ATRX and aberrant reactivation of the Wnt pathway in 1248. Kepes JJ (1993). Pleomorphic xanthoast- gliomas. Acta Neuropathol. 124(3):439-47.
mutation as a key molecular determinant in lo- adamantinomatous craniopharyngioma. J Pa- rocytoma: the birth of a diagnosis and a con- PMID:22661320
wer-grade glioma. Oncotarget. 3(10):1194-203. thol. 203(3):814-21. PMID:15221941 cept. Brain Pathol. 3(3):269-74. PMID:8293186 1264. Kienast Y, von Baumgarten L, Fuhrmann
PMID:23104868 1232. Kato S, Han SY, Liu W, Otsuka K, Shiba- 1249. Kepes JJ, Chen WY, Connors MH, Vo- M, Klinkert WE, Goldbrunner R, Herms J, et al.
1216. Kanner AA, Staugaitis SM, Castilla EA, ta H, Kanamaru R, et al. (2003). Understanding gel FS (1988). "Chordoid" meningeal tumors (2010). Real-time imaging reveals the single
Chernova O, Prayson RA, Vogelbaum MA, the function-structure and function-mutation in young individuals with peritumoral lympho- steps of brain metastasis formation. Nat Med.
et al. (2006). The impact of genotype on out- relationships of p53 tumor suppressor protein plasmacellular infiltrates causing systemic 16(1):116-22. PMID:20023634
come in oligodendroglioma: validation of the by high-resolution missense mutation analysis. manifestations of the Castleman syndrome. A 1265. Kijima C, Miyashita T, Suzuki M, Oka
loss of chromosome arm 1 p as an important Proc Natl Acad Sci US A. 100(14):8424-9. report of seven cases. Cancer. 62(2):391-406. H, Fujii K (2012). Two cases of nevoid basal
factor in clinical decision making. J Neurosurg. PMID:12826609 PMID:3383139 cell carcinoma syndrome associated with
104(4):542-50. PMID:16619658 1233. Katoh M, Aida T, Sugimoto S, Suwamura 1250. Kepes JJ, Fulling KH, Garcia JH (1982). meningioma caused by a PTCH1 or SUFU
1217. Kanno H, Nishihara H, Oikawa M, Ozaki Y, Abe H, Isu T, et al. (1995). Immunohistoche- The clinical significance of “adenoid" forma- germline mutation. Fam Cancer. 11(4):565-70.
Y, Murata J, Sawamura Y, et al. (2012). Expres- mical analysis of giant cell glioblastoma. Pathol tions of neoplastic astrocytes, imitating me- PMID:22829011
sion of 06-methylguanine DNA methyltransfera- Int. 45(4):275-82. PMID:7550996 tastatic carcinoma, in gliosarcomas. A review 1266. Kilday JP, Mitra B, Domerg C, Ward J,
se (MGMT) and immunohistochemical analysis 1234. Katsetos CD, Herman MM, Frankfurter A, of five cases. Clin Neuropathol. 1(4):139-50. Andreiuolo F, Osteso-lbanez T, et al. (2012).
of 12 pineal parenchymal tumors. Neuropatho- Gass P, Collins VP, Walker CC, et al. (1989). PMID:6188569 Copy number gain of 1q25 predicts poor pro-
logy. 32(6):647-53. PMID:22458700 Cerebellar desmoplastic medulloblastomas. A 1251. Kepes JJ, Lewis RC, Vergara GG (1980). gression-free survival for pediatric intracranial
1218. Kannuki S, Bando K, Soga T, Matsumoto further immunohistochemical characterization Cerebellar astrocytoma invading the muscula- ependymomas and enables patient risk strati-
K, Hirose T (1996). (A case report of dysem- of the reticulin-free pale islands. Arch Pathol ture and soft tissues of the neck. Case report. J fication: a prospective European clinical trial co-
bryoplastic neuroepithelial tumor associated Lab Med. 113(9):1019-29. PMID:2505732 Neurosurg. 52(3):414-8. PMID7359199 hort analysis on behalf of the Children’s Cancer
with neurofibromatosis type 1], No Shinkei 1235. Katsetos CD, Herman MM, Krishna L, 1252. Kepes JJ, Moral LA, Wilkinson SB, Leukaemia Group (CCLG), Societe Francaise
Geka. 24(2)183-8. PMID:8849480 Vender JR, Vinores SA, Agamanolis DP, et al. Abdullah A, Llena JF (1998). Rhabdoid trans- d’Oncologie Pediatrique (SFOP), and Internati-
1219. Kapadia SB, Frisman DM, Hitchcock (1995). Calbindin-D28k in subsets of medul- formation of tumor cells in meningiomas: a onal Society for Pediatric Oncology (SIOP). Clin
CL, Ellis GL, Popek EJ (1993). Melanotic neu- loblastomas and in the human medulloblasto- histologic indication of increased proliferative Cancer Res. 18(7):2001-11. PMID:22338015
roectodermal tumor of infancy. Clinicopatho- ma cell line D283 Med. Arch Pathol Lab Med. activity: report of four cases. Am J Surg Pathol. 1267. Kilday JP, Rahman R, Dyer S, Ridley L,
logical, immunohistochemical, and flow cyto- 119(8)734-43. PMID7646332 22(2):231-8. PMID:9500225 Lowe J, Coyle B, et al. (2009). Pediatric epen-
metric study. Am J Surg Pathol. 17(6):566-73. 1236. Katsetos CD, Krishna L, Friedberg E, 1253. Kepes JJ, Rubinstein LJ (1981). Mali- dymoma: biological perspectives. Mol Cancer
PMID:8392815 Reidy J, Karkavelas G, Savory J (1994). Lobar gnant gliomas with heavily lipidized (foamy) Res. 7(6)765-86. PMID:19531565
1220. Karafin M, Jallo Gl, Ayars M, Eberhart pilocytic astrocytomas of the cerebral hemi- tumor cells: a report of three cases with im- 1268. Killela PJ, Pirozzi CJ, Healy P, Reitman
CG, Rodriguez FJ (2011). Rosette forming spheres: II. Pathobiology-morphogenesis of munoperoxidase study. Cancer. 47(10):2451-9. ZJ, Lipp E, Rasheed BA, et al. (2014). Muta-
glioneuronal tumor in association with Noonan the eosinophilic granular bodies. Clin Neuropa- PMID7023643 tions in IDH1, IDH2, and in the TERT promo-
syndrome: pathobiological implications. Clin thol. 13(6):306-14. PMID7851045 1254. Kepes JJ, Rubinstein LJ, Eng LF (1979). ter define clinically distinct subgroups of adult
Neuropathol. 30(6):297-300. PMID:22011734 1237. Kaufman DL, Heinrich BS, Willett C, Perry Pleomorphic xanthoastrocytoma: a distinctive malignant gliomas. Oncotarget. 5(6):1515-25.
1221. Karaki S, Mochida J, Lee YH, Nishimura A, Finseth F, Sobel RA, et al. (2003). Somatic meningocerebral glioma of young subjects with PMID:24722048
K, Tsutsumi Y (1999). Low-grade malignant pe- instability of the NF2 gene in schwannomatosis. relatively favorable prognosis. A study of 12 1269. Killela PJ, Pirozzi CJ, Reitman ZJ, Jones
rineurioma of the paravertebral column, trans- Arch Neurol. 60(9):1317-20. PMID:12975302 cases. Cancer. 44(5):1839-52. PMID:498051 S, Rasheed BA, Lipp E, et al. (2014). The ge-
forming into a high-grade malignancy. Pathol 1238. Kaulich K, Blaschke B, Numann A, von 1255. Kerfoot C, Wienecke R, Menchine M, netic landscape of anaplastic astrocytoma. On-
Int. 49(9):820-5. PMID:10504555 Deimling A, Wiestler OD, Weber RG, et al. Emelin J, Maize JC Jr, Welsh CT, et al. (1996). cotarget. 5(6)1452-7. PMID:24140581
1222. Karamchandani JR, Nielsen TO, van de (2002). Genetic alterations commonly found in Localization of tuberous sclerosis 2 mRNA and 1270. Killela PJ, Reitman ZJ, Jiao Y, Bettegow-
Rijn M, West RB (2012). Sox10 and S100 in diffusely infiltrating cerebral gliomas are rare its protein product tuberin in normal human da C, Agrawal N, Diaz LA Jr, et al. (2013). TERT
the diagnosis of sot-tissue neoplasms. Appl or absent in pleomorphic xanthoastrocytoma. brain and in cerebral lesions of patients with promoter mutations occur frequently in gliomas
Immunohistochem Mol Morphol. 20(5):445-50. J Neuropathol Exp Neurol. 61(12):1092-9. tuberous sclerosis. Brain Pathol. 6(4):367-75. and a subset of tumors derived from cells with
PMID:22495377 PMID:12484572 PMID:8944308 low rates of self-renewal. Proc Natl Acad Sci U
1223. Karamitopoulou E, Perentes E, Diaman- 1239. Kaur B, Khwaja FW, Severson EA, Ma- 1256. Kesari S, Schiff D, Drappatz J, LaFrankie SA. 110(15):6021-6. PMID:23530248
tis I, Maraziotis T (1994). Ki-67 Immunoreacti- theny SL, Brat DJ, Van Meir EG (2005). Hypo- D, Doherty L, Macklin EA, et al. (2009). Phase 1271. Kim B, Chung CK, Myung JK, Park SH
vity in human central nervous system tumors: xia and the hypoxia-inducible-factor pathway in II study of protracted daily temozolomide for (2009). Pleomorphic xanthoastrocytoma asso-
a study with MIB 1 monoclonal antibody on ar- glioma growth and angiogenesis. Neuro Oncol. low-grade gliomas in adults. Clin Cancer Res. ciated with long-standing Taylor-type IIB-focal
chival material. Acta Neuropathol. 87(1 ):47-54. 7(2):134-53. PMID:15831232 15(1):330-7. PMID:19118062 cortical dysplasia in an adult. Pathol Res Pract.
PMID:7511316 1240. Kaur K, Kakkar A, Kumar A, Mallick S, 1257. Keser H, Barnes M, Moes G, Lee HS, 205(2)113-7. PMID18657915
1224. Karnes PS, Tran TN, Cui MY, Ratel C, Julka PK, Gupta D, et al. (2015). Integrating Tihan T (2014). Well-differentiated pediatric 1272. Kim BS, Kim DK, Park SH (2009). Pineal
Gilles FH, Barranger JA, et al. (1992). Cytoge- molecular subclassification of medulloblasto- glial neoplasms with features of oligodendrogli- parenchymal tumor of intermediate differentiati-
netic analysis of 39 pediatric central nervous mas into routine clinical practice: A simplified oma, angiocentric glioma and dysembryoplastic on showing malignant progression at relapse.
system tumors. Cancer Genet Cytogenet. approach. Brain Pathol. PMID:26222673 neuroepithelial tumors: a morphological diagno- Neuropathology. 29(5):602-8. PMID19170892
59(1):12-9. PMID1313329 1241. Kawano N, Yasui Y, Utsuki S, Oka H, Fujii stic challenge. Turk Patoloji Derg. 30(1 ):23-9. 1273. Kim DG, Lee DY, Paek SH, Chi JG, Choe
1225. Karpinski NC, Yaghmai R, Barba D, K, Yamashina S (2004). Light microscopic de- PMID:24448703 G, Jung HW (2002). Supratentorial primitive
Hansen LA (1999). Case of the month: March monstration of the microlumen of ependymoma: 1258. Kessler BA, Bookhout C, Jaikumar S, neuroectodermal tumors in adults. J Neuroon-
1999-A 26 year old HIV positive male with a study of the usefulness of antigen retrieval Hipps J, Lee YZ (2015). Disseminated oligo- col. 60(1 ):43-52. PMID12416545
dura based masses. Brain Pathol. 9(3):609-10. for epithelial membrane antigen (EMA) immu- dendroglial-like leptomeningeal tumor with ana- 1274. Kim DH, Suh YL (1997). Pseudopapillary
PMID:10416997 nostaining. Brain Tumor Pathol. 21 (1 ):17-21. plastic progression and presumed extraneural neurocytoma of temporal lobe with glial diffe-
1226. Karremann M, Butenhot S, Rausche U, P MID: 15696964 disease: case report. Clin Imaging. 39(2):300- rentiation. Acta Neuropathol. 94(2)187-91.
Pietsch T, Wolt JE, Kramm CM (2009). Pedi- 1242. Kehrer-Sawatzki H, Cooper DN (2008). 4. PMID:25518979 PMID:9255395
atric giant cell glioblastoma: New insights into Mosaicism in sporadic neurofibromatosis type 1259. Khalatbari MR, Hamidi M, Moharamzad Y 1275. Kim ES, Kwon MJ, Song JH, Kim DH,
a rare tumor entity. Neuro Oncol. 11(3):323-9. 1: variations on a theme common to other (2013). Primary alveolar rhabdomyosarcoma of Park HR (2015). Adenocarcinoma arising
PMID:19050301 hereditary cancer syndromes? J Med Genet. the brain with long-term survival. J Neurooncol. from intracranial recurrent mature teratoma
1227. Karremann M, Pietsch T, Janssen G, 45(10):622-31. PMID:18511569 115(1):131-3. PMID:23857335 and featuring mutated KRAS and wild-type
References 375
BRAF genes. Neuropathology. 35(1):44-9. Tumours. Pathology and Genetics of Tumours in sporadic neurofibromatosis 2 patients. Hum PMID:23530928
PMID:25039399 of the Nervous System. 3rd ed. Lyon: IARC Mol Genet. 7(13):2051-5. PMID:9817921 1324. Komori T, Scheithauer BW, Anthony DC,
1276. Kim KH, Roberts CW (2014). Mechanis- Press. 1309. Knobbe CB, Trampe-Kieslich A, Rei- Rosenblum MK, McLendon RE, Scott RM, et
ms by which SMARCB1 loss drives rhabdoid 1292. Kleihues P, Kiessling M, Janzer RC fenberger G (2005). Genetic alteration and al. (1998). Papillary glioneuronal tumor: a new
tumor growth. Cancer Genet. 207(9):365-72. (1987). Morphological markers in neuro-oncolo- expression of the phosphoinositol-3-kinase/ variant of mixed neuronal-glial neoplasm. Am J
PMID:24853101 gy. Curr Top Pathol. 77:307-38. PMID:2827963 Akt pathway genes PIK3CA and PIKE in human Surg Pathol. 22(10):1171-83. PMID:9777979
1277. Kim MS, Kim YS, Lee HK, Lee GJ, Choi 1293. Kleihues P, Louis DN, Scheithauer glioblastomas. Neuropathol Appl Neurobiol. 1325. Komori T, Scheithauer BW, Hirose T
CY, Lee CH (2014). Primary intracranial ectopic BW, Rorke LB, Reifenberger G, Burger PC, 31(5):486-90. PMID:16150119 (2002). A rosette-forming glioneuronal tumor of
craniopharyngioma in a patient with probable et al. (2002), The WHO classification of tu- 1310. Knowles DM (1999). Immunodeficien- the fourth ventricle: infratentorial form of dysem-
Gardner's syndrome. J Neurosurg. 120(2):337- mors of the nervous system. J Neuropathol cy-associated lymphoproliferative disorders. bryoplastic neuroepithelial tumor? Am J Surg
41. PMID:24266539 Exp Neurol. 61(3):215-25, discussion 226-9. Mod Pathol. 12(2):20O-17. PMID:10071343 Pathol. 26(5):582-91. PMID41979088
1278. Kim SD, Nakagawa H, Mizuno J, Inoue PMID:11895036 1311. Ko LJ, Prives C (1996). p53: puzzle 1326. Komotar RJ, Burger PC, Carson BS,
T (2005). Thoracic subpial intramedullary 1294. Kleihues P, Schauble B, zur Hausen A, and paradigm. Genes Dev. 10(9):1054-72. Brem H, Olivi A, Goldthwaite PT, et al. (2004).
schwannoma involving a ventral nerve root: Esteve J, Ohgaki H (1997). Tumors associa- PMID:8654922 Pilocytic and pilomyxoid hypothalamic/chias-
a case report and review of the literature. ted with p53 germline mutations: a synopsis 1312. Kochi N, Budka H (1987). Contribution matic astrocytomas. Neurosurgery. 54(1):72-9,
Surg Neurol. 63(4):389-93, discussion 393. of 91 families. Am J Pathol. 150(1):1-13. of histiocytic cells to sarcomatous develop- discussion 79-80. PMID44683543
PMID:15808734 PMID:9006316 ment of the gliosarcoma. An immunohistoche- 1327. Komuro Y, Mikami M, Sakaiya N, Ku-
1279. Kim Y, Lee SY, Yi KS, Cha SH, Gang MH, 1295. Kleinman CL, Gerges N, Papillon-Ca- mical study. Acta Neuropathol. 73(2):124-30. rahashi T, Komiyama S, Tei C, et al. (2001).
Cho BS, et al. (2014). Infratentorial and intrapa- vanagh S, Sin-Chan P, Pramatarova A, Quang PMID:3111162 Tumor imprint cytology of ovarian ependymo-
renchymal subependymoma in the cerebellum: DA, et al. (2014). Fusion of TTYH1 with the 1313. Koelsche C, Hovestadt V, Jones DT, Cap- ma. A case report. Cancer. 92(12):3165-9.
case report, Korean J Radiol. 15(1):151-5. C19MC microRNA cluster drives expression per D, Sturm D, Sahm F, et al. (2015). Melanotic PMID:11753996
PMID:24497806 of a brain-specific DNMT3B isoform in the tumors of the nervous system are characterized 1328. Kondziolka D, Parry PV, Lunsford LD,
1280. Kim YH, Kim JW, Park CK, Kim DG, Sohn embryonal brain tumor ETMR. Nat Genet. by distinct mutational, chromosomal and epi- Kano H, Flickinger JC, Rakfal S, et al. (2014).
CH, Chang KH, et al. (2010). Papillary tumor of 46(1 ):39-44. PMID:24316981 genomic profiles. Brain Pathol. 25(2):202-8. The accuracy of predicting survival in individual
pineal region presenting with leptomeninge- 1296. Kleinman GM, Schoene WC, Walshe PMID:25399693 patients with cancer. J Neurosurg. 120(1):24-
al seeding. Neuropathology. 30(6):654-60. TM 3rd, Richardson EP Jr (1978). Malignant 1314. Koelsche C, Sahm F, Capper D, Reuss D, 30. PMID:24160479
PMID:20374498 transformation in benign cerebellar astrocyto- Sturm D, Jones DT, et al. (2013). Distribution of 1329. Kong LY, Wei J, Haider AS, Liebelt BD,
1281. Kim YH, Nobusawa S, Mittelbronn ma. Case report. J Neurosurg. 49(1):111-8. TERT promoter mutations in pediatric and adult Ling X, Conrad CA, et al. (2014). Therapeutic
M, Paulus W, Brokinkel B, Keyvani K, et al. PMID:660255 tumors of the nervous system. Acta Neuropa- targets in subependymoma. J Neuroimmunol.
(2010). Molecular classification of low-grade 1297. Kleinschmidt-DeMasters BK, Aisner thol. 126(6):907-15. PMID:24154961 277(1-2)468-75. PMID:25465288
diffuse gliomas. Am J Pathol. 177(6):2708-14. DL, Birks DK, Foreman NK (2013). Epithelioid 1315. Koelsche C, Sahm F, Paulus W, Mittel- 1330. Konishi E, Ibayashi N, Yamamoto S,
PMID:21075857 GBMs show a high percentage of BRAF V600E bronn M, Giangaspero F, Antonelli M, et al. Scheithauer BW (2003). Isolated intracranial
1282. Kim YH, Nonoguchi N, Paulus W, Bro- mutation. Am J Surg Pathol. 37(5):685-98. (2014). BRAF V600E expression and distri- Rosai-Dorfman disease (sinus histiocytosis with
kinkel B, Keyvani K, Sure U, et al. (2012). Fre- PMID:23552385 bution in desmoplastic infantile astrocytoma/ massive lymphadenopathy). AJNR Am J Neuro-
quent BRAF gain in low-grade diffuse gliomas 1298. Kleinschmidt-DeMasters BK, Aisner DL, ganglioglioma. Neuropathol Appl Neurobiol. radiol. 24(3):515-8. PMID42637307
with 1p/19q loss. Brain Pathol. 22(6):834-40. Foreman NK (2015). BRAF VE1 Immunore- 40(3):337-44. PMID:23822828 1331. Konno S, Oka H, Utsuki S, Kondou K,
PMID:22568401 activity patterns in epithelioid glioblastomas 1316. Koelsche C, Sahm F, Wohrer A, Jeib- Tanaka S, Fujii K, et al. (2002). Germinoma with
1283. Kim YH, Ohta T, Oh JE, Le Calvez-Kelm positive for BRAF V600E mutation. Am J Surg mann A, Schittenhelm J, Kohlhof P, et al. a granulomatous reaction. Problems of differen-
F, McKay J, Voegele C, et al. (2014). TP53, Pathol. 39(4):528-40. PMID:25581727 (2014). BRAF-mutated pleomorphic xanthoast- tial diagnosis. Clin Neuropathol, 21(6):248-51.
MSH4, and LATS1 germline mutations in a fa- 1299. Kleinschmidt-DeMasters BK, Alassiri rocytoma is associated with temporal location, PMID42489672
mily with clustering of nervous system tumors. AH, Birks DK, Newell KL, Moore W, Lillehei KO reticulin fiber deposition and CD34 expression. 1332. Konovalov AN, Pitskhelauri Dl (2003).
Am J Pathol. 184(9):2374-81. PMID:25041856 (2010). Epithelioid versus rhabdoid glioblasto- Brain Pathol. 24(3) 221-9. PMID:24345274 Principles of treatment of the pineal re-
1284. Kimonis VE, Goldstein AM, Pastakia B, mas are distinguished by monosomy 22 and 1317. Koelsche C, Schweizer L, Renner M, gion tumors. Surg Neurol. 59(4):250-68.
Yang ML, Kase R, DiGiovanna JJ, et al. (1997). immunohistochemical expression of INI-1 but Warth A, Jones DT, Sahm F, et al. (2014). PMID42748006
Clinical manifestations in 105 persons with ne- not daudin 6. Am J Surg Pathol. 34(3):341-54. Nuclear relocation of STAT6 reliably predicts 1333. Kool M, Jones DT, Jager N, Northcott PA,
void basal cell carcinoma syndrome. Am J Med PMID:20118769 NAB2-STAT6 fusion for the diagnosis of solitary Pugh TJ, Hovestadt V, et al.; ICGC PedBrain
Genet. 69(3):299-308. PMID:9096761 1300. Kleinschmidt-DeMasters BK, Boylan A, fibrous tumour. Histopathology. 65(5):613-22. Tumor Project (2014). Genome sequencing of
1285. Kimura T, Budka H, Soler-Federsppiel S Capocelli K, Boyer PJ, Foreman NK (2011). PMID:24702701 SHH medulloblastoma predicts genotype-rela-
(1986). An immunocytochemical comparison of Multinodular leptomeningeal metastases from 1318. Koelsche C, Wohrer A, Jeibmann A, ted response to smoothened inhibition. Cancer
the glia-associated proteins glial fibrillary acidic ETANTR contain both small blue cell and ma- Schittenhelm J, Schindler G, Preusser M, et al. Cell. 25(3):393-405. PMID:24651015
protein (GFAP) and S-100 protein (S100P) in turing neuropil elements. Acta Neuropathol. (2013). Mutant BRAF V600E protein in ganglio- 1334. Kool M, Korshunov A, Remke M, Jones
human brain tumors. Clin Neuropathol. 5(1):21- 122(6):783-5. PMID:22033877 glioma is predominantly expressed by neuronal DT, Schlanstein M, Northcott PA, et al. (2012).
7. PMID:3512139 1301. Kleinschmidt-DeMasters BK, Lopes MB tumor cells. Acta Neuropathol. 125(6):891-900. Molecular subgroups of medulloblastoma:
1286. Kinsler VA, Thomas AC, Ishida M, Bul- (2013). Update on hypophysitis and TTF-1 PMID:23435618 an international meta-analysis of transcripto-
strode NW, Loughlin S, Hing S, et al. (2013). expressing sellar region masses. Brain Pathol. 1319. Koen JL, McLendon RE, George TM me, genetic aberrations, and clinical data of
Multiple congenital melanocytic nevi and neu- 23(5):495-514. PMID:23701182 (1998) . Intradural spinal teratoma: evidence for WNT, SHH, Group 3, and Group 4 medullob-
rocutaneous melanosis are caused by postzy- 1302. Kleinschmidt-DeMasters BK, Meltesen a dysembryogenic origin. Report of four cases. lastomas. Acta Neuropathol. 123(4)473-84.
gotic mutations in codon 61 of NRAS. J Invest L, McGavran L, Lillehei KO (2006). Characte- J Neurosurg. 89(5):844-51. PMID:9817426 PMID:22358457
Dermatol. 133(9):2229-36. PMID:23392294 rization of glioblastomas in young adults. Brain 1320. Koga T, Iwasaki H, Ishiguro M, Matsuzaki 1335. Kool M, Koster J, Bunt J, Hasselt NE, La-
1287. Kirkpatrick PJ, Honavar M, Janota Pathol. 16(4):273-86. PMID:17107596 A, Kikuchi M (2002). Losses in chromosomes keman A, van Sluis P, et al. (2008). Integrated
I, Polkey CE (1993). Control of temporal 1303. Kliewer KE, Cochran AJ (1989). A review 17, 19, and 22q in neurofibromatosis type 1 genomics identifies five medulloblastoma sub-
lobe epilepsy following en bloc resection of of the histology, ultrastructure, immunohisto- and sporadic neurofibromas: a comparative types with distinct genetic profiles, pathway sig-
low-grade tumors. J Neurosurg. 78(1):19-25. logy, and molecular biology of extra-adren- genomic hybridization analysis. Cancer Genet natures and clinicopathological features. PLoS
PMID:8416237 al paragangliomas. Arch Pathol Lab Med. Cytogenet. 136(2):113-20. PMID:12237234 One. 3(8):e3088. PMID48769486
1288. Kissil JL, Wilker EW, Johnson KC, Eck- 113(11):1209-18. PMID:2684087 1320A. Kogerman P, Grimm T, Kogerman 1336. Koperek O, Gelpi E, Birner P, Haberler
man MS, Yaffe MB, Jacks T (2003). Merlin, the 1304. Klintworth GK, Garner A, editors. (2008). L, Krause D, Unden AB, Sandstedt B, et al. C, Budka H, Hainfellner JA (2004). Value and
product of the Nf2 tumor suppressor gene, is an Garner and Klintworth’s Pathobiology of ocular (1999) . Mammalian suppressor-of-fused modu- limits of immunohistochemistry in differential di-
inhibitor of the p21-activated kinase, Pak1. Mol disease. 3rd Boca Raton. CRC Press. lates nuclear-cytoplasmic shuttling of Gli-1. Nat agnosis of clear cell primary brain tumors. Acta
Cell. 12(4):841-9. PMID:14580336 1305. Kloub O, Perry A, Tu PH, Lipper M, Cell Biol. 1(5):312-9. PMID:10559945 Neuropathol. 108(1):24-30. PMID45108012
1288A. Kita D, Yonekawa Y, Weller M, Ohgaki H Lopes MB (2005). Spindle cell oncocytoma 1321. Komakula S, Warmuth-Metz M, Hilden- 1337. Koral K, Koral KM, Sklar F (2012). An-
(2007). PIK3CA alterations in primary (de novo) of the adenohypophysis: report of two recur- brand P, Loevner L, Hewlett R, Salzman K, et giocentric glioma in a 4-year-old boy: imaging
and secondary glioblastomas. Acta Neuropa- rent cases. Am J Surg Pathol. 29(2):247-53. al. (2011). Pineal parenchymal tumor of inter- characteristics and review of the literature. Clin
thol. 113(3):295-302. PMID:17235514 PMID:15644783 mediate differentiation: imaging spectrum of Imaging. 36(1):61-4. PMID:22226445
1289. Kleihues P, Burger PC, Scheithauer 1306. Kluwe L, MacCollin M, Tatagiba M, Tho- an unusual tumor in 11 cases. Neuroradiology. 1338. Koral K, Weprin B, Rollins NK (2006).
BW (1993). The new WHO classification of mas S, Hazim W, Haase W, et al. (1998). Phe- 53(8):577-84. PMID:21080159 Sphenoid sinus craniopharyngioma simu-
brain tumours. Brain Pathol. 3(3):255-68. notypic variability associated with 14 splice-site 1322. Komakula ST, Fenton LZ, Klein- lating mucocele. Acta Radiol. 47(5)494-6.
PMID:8293185 mutations in the NF2 gene. Am J Med Genet. schmidt-DeMasters BK, Foreman NK (2007). PMID46796313
1290. Kleihues P, Burger PC, Scheithauer BW, 77(3):228-33. PMID:9605590 Pilomyxoid astrocytoma: neuroimaging with 1339. Kordek R, Biernat W, Sapieja W, Alwasiak
editors. (1993). Histological Typing of Tumours 1307. Kluwe L, Mautner V, Heinrich B, Dezube dinicopathologic correlates in 4 cases followed J, Liberski PP (1995). Pleomorphic xanthoast-
of the Central Nervous System. World Health R, Jacoby LB, Friedrich RE, et al. (2003). Mole- over time. J Pediatr Hematol Oncol. 29(7)465- rocytoma with a gangliomatous component: an
Organization International Histological Classifi- cular study of frequency of mosaicism in neuro- 70. PMID:17609624 immunohistochemical and ultrastructural study.
cation of Tumours. 2nd ed. Berlin, Heidelberg: fibromatosis 2 patients with bilateral vestibular 1323. Komori T, Arai N (2013). Dysembryo- Acta Neuropathol. 89(2)494-7. PMID:7732793
Springer Veriag. schwannomas. J Med Genet. 40(2):109-14. plastic neuroepithelial tumor, a pure glial 1340. Korfel A, Schlegel U (2013). Diagnosis
1291. Kleihues P, Cavenee WK, editors. (2000). PMID:12566519 tumor? Immunohistochemical and morphome- and treatment of primary CNS lymphoma. Nat
World Health Organization Classification of 1308. Kluwe L, Mautner VF (1998). Mosaicism tric studies. Neuropathology. 33(4)459-68. Rev Neurol. 9(6):317-27. PMID:23670107
376 References
1341. Korfel A, Weller M, Martus P, Roth P, correlated with increased Ki-67 labeling index. PMID:17549014 1387. Kujas M, Faillot T, Lalam T, Roncier B,
Klasen HA, Roeth A, et al. (2012). Prognostic Neurol India. 57(2):191-3. PMID:19439853 1371. Kros JM, Hop WC, Godschalk JJ, Krish- Catala M, Poirier J (2000). Astroblastomas re-
impact of meningeal dissemination in primary 1355. Kowalski RJ, Prayson RA, Mayberg nadath KK (1996). Prognostic value of the proli- visited. Report of two cases with immunocyto-
CNS lymphoma (PCNSL): experience from the MR (2004). Pituicytoma. Ann Diagn Pathol. feration-related antigen Ki-67 in oligodendrogli- chemical and electron microscopic study.
G-PCNSL-SG1 trial. Ann Oncol. 23(9):2374- 8(5):290-4. PMID:15494936 omas. Cancer. 78(5):1107-13. PMID:8780550 Histogenetic considerations. Neuropathol Appl
80. PMID:22396446 1356. Kozak KR, Moody JS (2009). Giant cell 1372. Kros JM, Schouten WC, Janssen PJ, Neurobiol. 26(3):295-8. PMID:10886687
1342. Kornreich L, Blaser S, Schwarz M, glioblastoma: a glioblastoma subtype with dis- van der Kwast TH (1996). Proliferation of ge- 1388. Kukreja S, Ambekar S, Sharma M, Sin
Shuper A, Vishne TH, Cohen IJ, et al. (2001). tinct epidemiology and superior prognosis. Neu- mistocytic cells and glial fibrillary acidic protein AH, Nanda A (2015). Outcome predictors in the
Optic pathway glioma: correlation of imaging ro Oncol. 11(6):833-41. PMID:19332771 (GFAP)-positive oligodendroglial cells in glio- management of spinal myxopapillary ependy-
findings with the presence of neurofibromato- 1357. Kraan W, Horlings HM, van Keimpema M, mas: a MIB-1/GFAP double labeling study. Acta moma: an integrative survival analysis. Worid
sis. AJNR Am J Neuroradiol. 22(10):1963-9. Schilder-Tol EJ, Oud ME, Scheepstra C, et al. Neuropathol. 91(1):99-103. PMID:8773153 Neurosurg. 83(5):852-9 PMID:25108296
PMID:11733333 (2013). High prevalence of oncogenic MYD88 1373. Kros JM, van den Brink WA, van Loon- 1389. Kukreja S, Ambekar S, Sin AH, Nanda A
1343. Korogi Y, Takahashi M, Ushio Y (2001). and CD79B mutations in diffuse large B-cell van Luyt JJ, Stefanko SZ (1997). Signet-ring (2014). Cumulative survival analysis of patients
MRI of pineal region tumors. J Neurooncol. lymphomas presenting at immune-privileged cell oligodendroglioma-report of two cases and with spinal myxopapillary ependymomas in the
54(3):251-61. PMID:11767291 sites. Blood Cancer J. 3:e139. PMID:24013661 discussion of the differential diagnosis. Acta first 2 decades of life. J Neurosurg Pediatr.
1344. Korshunov A, Golanov A (2001). The 1358. Kramm CM, Butenhoff S, Rausche U, Neuropathol. 93(6):638^f3. PMID:9194905 13(4):400-7. PMID:24527863
prognostic significance of DNA topoisomera- Warmuth-Metz M, Kortmann RD, Pietsch T, et 1374. Kros JM, Van Eden CG, Stefanko SZ, 1390. Kulkarni AV, Pierre-Kahn A, Zerah M
se ll-alpha (Ki-S1), p21/Cip-1, and p27/Kip-1 al. (2011). Thalamic high-grade gliomas in chil- Waayer-Van Batenburg M, van der Kwast (2004). Spontaneous regression of congenital
protein immunoexpression in oligodendrogli- dren: a distinct clinical subset? Neuro Oncol. TH (1990). Prognostic implications of glial spinal lipomas of the conus medullaris. Report
omas. Arch Pathol Lab Med. 125(7):892-8. 13(6):680-9. PMID:21636712 fibrillary acidic protein containing cell types in of two cases. J Neurosurg. 101(2) Suppl:226-7.
PMID:11419973 1359. Kraus JA, Koopmann J, Kaskel P, Maintz oligodendrogliomas. Cancer. 66(6):1204-12. PMID:15835113
1345. Korshunov A, Golanov A, Sycheva R, D, Brandner S, Schramm J, et al. (1995). Sha- PMID:2205356 1391. Kumar A, Pathak P, Purkait S, Faruq
Timirgaz V (2004). The histologic grade is a red allelic losses on chromosomes 1p and 19q 1375. Kros JM, Vecht CJ, Stefanko SZ (1991). M, Jha P, Mallick S, et al. (2015). Oncogenic
main prognostic factor for patients with intracra- suggest a common origin of oligodendroglioma The pleomorphic xanthoastrocytoma and its dif- KIAA1549-BRAF fusion with activation of
nial ependymomas treated in the microneuro- and oligoastrocytoma. J Neuropathol Exp Neu- ferential diagnosis: a study of five cases. Hum the MAPK/ERK pathway in pediatric oligo-
surgical era: an analysis of 258 patients. Can- rol. 54(1):91-5. PMID:7815084 Pathol. 22(11):1128-35. PMID:1743696 dendrogliomas. Cancer Genet. 208(3):91-5.
cer. 100(6):1230-7. PMID:15022291 1360. Kraus JA, Lamszus K, Glesmann N, Beck 1376. Krossnes BK, Wester K, Moen G, Mark PMID:25794445
1345A. Korshunov A, Jakobiec FA, Eberhart M, Wolter M, Sabel M, et al. (2001). Molecular SJ (2005). Multifocal dysembryoplastic neu- 1392. Kumar S, Kumar D, Kaldjian EP, Bau-
CG, Hovestadt V, Capper D, Jones DT, et al. genetic alterations in glioblastomas with oli- roepithelial tumour in a male with the XYY syn- serman S, Raffeld M, Jaffe ES (1997). Primary
(2015). Comparative integrated molecular godendroglial component. Acta Neuropathol. drome. Neuropathol Appl Neurobiol. 31(5):556- low-grade B-cell lymphoma of the dura: a muco-
analysis of intraocular medulloepitheliomas 101(4):311-20. PM ID: 11355302 60. PMID:16150126 sa associated lymphoid tissue-type lymphoma.
and central nervous system embryonal tumors 1361. Kreiger PA, Okada Y, Simon S, Rorke 1377. Krouwer HG, Davis RL, Silver P, Prados Am J Surg Pathol. 21(1):81-7. PMID:8990144
with multilayered rosettes confirms that they LB, Louis DN, Golden JA (2005). Losses of M (1991). Gemistocytic astrocytomas: a 1393. Kuratsu J, Matsukado Y, Sonoda H
are distinct nosologic entities. Neuropathology. chromosomes 1p and 19q are rare in pedi- reappraisal. J Neurosurg. 74(3):399-406. (1983). Pseudopsammoma bodies in meningo-
35(6):538-44. PMID:26183384 atric oligodendrogliomas. Acta Neuropathol. PMID:1993905 theliomatous meningioma. A histochemical and
1346. Korshunov A, Remke M, Gessi M, Ryz- 109(4):387-92. PMID:15739101 1378. Krueger DA, Northrup H; International ultrastructural study. Acta Neurochir (Wien).
hova M, Hielscher T, Witt H, et al. (2010). Focal 1362. Kresse SH, Skarn M, Ohnstad HO, Nann- Tuberous Sclerosis Complex Consensus Group 68(1-2):55-62. PMID:6858731
genomic amplification at 19q13.42 comprises ies HM, Bjerkehagen B, Myklebost O, et al. (2013). Tuberous sclerosis complex surveillan- 1394. Kurian KM, Summers DM, Statham PF,
a powerful diagnostic marker for embryonal (2008). DNA copy number changes in high-gra- ce and management: recommendations of the Smith C, Bell JE, Ironside JW (2005). Third ven-
tumors with ependymoblastic rosettes. Acta de malignant peripheral nerve sheath tumors by 2012 International Tuberous Sclerosis Com- tricular Chordoid glioma: clinicopathological stu-
Neuropathol. 120(2):253-60. PMID:20407781 array CGH. Mol Cancer. 7:48. PMID:18522746 plex Consensus Conference. Pediatr Neurol. dy of two cases with evidence for a poor clinical
1347. Korshunov A, Remke M, Werft W, Ben- 1363. Krieg M, Marti HH, Plate KH (1998). 49(4):255-65. PMID:24053983 outcome despite low grade histological featu-
ner A, Ryzhova M, Witt H, et al. (2010). Adult Coexpression of erythropoietin and vascular 1379. Krutilkova V, Trkova M, Fleitz J, Gregor V, res. Neuropathol Appl Neurobiol. 31(4):354-61.
and pediatric medulloblastomas are geneti- endothelial growth factor in nervous system Novotna K, Krepelova A, et al. (2005). Identifi- PMID:16008819
cally distinct and require different algorithms tumors associated with von Hippel-Lindau tu- cation of five new families strengthens the link 1395. Kuroiwa T, Bergey GK, Rothman Ml,
for molecular risk stratification. J Clin Oncol. mor suppressor gene loss of function. Blood. between childhood choroid plexus carcinoma Zoarski GH, Wolf A, Zagardo MT, et al. (1995).
28(18):3054-60. PMID:20479417 92(9):3388-93. PMID:9787178 and germline TP53 mutations. Eur J Cancer. Radiologic appearance of the dysembryoplastic
1348. Korshunov A, Ryzhova M, Jones DT, 1364. Krieger MD, Gonzalez-Gomez I, Levy 41(11):1597-603. PMID:15925506 neuroepithelial tumor. Radiology. 197(1):233-8.
Northcott PA, van Sluis P, Volckmann R, et al. ML, McComb JG (1997). Recurrence patterns 1380. Kubo O, Sasahara A, Tajika Y, Kawamura PMID:7568829
(2012). LIN28A immunoreactivity is a potent and anaplastic change in a long-term study H, Kawabatake H, Takakura K (1996). Pleomor- 1396. Kurose K, Araki T, Matsunaka T, Takada
diagnostic marker of embryonal tumor with mul- of pilocytic astrocytomas. Pediatr Neurosurg. phic xanthoastrocytoma with neurofibromatosis Y, Emi M (1999). Variant manifestation of Cow-
tilayered rosettes (ETMR). Acta Neuropathol. 27(1):1-11. PMID:9486830 type 1: case report. Noshuyo Byori. 13(1):79- den disease in Japan: hamartomatous polypo-
124(6):875-81. PMID:23161096 1365. Krishnan S, Brown PD, Scheithauer BW, 83. PMID:8916131 sis of the digestive tract with mutation of the
1349. Korshunov A, Sturm D, Ryzhova M, Ho- Ebersold MJ, HammackJE, Buckner JC (2004). 1381. Kubota T, Sato K, Arishima H, Takeuchi PTEN gene. Am J Hum Genet. 64(1):308-10.
vestadt V, Gessi M, Jones DT, et al. (2014). Choroid plexus papillomas: a single instituti- H, Kitai R, Nakagawa T (2006). Astroblastoma: PMID:9915974
Embryonal tumor with abundant neuropil and onal experience. J Neurooncol. 68(1):49-55. immunohistochemical and ultrastructural study 1397. Kurt E, Beute GN, Sluzewski M, van Rooij
true rosettes (ETANTR), ependymoblastoma, PMID:15174521 of distinctive epithelial and probable tanycytic WJ, Teepen JL (1996). Giant chondroma of the
and medulloepithelioma share molecular si- 1366. Kristof RA, Van Roost D, Wolf HK, Schr- differentiation. Neuropathology. 26(1):72-81. falx. Case report and review of the literature. J
milarity and comprise a single clinicopatholo- amm J (1997). Intravascular papillary endothe- PMID:16521483 Neurosurg. 85(6):1161^L PMID:8929512
gical entity. Acta Neuropathol. 128(2):279-89. lial hyperplasia of the sellar region. Report of 1382. Kuchelmeister K, Demirel T, Schlorer 1398. Kurt E, Zheng PP, Hop WC, van der Wei-
PMID:24337497 three cases and review of the literature. J Neu- E, Bergmann M, Gullotta F (1995). Dysem- den M, Bol M, van den Bent MJ, et al. (2006).
1350. Korshunov A, Sycheva R, Golanov A rosurg. 86(3):558-63. PMID:9046317 bryoplastic neuroepithelial tumour of the ce- Identification of relevant prognostic histopatho-
(2007). Recurrent cytogenetic aberrations 1367. Kros J, de Greve K, van Tilborg A, Hop W, rebellum. Acta Neuropathol. 89(4):385-90. logic features in 69 intracranial ependymomas,
in central neurocytomas and their biological Pieterman H, Avezaat C, et al. (2001). NF2 sta- PMID:7610772 excluding myxopapillary ependymomas and
relevance. Acta Neuropathol. 113(3):303-12. tus of meningiomas is associated with tumour 1383. Kuchelmeister K, Hugens-Penzel M, subependymomas. Cancer. 106(2):388-95.
PMID:17123091 localization and histology. J Pathol. 194(3):367- Jodicke A, Schachenmayr W (2006). Papillary PMID:16342252
1351. Korshunov A, Witt H, Hielscher T, Benner 72. PMID:11439370 tumour of the pineal region: histodiagnostic 1399. Kurtkaya-Yapicier O, Elmaci I, Boran B,
A, Remke M, Ryzhova M, et al. (2010). Molecu- 1368. Kros JM, Celia F, Bakker SL, Paz Y Geu- considerations. Neuropathol Appl Neurobiol. Kilig T, Sav A, Pamir MN (2002). Dysembryo-
lar staging of intracranial ependymoma in chil- ze D, Egeler RM, Egeler RM (2000). Papillary 32(2):203-8. PMID:16599948 plastic neuroepithelial tumor of the midbrain
dren and adults. J Clin Oncol. 28(19):3182-90. meningioma with pleural metastasis: case re- 1384. Kuchelmeister K, von Borcke IM, Klein H, tectum: a case report. Brain Tumor Pathol.
PMID:20516456 port and literature review. Acta Neurol Scand. Bergmann M, Gullotta F (1994). Pleomorphic 19(2):97-100. PMID:12622140
1352. Korten AG, ter Berg HJ, Spincemaille GH, 102(3):200-2. PMID:10987382 pineocytoma with extensive neuronal differen- 1400. Kurzwelly D, Glas M, Roth P, Weimann E,
van der Laan RT, Van de Wei AM (1998). In- 1369. Kros JM, Delwel EJ, de Jong TH, Tanghe tiation: report of two cases. Acta Neuropathol. Lohner H, Waha A, et al. (2010). Primary CNS
tracranial chondrosarcoma: review of the litera- HL, van Run PR, Vissers K, et al. (2002). Des- 88(5):448-53. PMID:7847074 lymphoma in the elderly: temozolomide therapy
ture and report of 15 cases. J Neurol Neurosurg moplastic infantile astrocytoma and ganglioglio- 1385. Kudo H, Oi S, Tamaki N, Nishida Y, Mat- and MGMT status. J Neurooncol. 97(3):389-92.
Psychiatry. 65(1):88-92. PMID:9667567 ma: a search for genomic characteristics. Acta sumoto S (1990). Ependymoma diagnosed PMID:19841864
1353. Koschny R, Holland H, Koschny T, Neuropathol. 104(2):144-8. PMID:12111357 in the first year of life in Japan in collaborati- 1401. Kwon CH, Zhu X, Zhang J, Knoop LL,
Vitzthum HE (2006). Comparative geno- 1370. Kros JM, Gorlia T, Kouwenhoven MC, on with the International Society for Pediatric Tharp R, Smeyne RJ, et al. (2001). Pten
mic hybridization pattern of non-anaplastic Zheng PP, Collins VP, Figarella-Branger D, et Neurosurgery. Childs Nerv Syst. 6(7):375-8. regulates neuronal soma size: a mouse mo-
and anaplastic oligodendrogliomas-a me- al. (2007). Panel review of anaplastic oligo- PMID:1669244 del of Lhermitte-Dudos disease. Nat Genet.
ta-analysis. Pathol Res Pract. 202(1 ):23-30. dendroglioma from European Organization For 1386. Kuhlmann T, Lassmann H, Briick W 29(4):404-11. PMID:11726927
PMID: 16356658 Research and Treatment of Cancer Trial 26951: (2008). Diagnosis of inflammatory demye- 1402. Kuchler J, Hartmann W, Waha A, Koch
1354. Koutourousiou M, Georgakoulias N, Kon- assessment of consensus in diagnosis, influen- lination in biopsy specimens: a practical A, Endl E, Wurst P, et al. (2011). p75(NTR) in-
togeorgos G, Seretis A (2009). Subependymo- ce of 1p/19q loss, and correlations with outco- approach. Acta Neuropathol. 115(3):275-87. duces apoptosis in medulloblastoma cells. Int J
mas of the lateral ventricle: tumor recurrence me. J Neuropathol Exp Neurol. 66(6):545-51. PMID:18175128 Cancer. 128(8):1804-12. PMID:20549701
References 377
1403. Kuker W, Nagele T, Korfel A, Heckl S, malignant peripheral nerve sheath tumors. Ann CTNNBI-mutated adamantinomatous cranio- 1451. Lee DY, Chung CK, Hwang YS, Choe
Thiel E, Bamberg M, et al. (2005). Primary cen- Surg Oncol. 20(1):66-72. PMID:22878618 pharyngioma. Acta Neuropathol. 127(6):927-9. G, Chi JG, Kim HJ, et al. (2000). Dysembryo-
tral nervous system lymphomas (PCNSL): MRI 1417. Lai A, Kharbanda S, Pope WB, Tran A, PMID:24715106 plastic neuroepithelial tumor: radiological fin-
features at presentation in 100 patients. J Neu- Solis OE, Peale F, et al. (2011). Evidence for 1433. Larson JJ, Tew JM Jr, Simon M, Menon dings (including PET, SPECT, and MRS) and
rooncol. 72(2):169-77. PMID:15925998 sequenced molecular evolution of IDH1 mutant AG (1995). Evidence for clonal spread in the surgical strategy. J Neurooncol. 47(2):167-74.
1403A. Kusters-Vandevelde HV, Creytens D, glioblastoma from a distinct cell of origin. J Clin development of multiple meningiomas. J Neu- PMID:10982159
Grunsven AC, Jeunink M, Winnepenninckx V, Oncol. 29(34):4482-90. PMID:22025148 rosurg. 83(4):705-9. PMID:7674021 1452. Lee EB, Tihan T, Scheithauer BW, Zhang
Groenen PJ, et al. (2016). SF3B1 and EIF1AX 1418. Laigle-Donadey F, Martin-Duverneuil 1434. Lashner BA, Riddell RH, Winans CS PJ, Gonatas NK (2009). Thyroid transcription
mutations occur in primary leptomeningeal me- N, Lejeune J, Criniere E, Capelle L, Duffau (1986). Ganglioneuromatosis of the colon factor 1 expression in sellar tumors: a histo-
lanocytic neoplasms; yet another similarity to H, et al. (2004). Correlations between mole- and extensive glycogenic acanthosis in Cow- genetic marker? J Neuropathol Exp Neurol.
uveal melanomas. Acta Neuropathol Commun. cular profile and radiologic pattern in oligo- den's disease. Dig Dis Sci. 31(2):213-6. 68(5):482-8. PMID:19525896
4(1):5. PMID:26769193 dendroglial tumors. Neurology. 63(12):2360-2. PMID:3943449 1453. Lee EQ (2015). Nervous system me-
1404. Kusters-Vandevelde HV, Klaasen A, Kus- PMID:15623700 1435. Laskin WB, Weiss SW, Bratthauer GL tastases from systemic cancer. Continuum
ters B, Groenen PJ, van Engen-van Grunsven 1419. Laigle-Donadey F, Taillibert S, Mokhta- (1991). Epithelioid variant of malignant periphe- (Minneap Minn). 21 2 Neuro-oncology:415-28.
IA, van Dijk MR, et al. (2010). Activating muta- ri K, Hildebrand J, Delattre JY (2005). Dural ral nerve sheath tumor (malignant epithelioid PMID:25837904
tions of the GNAQ gene: a frequent event in pri- metastases. J Neurooncol. 75(1):57-61. schwannoma). Am J Surg Pathol. 15(12):1136- 1454. Lee HY, Yoon CS, Sevenet N, Rajalingam
mary melanocytic neoplasms of the central ner- PMID:16215816 45. PMID:1746681 V, Delattre O, Walford NQ (2002). Rhabdoid
vous system. Acta Neuropathol. 119(3):317-23. 1420. Lakings DR, Gehrke CW, Waalkes TP 1436. Lassman AB, Iwamoto FM, CloughesyTF, tumor of the kidney is a component of the rh-
PMID:19936769 (1976). Determination of trimethylsilyl methyla- Aldape KD, Rivera AL, Eichler AF, et al. (2011). abdoid predisposition syndrome. Pediatr Dev
1405. Kusters-Vandevelde HV, Kusters B, van ted nucleic acid bases in urine by gas-liquid International retrospective study of over 1000 Pathol. 5(4):395-9. PMID:12016529
Engen-van Grunsven AC, Groenen PJ, Wesse- chromatography . J Chromatogr 116: 69-81. adults with anaplastic oligodendroglial tumors. 1455. Lee JH, Sundaram V, Stein DJ, Kinney
ling P, Blokx WA (2015). Primary melanocytic PMID:1411 Neuro Oncol. 13(6):649-59. PMID:21636710 SE, Stacey DW, Golubic M (1997). Reduced
tumors of the central nervous system: a review 1421. Lai A, Dahiya S, Gonzales M, Hiniker 1437. Lau D, La Marca F, Camelo-Piragua S, expression of schwannomin/merlin in hu-
with focus on molecular aspects. Brain Pathol. A, Prayson R, Kleinschmidt-DeMasters BK, Park P (2013). Metastatic paraganglioma of man sporadic meningiomas. Neurosurgery.
25(2):209-26. PMID:25534128 et al. (2014). lgG4 overexpression is rare in the spine: case report and review of the lite- 40(3):578-87. PMID:9055299
1406. Kusters-Vandevelde HV, van Engen-van meningiomas with a prominent inflammatory rature. Clin Neurol Neurosurg. 115(9):1571-4. 1456. Lee JY, Dong SM, Park WS, Yoo NJ, Kim
Grunsven IA, Kusters B, van Dijk MR, Groe- component: a review of 16 cases. Brain Pathol. PMID:23398849 CS, Jang JJ, et al. (1998). Loss of heterozygo-
nen PJ, Wesseling P, et al. (2010). Improved 24(4):352-9. PMID:24467316 1438. Lauer DH, Enzinger FM (1980). Cranial sity and somatic mutations of the VHL tumor
discrimination of melanotic schwannoma from 1422. Lam CW, Xie J, To KF, Ng HK, Lee KC, fasciitis of childhood. Cancer. 45(2):401-6. suppressor gene in sporadic cerebellar he-
melanocytic lesions by combined morphological Yuen NW, et al. (1999). A frequent activa- PMID:7351023 mangioblastomas. Cancer Res. 58(3):504-8.
and GNAQ mutational analysis. Acta Neuropa- ted smoothened mutation in sporadic basal 1439. Lavrnic S, Macvanski M, Ristic-Balos D, PMID:9458097
thol. 120(6):755-64. PMID:20865267 cell carcinomas. Oncogene. 18(3):833-6. Gavrilov M, Damjanovic D, Gavrilovic S, et al. 1457. Lee JY, Wakabayashi T, Yoshida J
1407. Labreche K, Simeonova I, Kamoun A, PMID:9989836 (2012). Papillary glioneuronal tumor: unexplo- (2005). Management and survival of pineob-
Gleize V, Chubb D, Letouze E, et al.; POLA 1423. Lamb RF, Roy C, Diefenbach TJ, Vinters red entity. J Neurol Surg A Cent Eur Neurosurg. lastoma: an analysis of 34 adults from the
Network (2015). TCF12 is mutated in anapla- HV, Johnson MW, Jay DG, et al. (2000). The 73(4):224-9. PMID:21842459 brain tumor registry of Japan. Neurol Med
stic oligodendroglioma. Nat Commun. 6:7207. TSC1 tumour suppressor hamartin regula- 1440. Laws ER Jr, Goldberg WJ, Bernstein Chir (Tokyo). 45(3):132-41, discussion 141-2.
PMID:26068201 tes cell adhesion through ERM proteins and JJ (1993). Migration of human malignant ast- PMID:15782004
1408. Labussiere M, Di Stefano AL, Gleize the GTPase Rho. Nat Cell Biol. 2(5):281-7. rocytoma cells in the mammalian brain: Sche- 1458. Lee S, Cimica V, Ramachandra N, Zag-
V, Boisselier B, Giry M, Mangesius S, et al. PMID:10806479 rer revisited. Int J Dev Neurosci. 11(5):691-7. zag D, Kalpana GV (2011). Aurora A is a repres-
(2014). TERT promoter mutations in gliomas, 1424. Lambert SR, Witt H, Hovestadt V, Zuck- PMID:8116480 sed effector target of the chromatin remodeling
genetic associations and clinico-pathological nick M, Kool M, Pearson DM, et al. (2013). 1441. Le DT, Uram JN, Wang H, Bartlett BR, protein INI1/hSNF5 required for rhabdoid tu-
correlations. Br J Cancer. 111(10):2024-32. Differential expression and methylation of brain Kemberling H, Eyring AD, et al. (2015). PD-1 mor cell survival. Cancer Res. 71(9):3225-35.
PMID:25314060 developmental genes define location-specific Blockade in Tumors with Mismatch-Repair PMID:21521802
1409. Lach B, Duggal N, DaSilva VF, Benoit subsets of pilocytic astrocytoma. Acta Neuropa- Deficiency. N Engl J Med. 372(26):2509-20. 1459. Lee SH, Appleby V, Jeyapalan JN, Palmer
BG (1996). Association of pleomorphic xan- thol. 126(2):291-301. PMID:23660940 PMID:26028255 RD, Nicholson JC, Sottile V, et al. (2011). Varia-
thoastrocytoma with cortical dysplasia and neu- 1425. Lambiv WL, Vassallo I, Delorenzi M, Shay 1442. Le LQ, Shipman T, Burns DK, Parada ble methylation of the imprinted gene, SNRPN,
ronal tumors. A report of three cases. Cancer. T, Diserens AC, Misra A, et al. (2011). The Wnt LF (2009). Cell of origin and microenviron- supports a relationship between intracranial
78(12):2551-63. PMID:8952564 inhibitory factor 1 (WIF1) is targeted in gliob- ment contribution for NF1-associated dermal germ cell tumours and neural stem cells. J Neu-
1410. Lach B, Duncan E, Rippstein P, Benoit lastoma and has a tumor suppressing function neurofibromas. Cell Stem Cell. 4(5):453-63. rooncol. 101(3):419-28. PMID:20582452
BG (1994). Primary intracranial pleomorphic potentially by induction of senescence. Neuro PMID:19427294 1460. Lee W, Teckie S, WiesnerT, Ran L, Prieto
angioleiomyoma-a new morphologic vari- Oncol. 13(7):736-47. PMID:21642372 1443. Le Mercier M, Hastir D, Moles Lopez X, Granada CN, Lin M, et al. (2014). PRC2 is recur-
ant. An immunohistochemical and electron 1426. Lamont JM, McManamy CS, Pearson De Neve N, Maris C, TrepantAL, etal. (2012). A rently inactivated through EED or SUZ12 loss in
microscopic study. Cancer. 74(7):1915-20. AD, Clifford SC, Ellison DW (2004). Combined simplified approach for the molecular classifica- malignant peripheral nerve sheath tumors. Nat
PMID:8082097 histopathological and molecular cytogenetic tion of glioblastomas. PLoS One. 7(9):e45475. Genet. 46(11):1227-32. PMID:25240281
1411. Lachenal F, Cotton F, Desmurs-Clavel stratification of medulloblastoma patients. Clin PMID:23029035 1461. Leeds NE, Lang FF, Ribalta T, Sawaya
H, Haroche J, Taillia H, Magy N, et al. (2006). Cancer Res. 10(16):5482-93. PMID:15328187 1445. LeBoit PE, Burg G, Weedon D, Sarasin R, Fuller GN (2006). Origin of Chordoid glioma
Neurological manifestations and neuroradiolo- 1427. Lamzabi I, Arvanitis LD, Reddy VB, A, editors. (2005). World Health Organization of the third ventricle. Arch Pathol Lab Med.
gical presentation of Erdheim-Chester disea- Bitterman P, Gattuso P (2013). Immunophe- Classification of Tumours. Pathology and Ge- 130(4):460-4. PMID:16594739
se: report of 6 cases and systematic review notype of myxopapillary ependymomas. Appl netics of Skin Tumours. 3rd ed. Lyon: IARC 1462. Leenstra JL, Rodriguez FJ, Frechette
of the literature. J Neurol. 253(10):1267-77. Immunohistochem Mol Morphol. 21(6):485-9. Press. 1157. CM, Giannini C, Stafford SL, Pollock BE, et al.
PMID:17063320 PMID:23455181 1446. Lebrun C, Fontaine D, Ramaioli A, Van- (2007). Central neurocytoma: management re-
1412. Lack EE (1994). Paragangliomas. In: 1428. Lang FF, Epstein FJ, Ransohoff J, Allen denbos F, Chanalet S, Lonjon M, et al.; Nice commendations based on a 35-year experien-
Sternberg SS, editor. Diagnostic Surgical Pa- JC, Wisoff J, Abbott IR, et al. (1993). Central Brain Tumor Study Group (2004). Long-term ce. IntJ Radiat Oncol Biol Phys. 67(4):1145-54.
thology. New York: Raven Press; pp. 559-621. nervous system gangliogliomas. Part 2: Cli- outcome of oligodendrogliomas. Neurology. PMID:17187939
1413. Lafay-Cousin L, Hader W, Wei XC, nical outcome. J Neurosurg. 79(6):867-73. 62(10):1783-7. PMID:15159478 1463. Lehman NL (2008). Patterns of brain in-
Nordal R, Strother D, Hawkins C, et al. (2014). PMID:8246055 1447. Lechapt-Zalcman E, Chapon F, Guillamo filtration and secondary structure formation in
Post-chemotherapy maturation in supratentorial 1429. Langford LA (1986). The ultrastructure JS, Khouri S, Menegalli-Boggelli D, Loussouarn supratentorial ependymal tumors. J Neuropa-
primitive neuroectodermal tumors. Brain Pathol. of the ependymoblastoma. Acta Neuropathol. D, et al. (2011). Long-term clinicopathological thol Exp Neurol. 67(9):900-10. PMID:18716554
24(2):166-72. PMID:24033491 71(1-2):136-41. PMID.3776467 observations on a papillary tumour of the pineal 1464. Lehman NL, Horoupian DS, Warnke
1414. Lafay-Cousin L, Hawkins C, Carret AS, 1430. Langford LA, Camel MH (1987). Pali- region. Neuropathol Appl Neurobiol. 37(4):431- RA, Sundram UN, Peterson K, Harsh GR 4th
Johnston D, Zelcer S, Wilson B, et al. (2012). sading pattern in cerebral neuroblastoma mi- 5. PMID:20942871 (2002) . Dural marginal zone lymphoma with
Central nervous system atypical teratoid rhab- micking the primitive polar spongioblastoma. 1448. Lee D, Cho YH, Kang SY, Yoon N, Sung massive amyloid deposition: rare low-grade
doid tumours: the Canadian Paediatric Brain An ultrastructural study. Acta Neuropathol. CO, Suh YL (2015). BRAF V600E mutations primary central nervous system B-cell lympho-
Tumour Consortium experience. Eur J Cancer, 73(2):153-9. PMID:3604582 are frequent in dysembryoplastic neuroepit- ma. Case report. J Neurosurg. 96(2):368-72.
48(3):353-9. PMID:22023887 1431. Lannering B, Rutkowski S, Doz F, Pizer helial tumors and subependymal giant cell PMID:11838814
1415. Lafay-Cousin L, Keene D, Carret AS, B, Gustafsson G, Navajas A, et al. (2012). Hy- astrocytomas. J Surg Oncol. 111(3):359-64. 1465. Lehman NL, Jorden MA, Huhn SL,
Fryer C, Brassard J, Crooks B, et al. (2011). perfractionated versus conventional radiothera- PMID:25346165 Barnes PD, Nelson GB, Fisher PG, et al.
Choroid plexus tumors in children less than 36 py followed by chemotherapy in standard-risk 1449. Lee D, Suh YL (2010). Histologically con- (2003) . Cortical ependymoma. A case report
months: the Canadian Pediatric Brain Tumor medulloblastoma: results from the randomized firmed intracranial germ cell tumors; an analysis and review. Pediatr Neurosurg. 39(1):50-4.
Consortium (CPBTC) experience. Childs Nerv multicenter HIT-SIOP PNET 4 trial. J Clin Oncol. of 62 patients in a single institute. Virchows PMID:12784079
Syst. 27(2):259-64. PMID:20809071 30(26):3187-93. PMID:22851561 Arch. 457(3):347-57. PMID:20652714 1466. Lekanne Deprez RH, Bianchi AB, Groen
1416. LaFemina J, Qin LX, Moraco NH, Anto- 1432. Larkin SJ, Preda V, Karavitaki N, Gross- 1450. Lee DK, Jung HW, Kim DG, Paek SH, NA, Seizinger BR, Hagemeijer A, van Drunen
nescu CR, Fields RC, Crago AM, et al. (2013). man A, Ansorge O (2014). BRAF V600E Gwak HS, Choe G (2001). Postoperative spinal E, et al. (1994). Frequent NF2 gene tran-
Oncologic outcomes of sporadic, neurofibro- mutations are characteristic for papillary seeding of craniopharyngioma. Case report. J script mutations in sporadic meningiomas and
matosis-associated, and radiation-induced craniopharyngioma and may coexist with Neurosurg. 94(4):617-20. PMID:11302661 vestibular schwannomas. Am J Hum Genet.
378 References
54(6):1022-9. PMID:7911002 156(4):627-39. PMID:24553727 Kleinschmidt-DeMasters BK (2008). Radiati- Hou GQ, et al. (2013). MR imaging of cereb-
1467. Lellouch-Tubiana A, Boddaerl N, Bour- 1485. Li DM, Sun H (1997). TEP1, encoded by on-induced meningiomas: clinical, cytogenetic, ral extraventricular neurocytoma: a report of 9
geois M, Fohlen M, Jouvet A, Delalande 0, et a candidate tumor suppressor locus, is a no- and microarray features. Acta Neuropathol. cases. AJNR Am J Neuroradiol. 34(3):541-6.
al. (2005). Angiocentric neuroepithelial tumor vel protein tyrosine phosphatase regulated by 116(3)289-301. PMID:18604545 PMID23042917
(ANET): a new epilepsy-related clinicopatholo- transforming growth factor beta. Cancer Res. 1502. Lim SC, Jang SJ (2006). Myxopapillary 1519. Liu XY, Gerges N, Korshunov A, Sabha
gical entity with distinctive MRI. Brain Pathol. 57(11):2124-9. PMID:9187108 ependymoma of the fourth ventricle. Clin Neurol N, Khuong-Quang DA, Fontebasso AM, et al.
15(4):281-6. PMID:16389940 1486. LI FP, Fraumeni JF Jr, Mulvihill JJ, Blatt- Neurosurg. 108(2)211-4. PMIDT6412846 (2012). Frequent ATRX mutations and loss of
1468. Lellouch-Tubiana A, Bourgeois M, Veke- ner WA, Dreyfus MG, Tucker MA, et al. (1988). A 1503. Lim T, Kim SJ, Kim K, Lee Jl, Lim H, Lee expression in adult diffuse astrocytic tumors
mans M, Robain 0 (1995). Dysembryoplastic cancer family syndrome in twenty-four kindreds. DJ, et al. (2011). Primary CNS lymphoma other carrying IDH1/IDH2 and TP53 mutations. Acta
neuroepithelial tumors in two children with Cancer Res. 48(18):5358-62. PMID:3409256 than DLBCL: a descriptive analysis of clinical Neuropathol. 124(5):615-25. PMID22886134
neurofibromatosis type 1. Acta Neuropathol. 1487. Li G, Mitra S, Karamchandani J, Edwards features and treatment outcomes. Ann He- 1520. Liverman C, Mafra M, Chuang SS, Shi-
90(3):319-22. PMID:8525807 MS, Wong AJ (2010). Pineal parenchymal matol, 90(12):1391-8. PMID21479535 vane A, Chakrabarty A, Highley R, et al. (2015).
1469. Lemke D, Pfenning PN, Sahm F, Klein tumor of intermediate differentiation: clinico- 1504. Lin AL, Liu J, Evans J, Leuthardt EC, A dinicopathologic study of 11 rosette-forming
AC, Kempt T, Wamken U, et al. (2012). Costi- pathological report and analysis of epidermal Rich KM, Dacey RG, et al. (2014). Codeletions meningiomas: a rare and potentially confu-
mulatory protein 4lgB7H3 drives the malignant growth factor receptor variant III expression. at 1p and 19q predict a lower risk of pseudo- sing pattern. Acta Neuropathol. 130(2):311-3.
phenotype of glioblastoma by mediating immu- Neurosurgery. 66(5):963-8, discussion 968. progression in oligodendrogliomas and mixed PMID26106026
ne escape and invasiveness. Clin Cancer Res. PMID:20404701 oligoastrocytomas. Neuro Oncol. 16(1):123-30. 1521. Lloyd KM 2nd, Dennis M (1963). Cow-
18(1 ):105-17. PMID:22080438 1488. Li J, Simpson L, Takahashi M, Miliare- PMID24285548 den's disease. A possible new symptom com-
1470. Leonard JR, Perry A, Rubin JB, King AA, sis C, Myers MP, Tonks N, et al. (1998). The 1505. Lin NU, Amiri-Kordestani L, Palmieri plex with multiple system involvement. Ann
Chicoine MR, Gutmann DH (2006). The role of PTEN/MMAC1 tumor suppressor induces cell D, Liewehr DJ, Steeg PS (2013). CNS me- Intern Med. 58:136^12. PMID43931122
surgical biopsy in the diagnosis of glioma in in- death that is rescued by the AKT/protein kina- tastases in breast cancer: old challenge, new 1522. Lodding P, Kindblom LG, Angervall L,
dividuals with neurofibromatosis-1. Neurology. se B oncogene. Cancer Res. 58(24):5667-72. frontiers. Clin Cancer Res. 19(23):6404-18. Stenman G (1990). Cellular schwannoma. A
67(8):1509-12. PMID:17060590 PMID:9865719 PMID24298071 dinicopathologic study of 29 cases. Virchows
1471. Leone PE, Bello MJ, Mendiola M, Kusak 1489. Li J, Yen C, Liaw D, Podsypanina K, Bose 1506. Lin SL, Wang JS, Huang CS, Tseng Arch A Pathol Anat Histopathol. 416(3)237^18.
ME, De Campos JM, Vaquero J, et al. (1998). S, Wang SI, et al. (1997). PTEN, a putative HH (1996). Primary intracerebral leiomyo- PMID2105560
Allelic status of 1 p, 14q, and 22q and NF2 gene protein tyrosine phosphatase gene mutated ma: a case with eosinophilic inclusions of 1523. Loh JK, Lieu AS, Chai CY, Howng SL
mutations in sporadic schwannomas. Int J Mol in human brain, breast, and prostate cancer. actin filaments. Histopathology. 28(4):365-9. (2011). Malignant transformation of a desmo-
Med. 1(5):889-92. PMID:9852312 Science. 275(5308):1943-7. PMID:9072974 PMID:8732347 plastic infantile ganglioglioma. Pediatr Neurol.
1472. Leoz ML, Carballal S, Moreira L, Ocafia T, 1490. Li JY, Langford LA, Adesina A, Bodhired- 1507. Lin YJ, Yang QX, Tian XY, Li B, Li Z 45(2)435-7. PMID21763958
Balaguer F (2015). The genetic basis of familial dy SR, Wang M, Fuller GN (2012). The high (2013). Unusual primary intracranial dural-ba- 1524. Longatti P, Basaldella L, Orvieto E, Dei
adenomatous polyposis and its implications for mitotic count detected by phospho-histone H3 sed poorly differentiated synovial sarcoma with Tos AP, Martinuzzi A (2006). Aquaporin 1 ex-
clinical practice and risk management. Appl Clin Immunostain does not alter the benign behavi- t(X; 18)(p11; q11). Neuropathology. 33(1):75- pression in cystic hemangioblastomas. Neuros-
Genet. 8:95-107. PMID:25931827 or of angiocentric glioma. Brain Tumor Pathol. 82. PMID22537253 ci Lett. 392(3)478-80. PMID46300893
1473. Lermen O, Frank S, Hassler W 29(1):68-72. PMID:21892765 1508. Lindberg N, Jiang Y, Xie Y, Bolouri H, 1525. Longy M, Lacombe D (1996). Cowden
(2010). Postoperative spinal recurren- 1491. Li M, Lee KF, Lu Y, Clarke I, Shih D, Eber- Kastemar M, Olofsson T, et al. (2014). On- disease. Report of a family and review. Ann
ce of craniopharyngioma, Acta Neurochir hart C, et al. (2009). Frequent amplification of cogenic signaling is dominant to cell of origin Genet. 39(1):35-42. PMID:9297442
(Wien). 152(2):309-11, discussion 311. achr19q13.41 microRNA polycistron in aggres- and dictates astrocytic or oligodendroglial 1526. Lopes MB, Altermatt HJ, Scheithauer
PMID:19838829 sive primitive neuroectodermal brain tumors. tumor development from oligodendrocyte pre- BW, Shepherd CW, VandenBerg SR (1996).
1474. Lester RA, Brown LC, Eckel LJ, Foote RT, Cancer Cell. 16(6):533-46. PMID:19962671 cursor cells. J Neurosci. 34(44)44644-51. Immunohistochemical characterization of sub-
NageswaraRao AA, Buckner JC, et al. (2014). 1492. Li P, James SL, Evans N, Davies AM, PMID25355217 ependymal giant cell astrocytomas. Acta Neu-
Clinical outcomes of children and adults with Herron B, Sumathi VP (2007). Paraganglio- 1509. Lindstrom KM, Cousar JB, Lopes MB ropathol. 91(4):368-75. PMID:8928613
central nervous system primitive neuroecto- ma of the cauda equina with subarachnoid (2010). lgG4-related meningeal disease: clini- 1526A. Los M, Jansen GH, Kaelin WG, Lips
dermal tumor. J Neurooncol. 120(2):371-9. haemorrhage. Clin Radiol. 62(3):277-80. co-pathological features and proposal for dia- CJ, Blijham GH, Voest EE (1996). Expressi-
PMID:25115737 PMID:17293223 gnostic criteria. Acta Neuropathol. 120(6):765- on pattern of the von Hippel-Lindau protein
1475. Letouze E, Martinelli C, Loriot C, Burni- 1493. Li W, Cooper J, Zhou L, Yang C, Erd- 76. PMID20844883 in human tissues. Lab Invest. 75(2)231-8.
chon N, Abermil N, Ottolenghi C, et al. (2013). jument-Bromage H, Zagzag D, et al. (2014). 1510. Lindstrom E, Shimokawa T, Toftgard PMID:8765323
SDH mutations establish a hypermethylator Merlin/NF2 loss-driven tumorigenesis linked to R, Zaphiropoulos PG (2006). PTCH muta- 1527. Losa M, Saeger W, Mortini P, Pandolfi
phenotype in paraganglioma. Cancer Cell. CRL4(DCAF1 (-mediated inhibition of the hippo tions: distribution and analyses. Hum Mutat. C, Terreni MR, Taccagni G, et al. (2000). Acro-
23(6):739-52. PMID:23707781 pathway kinases Latsl and 2 in the nucleus. 27(3)215-9. PMID:16419085 megaly associated with a granular cell tumor of
1476. Levin N, Lavon I, Zelikovitsh B, Fuchs Cancer Cell. 26(1):48-60. PMID:25026211 1511. Linnebank M, Moskau S, Kowoll A, the neurohypophysis: a clinical and histological
D, Bokstein F, Fellig Y, et al. (2006). Progres- 1494. Li W, Graeber MB (2012). The molecular Semmler A, Bangard C, Vogt-Schaden M, et study. Case report. J Neurosurg. 93(1)421-6.
sive low-grade oligodendrogliomas: response profile of microglia under the influence of glioma. al. (2012). Association of transcobalamin c. PMID40883914
to temozolomide and correlation between Neuro Oncol. 14(8):958-78. PMID:22573310 776C>G with overall survival in patients with 1528. Lossos C, Bayraktar S, Weinzieri E, You-
genetic profile and 06-methylguanine DNA 1495. Li YS, Ramsay DA, Fan YS, Armstrong primary central nervous system lymphoma. Br J nes SF, Hosein PJ, Tibshirani RJ, et al. (2014).
methyltransferase protein expression. Cancer. RF, Del Maestro RF (1995). Cytogenetic evi- Cancer. 107(11):1840-3. PMID23099805 LM02 and BCL6 are associated with improved
106(8):1759-65. PMID:16541434 dence that a tumor suppressor gene in the long 1512. Linnebank M, Schmidt S, Kolsch H, survival in primary central nervous system
1477. Levine AJ (1997). p53, the cellular gate- arm of chromosome 1 contributes to glioma Linnebank A, Heun R, Schmidt-Wolf IG, et al. lymphoma. Br J Haematol. 165(5):640-8.
keeper for growth and division. Cell. 88(3):323- growth. Cancer Genet Cytogenet. 84(1):46-50. (2004). The methionine synthase polymorphism PMID24571259
31. PMID:9039259 PMID:7497442 D919G alters susceptibility to primary cent- 1529. Lotan I, Khlebtovsky A, Inbar E, Strenov
1478. Levy RA (1993). Paraganglioma of the 1496. Li ZJ, Lan XL, Hao FY, Yao WC, Wang ral nervous system lymphoma. Br J Cancer. J, Djaldetti R, Steiner I (2012). Primary brain
filum terminate: MR findings. AJR Am J Roent- MY, Chen XD, et al. (2014). Primary cerebel- 90(10)4969-71. PMID:15138479 T-cell lymphoma in an HTLV-1 serologically
genol. 160(4):851-2. PMID:8456679 lar paraganglioma: a pediatric case report 1513. Lipper S, Decker RE (1984). Parag- positive male. J Neurol Sci. 314(1-2)463-5.
1479. Lewis JJ, Brennan MF (1996). Soft tis- and review of the literature. Pediatr Neurol. anglioma of the cauda equina. A histologic, PMID22118868
sue sarcomas. Curr Probl Surg. 33(10):817-72. 50(4):303-6. PMID:24485927 immunohistochemical, and ultrastructural stu- 1530. Louis DN (1994). The p53 gene and pro-
PMID:8885853 1497. Liang L, Korogi Y, Sugahara T, Ikushima dy and review of the literature. Surg Neurol. tein in human brain tumors. J Neuropathol Exp
1480. Lewis PW, Muller MM, Koletsky MS, I, Shigematsu Y, Okuda T, et al. (2002). MRI of 22(4)415-20. PMID:6474349 Neurol. 53(1)41-21. PMID:8301315
Cordero F, Lin S, Banaszynski LA, etal. (2013). intracranial germ-cell tumours. Neuroradiology. 1514. Liss L, Kahn EA (1958). Pituicytoma, 1531. Louis DN, Hamilton AJ, Sobel RA, Oje-
Inhibition of PRC2 activity by a gain-of-function 44(5):382-8. PMID:12012121 tumor of the sella turcica; a clinicopatho- mann RG (1991). Pseudopsammomatous
H3 mutation found in pediatric glioblastoma. 1498. Liang X, Shen D, Huang Y, Yin C, Boja- logical study. J Neurosurg. 15(5)481-8. meningioma with elevated serum carcinoem-
Science. 340(6134):857-61. PMID:23539183 nowski CM, Zhuang Z, et al. (2007). Molecular PMID4 3576191 bryonic antigen: a true secretory meningio-
1481. Lewis RA, Gerson LP, Axelson KA, pathology and CXCR4 expression in surgically 1515. Listernick R, Charrow J, Greenwald M, ma. Case report. J Neurosurg. 74(1)429-32.
Riccardi VM, Whitford RP (1984). von Reck- excised retinal hemangioblastomas associated Mets M (1994). Natural history of optic pathway PMID4984492
linghausen neurofibromatosis. II. Incidence of with von Hippel-Lindau disease. Ophthalmolo- tumors in children with neurofibromatosis type 1532. Louis DN, Hedley-Whyte ET, Martuza RL
optic gliomata. Ophthalmology. 91(8):929-35. gy. 114(1 ):147-56. PMID:17070589 1: a longitudinal study. J Pediatr. 125(1):63-6. (1990). Sarcomatous proliferation of the vascu-
PMID:6436764 1499. Liaw D, Marsh DJ, Li J, Dahia PL, Wang PMID:8021787 lature in a subependymoma: a follow-up study
1482. Lhermitte J, Dudos P (1920). Sur un gan- SI, Zheng Z, et al. (1997). Germline mutations 1516. Listernick R, Femer RE, Liu GT, Gut- of sarcomatous dedifferentiation. Acta Neuro-
glioneurome diffus du coertex du cervelet. Bull of the PTEN gene in Cowden disease, an inhe- mann DH (2007). Optic pathway gliomas in pathol. 80(5):573-4. PMID2251917
Assoc Fr Etud Cancer. 9:99-107. rited breast and thyroid cancer syndrome. Nat neurofibromatosis-1: controversies and re- 1533. Louis DN, Ohgaki H, Wiestler OD, Cave-
1483. Li D, Schauble B, Moll C, Fisch U (1996). Genet. 16(1):64-7. PMID:9140396 commendations. Ann Neurol. 61(3)489-98. nee WK, editors. (2007). WHO Classification of
Intratemporal facial nerve perineurioma. Laryn- 1500. Ligon KL, Alberta JA, Kho AT, Weiss J, PMID47387725 Tumours of the Central Nervous System. 4th
goscope. 106(3 Pt 1 ):328-33. PMID:8614198 Kwaan MR, Nutt CL, et al. (2004). The oligo- 1517. Listernick R, Mancini AJ, Charrow J ed. Lyon: International Agency for Research
1484. Li D, Wang JM, Li GL, Hao SY, Yang dendroglial lineage marker OLIG2 is universally (2003). Segmental neurofibromatosis in child- on Cancer.
Y, Wu Z, et al. (2014). Clinical, radiological, expressed in diffuse gliomas. J Neuropathol hood. Am J Med Genet A. 121A(2):132-5. 1534. Louis DN, Ohgaki H, Wiestler OD, Ca-
and pathological features of 16 papillary gli- Exp Neurol. 63(5):499-509. PMID:15198128 PMID42910491 venee WK, Burger PC, Jouvet A, et al. (2007).
oneuronal tumors. Acta Neurochir (Wien). 1501. Lillehei KO, Donson AM, 1518. Liu K, Wen G, Lv XF, Deng YJ, Deng YJ, The 2007 WHO classification of tumours of
References 379
the central nervous system. Acta Neuropathol. H, Eiger CE, Wiestler OD, et al. (2003). The and renal cell carcinoma. J Med Genet. complex. Acta Neuropathol. 123(5):685-93.
114(2):97-109. PMID:17618441 spectrum of long-term epilepsy-associated 27(5):311-4. PMID:2352258 PMID:22327361
1535. Louis DN, Perry A, Burger P, Ellison DW, tumors: long-term seizure and tumor outco- 1568. Mahzoni P, Zavareh MH, Bagheri M, 1583. Marden FA, Wippold FJ 2nd, Perry A
Reifenberger G, von Deimling A, et at; Inter- me and neurosurgical aspects. Epilepsia. Hani N, Moqtader B (2012). Intracranial RO- (2003). Fast magnetic resonance imaging
national Society Of Neuropathology-Haarlem 44(6):822-30. PMID:12790896 SAI-DORFMAN Disease. J Res Med Sci. in steady-state precession (true FISP) in the
(2014) . International Society Of Neuropatholo- 1552. Luyken C, Bltimcke I, Fimmers R, Urbach 17(3):304-7. PMID:23267385 prenatal diagnosis of a congenital brain tera-
gy-Haarlem consensus guidelines for nervous H, Wiestler OD, Schramm J (2004). Supratento- 1569. Maier H, Ofner D, Hittmair A, Kitz K, Bu- toma. J Comput Assist Tomogr. 27(3):427-30.
system tumor classification and grading. Brain rial gangliogliomas: histopathologic grading and dka H (1992). Classic, atypical, and anaplastic PMID:12794611
Pathol. 24(5):429-35. PMID:24990071 tumor recurrence in 184 patients with a median meningioma: three histopathological subtypes 1584. Margetts JC, Kalyan-Raman UP
1536. Louis DN, Ramesh V, Gusella JF (1995). follow-up of 8 years. Cancer. 101(1):146-55. of clinical relevance. J Neurosurg. 77(4):616- (1989). Giant-celled glioblastoma of brain. A
Neuropathology and molecular genetics of PMID:15222000 23. PMID:1527622 clinico-pathological and radiological study of
neurofibromatosis 2 and related tumors. Brain 1553. Lubbe J, von Ammon K, Watanabe K, 1570. Majores M, von Lehe M, Fassunke J, ten cases (including immunohistochemistry
Pathol. 5(2):163-72. PMID:7670657 Hegi ME, Kleihues P (1995). Familial brain tu- Schramm J, Becker AJ, Simon M (2008). Tu- and ultrastructure). Cancer. 63(3):524-31.
1537. Louis DN, Richardson EP Jr, Dickersin mour syndrome associated with a p53 germline mor recurrence and malignant progression PMID:2912529
GR, Petrucci DA, Rosenberg AE, Ojemann deletion of codon 236. Brain Pathol. 5(1):15-23. of gangliogliomas. Cancer. 113(12):3355-63. 1585. Marigo V, Davey RA, Zuo Y, Cunningham
RG (1989). Primary intracranial leiomyosarco- PMID:7767487 PMID:18988291 JM, Tabin CJ (1996). Biochemical evidence
ma. Case report. J Neurosurg. 71(2):279-82. 1554. Lynch ED, Ostermeyer EA, Lee MK, 1571. Majos C, Aguilera C, Cos M, Camins A, that patched is the Hedgehog receptor. Nature.
PMID:2746352 Arena JF, Ji H, Dann J, et al. (1997). Inherited Candiota AP, Delgado-Goni T, et al. (2009). In 384(6605):176-9. PMID:8906794
1538. Louis DN, von Deimling A, Dickersin GR, mutations in PTEN that are associated with vivo proton magnetic resonance spectroscopy 1586. Markesbery WR, Duffy PE, Cowen D
Dooling EC, Seizinger BR (1992). Desmoplastic breast cancer, Cowden disease, and juvenile of intraventricular tumours of the brain. Eur Ra- (1973). Granular cell tumors of the central
cerebral astrocytomas of infancy: a histopatho- polyposis. Am J Hum Genet. 61(6):1254-60. diol. 19(8):2049-59. PMID:19277673 nervous system. J Neuropathol Exp Neurol.
logic, immunohistochemical, ultrastructural, PMID:9399897 1572. Makino K, Nakamura H, Yano S, Kuratsu 32(1 ):92-109. PMID:4346659
and molecular genetic study. Hum Pathol. 1555. MacCollin M, Chiocca EA, Evans J; Kumamoto Brain Tumor Group (2010). Po- 1587. Markesbery WR, Haugh RM, Young AB
23(12):1402-9. PMID:1468778 DG, Friedman JM, Horvitz R, Jaramillo D, pulation-based epidemiological study of primary (1981). Ultrastructure of pineal parenchymal
1539. Lovly CM, Gupta A, Lipson D, Otto G, et al. (2005). Diagnostic criteria for schwan- intracranial tumors in childhood. Childs Nerv neoplasms, Acta Neuropathol. 55(2):143-9.
Brennan T, Chung CT, et al. (2014). Inflam- nomatosis. Neurology. 64(11):1838-45. Syst. 26(8): 1029-34. PMID:20349186 PMID:7315200
matory myofibroblastic tumors harbor multiple PMID:15955931 1573. Makino K, Nakamura H, Yano S, Kuratsu 1588. Marsh A, Wicking C, Wainwright B,
potentially actionable kinase fusions. Cancer 1556. MacCollin M, Ramesh V, Jacoby LB, J; Kumamoto Brain Tumor Research Group Chenevix-Trench G (2005). DHPLC analysis
Discov. 4(8):889-95. PMID:24875859 Louis DN, Rubio MP, Pulaski K, et al. (1994). (2013). Incidence of primary central nervous of patients with Nevoid Basal Cell Carcinoma
1540. Lu C, Ward PS, Kapoor GS, Rohle D, Mutational analysis of patients with neurofibro- system germ cell tumors in childhood: a regio- Syndrome reveals novel PTCH missense muta-
Turcan S, Abdel-Wahab 0, et al. (2012). IDH matosis 2. Am J Hum Genet. 55(2):314-20. nal survey in Kumamoto prefecture in southern tions in the sterol-sensing domain. Hum Mutat.
mutation impairs histone demethylation and PMID:7913580 Japan. Pediatr Neurosurg. 49(3):155-8. 26(3):283. PMID:16088933
results in a block to cell differentiation. Nature. 1557. MacCollin M, Willett C, Heinrich B, Ja- PMID:24751890 1589. Marsh DJ, Coulon V, Lunetta KL, Roc-
483(7390):474-8. PMID:22343901 coby LB, Acierno JS Jr, Perry A, et al. (2003). 1574. Makkar HS, Frieden IJ (2002). Conge- ca-Serra P, Dahia PL, Zheng Z, et al, (1998).
1541. Lu JQ, Patel S, Wilson BA, Pugh J, Meh- Familial schwannomatosis: exclusion of the nital melanocytic nevi: an update for the pe- Mutation spectrum and genotype-phenotype
ta V (2013). Malignant glioma with angiocentric NF2 locus as the germline event. Neurology. diatrician. Curr Opin Pediatr. 14(4):397-403. analyses in Cowden disease and Bannay-
features. J Neurosurg Pediatr. 11(3):350-5. 60(12):1968-74. PMID:12821741 PMID:12130901 an-Zonana syndrome, two hamartoma syndro-
PMID:23240849 1558. MacCollin M, Woodfin W, Kronn D, Short 1575. Malkin D, Li FP, Strong LC, Fraumeni JF mes with germline PTEN mutation. Hum Mol
1542. Lu L, Dai Z, Zhong Y, Lv G (2013). MP (1996). Schwannomatosis: a clinical and Jr, Nelson CE, Kim DH, et al. (1990). Germ line Genet. 7(3):507-15. PMID:9467011
Cervical intradural paraganglioma presen- pathologic study. Neurology. 46(4):1072-9. p53 mutations in a familial syndrome of breast 1590. Marsh DJ, Dahia PL, Caron S, Kum
ting as progressive cervicodynia: case report PMID:8780094 cancer, sarcomas, and other neoplasms. Scien- JB, Frayling IM, Tomlinson IP, et al. (1998).
and literature review. Clin Neurol Neurosurg. 1559. Machein MR, Plate KH (2004). Role of ce. 250(4985):1233-8. PMID:1978757 Germline PTEN mutations in Cowden syndro-
115(3):359-61. PMID:22721774 VEGF in developmental angiogenesis and in 1576. Mallory SB (1995). Cowden syndrome me-like families. J Med Genet. 35(11 ):881-5.
1543. Lu-Emerson C, Duda DG, Emblem KE, tumor angiogenesis in the brain. Cancer Treat (multiple hamartoma syndrome). Dermatol Clin. PMID:9832031
Taylor JW, Gerstner ER, Loeffler JS, et al. Res. 117:191-218. PMID:15015562 13(1):27-31. PMID:7712647 1591. Marsh DJ, Dahia PL, Zheng Z, Liaw D,
(2015) . Lessons from anti-vascular endotheli- 1560. Mack SC, Witt H, Piro RM, Gu L, Zuy- 1577. Malmstrom A, Gronberg BH, Marosi C, Parsons R, Gorlin RJ, et al. (1997). Germline
al growth factor and anti-vascular endothelial derduyn S, Stiitz AM, et al. (2014). Epigenomic Stupp R, Frappaz D, Schultz H, et al.; Nordic mutations in PTEN are present in Bannay-
growth factor receptor trials in patients with alterations define lethal CIMP-positive ependy- Clinical Brain Tumour Study Group (NCBTSG) an-Zonana syndrome. Nat Genet. 16(4):333-4.
glioblastoma. J Clin Oncol. 33(10):1197-213. momas of infancy. Nature. 506(7489):445-50. (2012). Temozolomide versus standard 6-week PMID:9241266
PMID:25713439 PMID:24553142 radiotherapy versus hypofractionated radiothe- 1592. Marsh DJ, Kum JB, Lunetta KL, Bennett
1544. Lubs ML, Bauer MS, Formas ME, Djo- 1561. Mackenzie IR (1999). Central neurocyto- rapy in patients older than 60 years with gliob- MJ, Gorlin RJ, Ahmed SF, et al. (1999). PTEN
kic B (1991). Lisch nodules in neurofibroma- ma: histologic atypia, proliferation potential, lastoma: the Nordic randomised, phase 3 trial. mutation spectrum and genotype-phenotype
tosis type 1. N Engl J Med. 324(18):1264-6. and clinical outcome. Cancer. 85(7):1606-10. Lancet Oncol. 13(9):916-26. PMID:22877848 correlations in Bannayan-Riley-Ruvalcaba
PMID:1901624 PMID:10193953 1578. Manjila S, Ray A, Hu Y, Cai DX, Cohen syndrome suggest a single entity with Cowden
1545. Ludwin SK, Rubinstein LJ, Russell DS 1562. Mader I, Stock KW, Radue EW, Stein- ML, Cohen AR (2011). Embryonal tumors with syndrome. Hum Mol Genet. 8(8):1461-72.
(1975). Papillary meningioma: a malignant va- brich W (1996). Langerhans cell histiocytosis in abundant neuropil and true rosettes: 2 illustrati- PMID:10400993
riant of meningioma. Cancer. 36(4):1363-73. monocygote twins: case reports. Neuroradiolo- ve cases and a review of the literature. Neuro- 1593. Marsh DJ, Roth S, Lunetta KL, Hemminki
PMID:1175134 gy. 38(2):163-5. PMID:8692432 surg Focus. 30(1 ):E2. PMID:21194275 A, Dahia PL, Sistonen P, et al. (1997). Exclusi-
1546. Lun M, Lok E, Gautam S, Wu E, Wong 1563. Maehama T, Dixon JE (1998). The tumor 1579. Mantripragada KK, Spuriock G, Kluwe on of PTEN and 10q22-24 as the susceptibility
ET (2011). The natural history of extracranial suppressor, PTEN/MMAC1, dephosphoryla- L, Chuzhanova N, Ferner RE, Frayling IM, et locus for juvenile polyposis syndrome. Cancer
metastasis from glioblastoma multiforme. J tes the lipid second messenger, phospha- al. (2008). High-resolution DNA copy number Res. 57(22):5017-21. PMID:9371495
Neurooncol. 105(2):261-73. PMID:21512826 tidylinositol 3,4,5-trisphosphate, J Biol Chem. profiling of malignant peripheral nerve sheath 1594. Marsh DJ, Trahair TN, Martin JL, Chee
1547. Luse SA, Kernohan JW (1955). Granu- 273(22):13375-8. PMID:9593664 tumors using targeted microarray-based com- WY, Walker J, Kirk EP, et al. (2008). Rapamy-
lar-cell tumors of the stalk and posterior lobe 1564. Maertens O, Brems H, Vandesompele parative genomic hybridization. Clin Cancer cin treatment for a child with germline PTEN
of the pituitary gland. Cancer. 8(3):616-22. J, De Raedt T, Heyns I, Rosenbaum T, et al. Res. 14(4):1015-24. PMID:18281533 mutation. Nat Clin Pract Oncol. 5(6):357-61.
PMID.14379151 (2006). Comprehensive NF1 screening on cul- 1580. Marano SR, Johnson PC, Spetzler RF PMID:18431376
1548. Lusis EA, Watson MA, Chicoine MR, tured Schwann cells from neurofibromas. Hum (1988). Recurrent Lhermitte-Duclos disease in 1595. Marshman LA, Pollock JR, King A, Cha-
Lyman M, Roerig P, Reifenberger G, et al. Mutat. 27(10):1030-40. PMID:16941471 a child. Case report. J Neurosurg. 69(4):599- wda SJ (2005). Primary extradural epithelioid
(2005). Integrative genomic analysis identifies 1565. Maesawa C, Tamura G, Iwaya T, Ogasa- 603. PMID:3418394 leiomyosarcoma of the cervical spine: case
NDRG2 as a candidate tumor suppressor gene wara S, Ishida K, Sato N, et al. (1998). Muta- 1581. Marcel V, Dichtel-Danjoy ML, Sagne C, report and literature review. Neurosurgery.
frequently inactivated in clinically aggressive tions in the human homologue of the Droso- Hafsi H, Ma D, Ortiz-Cuaran S, et al. (2011). 57(2):E372, discussion E372. PMID:16094142
meningioma. Cancer Res. 65(16):7121-6. phila patched gene in esophageal squamous Biological functions of p53 isoforms through 1596. Martinez R, Roggendorf W, Baretton G,
PMID:16103061 cell carcinoma. Genes Chromosomes Cancer. evolution: lessons from animal and cellular Klein R, Toedt G, Lichter P, et al. (2007). Cyto-
1549. Lutterbach J, Fauchon F, Schild SE, Ch- 21 (3):276-9. PMID:9523206 models. Cell Death Differ. 18(12):1815-24. genetic and molecular genetic analyses of giant
ang SM, Pagenstecher A, Volk B, et al. (2002). 1566. Magri L, Cambiaghi M, Cominelli M, Al- PMID:21941372 cell glioblastoma multiforme reveal distinct pro-
Malignant pineal parenchymal tumors in adult faro-Cervello C, Cursi M, Pala M, et al. (2011). 1581A. Marciscano AE, Stemmer-Rachami- files in giant cell and non-giant cell subpopula-
patients: patterns of care and prognostic fac- Sustained activation of mTOR pathway in mov AO, Niemierko A, Larvie M, Curry WT, tions. Cancer Genet Cytogenet. 175(1):26-34.
tors. Neurosurgery. 51(1):44-55, discussion embryonic neural stem cells leads to develop- Barker FG 2nd, et al. (2016). Benign menin- P MID: 17498554
55-6. PMID:12182434 ment of tuberous sclerosis complex-associ- giomas (WHO Grade I) with atypical histolo- 1597. Martinez-Diaz H, Kleinschmidt-DeMas-
1550. Lutterbach J, Liegibel J, Koch D, Madlin- ated lesions. Cell Stem Cell. 9(5):447-62. gical features: correlation of histopathological ters BK, Powell SZ, Yachnis AT (2003). Giant
ger A, Frommhold H, Pagenstecher A (2001). PMID:22056141 features with clinical outcomes. J Neurosurg. cell glioblastoma and pleomorphic xanthoast-
Atypical teratoid/rhabdoid tumors in adult pati- 1567. Maher ER, Yates JR, Ferguson-Smith 124(1):106-14. PMID:26274991 rocytoma show different immunohistochemical
ents: case report and review of the literature. J MA (1990). Statistical analysis of the two stage 1582. Marcotte L, Aronica E, Baybis M, Crino PB profiles for neuronal antigens and p53 but share
Neurooncol. 52(1):49-56. PMID:11451202 mutation model in von Hippel-Lindau disease, (2012). Cytoarchitectural alterations are wides- reactivity for class III beta-tubulin. Arch Pathol
1551. Luyken C, Bliimcke I, Fimmers R, Urbach and in sporadic cerebellar haemangioblastoma pread in cerebral cortex in tuberous sclerosis Lab Med. 127(9):1187-91. PMID:12946225
380 References
1598. Martinez-Salazar A, Supler M, Rojiani AM gastrointestinal stromal tumors. J Clin Endocri- Z, Abel TW, et al. (2009). Diagnostic utility of (1995). Screening for germ-line mutations in
(1997). Primary intracerebral malignant fibrous nol Metab. 92(8):2938^13. PMID:17535989 SALL4 in primary germ cell tumors of the cen- the NF2 gene. Genes Chromosomes Cancer.
histiocytoma: immunohistochemical findings 1615. Mawrin C, Perry A (2010). Pathologi- tral nervous system: a study of 77 cases. Mod 12(2):117-27. PMID:7535084
and etiopathogenetic considerations. Mod Pa- cal classification and molecular genetics of Pathol. 22(12): 1628-36. PMID:19820689 1648. Merino DM, Shlien A, Villani A, Pien-
thol. 10(2):149-54. PMID:9127321 meningiomas. J Neurooncol. 99(3):379-91. 1632. Meijer-Jorna LB, Aronica E, van der Loos kowska M, Mack S, Ramaswamy V, et al.
1599. Martuza RL, Eldridge R (1988). Neu- PMID.20809251 CM, Troost D, van der Wal AC (2012). Conge- (2015). Molecular characterization of choroid
rofibromatosis 2 (bilateral acoustic neurofi- 1616. Mayer-Proschel M, Kalyani AJ, Mujtaba nital vascular malformations-cerebral lesions plexus tumors reveals novel clinically relevant
bromatosis). N Engl J Med. 318(11):684-8. T, Rao MS (1997). Isolation of lineage-restric- differ from extracranial lesions by their immu- subgroups. Clin Cancer Res. 21(1):184-92.
PMID:3125435 ted neuronal precursors from multipotent neu- ne expression of the glucose transporter pro- PMID:25336695
1600. Marucci G, Di Oto E, Farnedi A, Panzac- roepithelial stem cells. Neuron. 19(4):773-85. tein GLUT! Clin Neuropathol. 31(3):135-41. 1649. Merker VL, Esparza S, Smith MJ,
chi R, Ligorio C. Foschini MP (2012). Nogo-A: a PMID:9354325 PMID:22551917 Stemmer-Rachamimov A, Plotkin SR (2012).
useful marker for the diagnosis of oligodendro- 1617. Mazur MA, Gururangan S, Bridge JA, 1633. Meis JM, Ho KL, Nelson JS (1990). Clinical features of schwannomatosis: a re-
glioma and for identifying 1p19q codeletion. Cummings TJ, Mukundan S, Fuchs H, et al. Gliosarcoma: a histologic and immunohisto- trospective analysis of 87 patients. Oncologist.
Hum Pathol. 43(3):374-80. PMID:21835431 (2005). Intracranial Ewing sarcoma. Pediatr chemical reaffirmation. Mod Pathol. 3(1):19-24. 17(10):1317-22. PMID:22927469
1601. Maruoka R, Takenouchi T, Torii C, Shimi- Blood Cancer. 45(6):850-6. PMID:15929128 PMID:2155418 1650. Merlin E, Chabrier S, Verkarre V, Cra-
zu A, Misu K, Higasa K, et al. (2014). The use 1618. McCabe MG, Ichimura K, Liu L, Plant 1634. Mellinghoff IK, Wang MY, Vivanco I, mer E, Delabesse E, Stephan JL (2008).
of next-generation sequencing in molecular dia- K, Backlund LM, Pearson DM, et al. (2006). Haas-Kogan DA, Zhu S, Dia EQ, et al. (2005). Primary leptomeningeal ALK+ lymphoma in
gnosis of neurofibromatosis type 1: a validation High-resolution array-based comparative ge- Molecular determinants of the response of gli- a 13-year-old child. J Pediatr Hematol Oncol.
study. Genet Test Mol Biomarkers. 18(11):722- nomic hybridization of medulloblastomas and oblastomas to EGFR kinase inhibitors. N Engl J 30(12):963-7. PMID:19131793
35. PMID:25325900 supratentorial primitive neuroectodermal tu- Med. 353(19):2012-24. PMID:16282176 1651. Merrell R, Nabors LB, Perry A, Palmer
1602. Maruya J, Seki Y, Morita K, Nishimaki K, mors. J Neuropathol Exp Neurol. 65(6):549-61. 1635. Memoli VA, Brown EF, Gould VE (1984). CA (2006). 1p/19q chromosome deletions in
Minakawa T (2006). Meningeal hemangiope- PMID:16783165 Glial fibrillary acidic protein (GFAP) Immuno- metastatic oligodendroglioma. J Neurooncol.
ricytoma manifesting as massive intracranial 1619. McClatchey Al, Giovannini M (2005). reactivity in peripheral nerve sheath tumors. 80(2):203-7. PMID:16710746
hemorrhage-two case reports. Neurol Med Chir Membrane organization and tumorigenesis-the Ultrastruct Pathol. 7(4):269-75. PMID:6543600 1652. Messiaen LM, Callens T, Mortier G,
(Tokyo). 46(2):92-7. PMID:16498220 NF2 tumor suppressor, Merlin. Genes Dev. 1636. Mena H, Ribas JL, Enzinger FM, Parisi Beysen D, Vandenbroucke I, Van Roy N, et
1603. Massimino M, Antonelli M, Gandola 19(19):2265-77. PMID:16204178 JE (1991). Primary angiosarcoma of the central al. (2000). Exhaustive mutation analysis of the
L, Miceli R, Polio B, Biassoni V, et al. (2013). 1620. McCubrey JA, Steelman LS, Abrams SL, nervous system. Study of eight cases and re- NF1 gene allows identification of 95% of muta-
Histological variants of medulloblastoma are Lee JT, Chang F, Bertrand FE, et al. (2006). Ro- view of the literature. J Neurosurg. 75(1):73-6. tions and reveals a high frequency of unusual
the most powerful clinical prognostic indi- les of the RAF/MEK/ERK and PI3K/PTEN/AKT PM ID :2045922 splicing defects. Hum Mutat. 15(6):541-55.
cators. Pediatr Blood Cancer. 60(2):210-6. pathways in malignant transformation and drug 1637. Mena H, Ribas JL, Pezeshkpour GH, PMID:10862084
PMID:22693015 resistance. Adv Enzyme Regul. 46:249-79. Cowan DN, Parisi JE (1991). Hemangiope- 1653. Mester J, Eng C (2012). Estimate of
1604. Massimino M, Solero CL, Garre ML, Bi- PMID:16854453 ricytoma of the central nervous system: a de novo mutation frequency in probands with
assoni V, Cama A, Genitori L, et al. (2011). Se- 1621. McGarvey TW, Maruta Y, Tomaszews- review of 94 cases. Hum Pathol. 22(1):84-91. PTEN hamartoma tumor syndrome. Genet
cond-look surgery for ependymoma: the Italian ki JE, Linnenbach AJ, Malkowicz SB (1998). PMID:1985083 Med. 14(9):819-22. PMID:22595938
experience. J Neurosurg Pediatr. 8(3):246-50. PTCH gene mutations in invasive transitional 1638. Mena H, Rushing EJ, Ribas JL, Delahunt 1654. Mete O, Lopes MB, Asa SL (2013). Spind-
PMID:21882914 cell carcinoma of the bladder. Oncogene. B, McCarthy WF (1995). Tumors of pineal pa- le cell oncocytomas and granular cell tumors of
1605. Masuoka J, Brandner S, Paulus W, 17(9):1167-72. PMID:9764827 renchymal cells: a correlation of histological the pituitary are variants of pituicytoma. Am J
Soffer D, Vital A, Chimelli L, et al. (2001). 1622. McGirr SJ, Kelly PJ, Scheithauer BW features, including nucleolar organizer re- Surg Pathol. 37(11):1694-9. PMID:23887161
Germline SDHD mutation in paraganglioma (1987). Stereotactic resection of juvenile pi- gions, with survival in 35 cases. Hum Pathol. 1655. Mete O, Tischler AS, de Krijger R, McNi-
of the spinal cord. Oncogene. 20(36):5084-6. locytic astrocytomas of the thalamus and 26(1 ):20-30. PMID:7821912 col AM, Eisenhofer G, Pacak K, et al. (2014).
PMID:11526495 basal ganglia. Neurosurgery. 20(3):447-52. 1639. Mendrzyk F, Korshunov A, Benner A, Protocol for the examination of specimens
1606. Mathew RK, O'Kane R, Parslow R, Stiller PMID:3553982 Toedt G, Pfister S, Radlwimmer B, et al. (2006). from patients with pheochromocytomas and
C, Kenny T, Picton S, et al. (2014). Comparison 1623. McHugh BJ, Baranoski JF, Malhotra A, Identification of gains on 1q and epidermal extra-adrenal paragangliomas. Arch Pathol Lab
of survival between the UK and US after sur- Vortmeyer AO, Sze G, Duncan CC (2014). In- growth factor receptor overexpression as Med. 138(2):182-8. PMID:24476517
gery for most common pediatric CNS tumors. tracranial infantile hemangiopericytoma. J Neu- independent prognostic markers in intracra- 1656. Metellus P, BouvierC, Guyotat J, Fuentes
Neuro Oncol. 16(8):1137-45. PMID:24799454 rosurg Pediatr. 14(2):149-54. PMID:24905842 nial ependymoma. Clin Cancer Res. 12(7 Pt S, Jouvet A, Vasiljevic A, et al. (2007). Solitary
1607. Mathews JD, Forsythe AV, Brady Z, But- 1624. McKusick VA. Online Mendelian Inheri- 1):2070-9. PMID:16609018 fibrous tumors of the central nervous system:
ler MW, Goergen SK, Byrnes GB, et al. (2013). tance in Man [www.omim.org] 1640. Mendrzyk F, Radlwimmer B, Joos S, Ko- clinicopathological and therapeutic considera-
Cancer risk in 680,000 people exposed to 1625. McLendon RE, Bentley RC, Parisi JE, kocinski F, Benner A, Stange DE, et al. (2005). tions of 18 cases. Neurosurgery. 60(4):715-22,
computed tomography scans in childhood or Tien RD, Harrison JC, Tarbell NJ, et al. (1997). Genomic and protein expression profiling discussion 722. PMID:17415209
adolescence: data linkage study of 11 million Malignant supratentorial glial-neuronal neo- identifies CDK6 as novel independent progno- 1657. Meyer P, Eberle MM, Probst A, Tolnay
Australians. BMJ. 346:f2360. PMID:23694687 plasms: report of two cases and review of the stic marker in medulloblastoma. J Clin Oncol. M (2000). [Ganglioglioma of optic nerve in
1608. Mathews T, Moossy J (1974). Gliomas literature. Arch Pathol Lab Med. 121 (5):485-92. 23(34):8853-62. PMID:16314645 neurofibromatosis type 1. Case report and re-
containing bone and cartilage. J Neuropathol PMID:9167602 1641. Menke JR, Raleigh DR, Gown AM, Tho- view of the literature], Klin Monbl Augenheilkd.
Exp Neurol. 33(3):456-71. PMID:4365915 1626. McManamy CS, Lamont JM, Taylor RE, mas S, Perry A, Tihan T (2015). Somatostatin 217(1):55-8. PMID:10949818
1609. Mathon B, Carpentier A, Clemenceau Cole M, Pearson AD, Clifford SC, et al.; Uni- receptor 2a is a more sensitive diagnostic 1658. Meyer-Puttlitz B, Hayashi Y, Waha A,
S, Boch AL, Bitar A, Mokhtari K, et al. (2012). ted Kingdom Children's Cancer Study Group marker of meningioma than epithelial membra- Rollbrocker B, Bostrom J, Wiestler OD, et al.
[Paraganglioma of the cauda equina region: (2003). Morphophenotypic variation predicts ne antigen. Acta Neuropathol. 130(3):441-3. (1997). Molecular genetic analysis of giant
Report of six cases and review of the literature], clinical behavior in childhood non-desmoplastic PMID:26195322 cell glioblastomas. Am J Pathol. 151(3):853-7.
Neurochirurgie. 58(6):341-5. PMID:22770767 medulloblastomas. J Neuropathol Exp Neurol. 1642. Menko FH, Kaspers GL, Meijer GA, PMID:9284834
1610. Matsushima T, Inoue T, Takeshita I, Fukui 62(6):627-32. PMID:12834107 Claes K, van Hagen JM, Gille JJ (2004). A ho- 1659. Meyers SP, Khademian ZP, Biegel JA,
M, Iwaki T, Kitamoto T (1988). Choroid plexus 1627. McManamy CS, Pears J, Weston CL, mozygous MSH6 mutation in a child with cafe- Chuang SH, Korones DN, Zimmerman RA
papillomas: an immunohistochemical study Hanzely Z, Ironside JW, Taylor RE, et al.; Clini- au-lait spots, oligodendroglioma and rectal can- (2006). Primary intracranial atypical teratoid/
with particular reference to the coexpression cal Brain Tumour Group (2007). Nodule forma- cer. Fam Cancer. 3(2):123-7. PMID:15340263 rhabdoid tumors of infancy and childhood:
of prealbumin. Neurosurgery. 23(3):384-9. tion and desmoplasia in medulloblastomas-de- 1643. Merchant TE, Jenkins JJ, Burger PC, MRI features and patient outcomes. AJNR Am
PMID:3226520 fining the nodular/desmoplastic variant and its Sanford RA, Sherwood SH, Jones-Wallace D, J Neuroradiol. 27(5):962-71. PMID:16687525
1611. Matsutani M; Japanese Pediatric Brain biological behavior. Brain Pathol. 17(2):151-64. et al. (2002). Influence of tumor grade on time to 1660. Meyers SP, Khademian ZP, Chuang SH,
Tumor Study Group (2001). Combined chemo- PMID:17388946 progression after irradiation for localized epen- Pollack IF, Korones DN, Zimmerman RA(2004).
therapy and radiation therapy for CNS germ cell 1628. McMenamin ME, Fletcher CD (2001). dymoma in children. Int J Radiat Oncol Biol Choroid plexus carcinomas in children: MRI
tumors-the Japanese experience. J Neuroon- Expanding the spectrum of malignant change Phys. 53(1):52-7. PMID:12007941 features and patient outcomes. Neuroradiology.
col. 54(3):311-6. PMID:11767296 in schwannomas: epithelioid malignant change, 1644. Merchant TE, Li C, Xiong X, Kun LE, 46(9):770-80. PMID:15309348
1612. Matsutani M, Sano K, Takakura K, Fuji- epithelioid malignant peripheral nerve sheath Boop FA, Sanford RA (2009). Conformal ra- 1661. Michal M, Kazakov DV, Belousova I, Bi-
maki T, Nakamura O, Funata N, et al. (1997). tumor, and epithelioid angiosarcoma: a study diotherapy after surgery for paediatric epen- sceglia M, Zamecnik M, Mukensnabl P (2004).
Primary intracranial germ cell tumors: a clinical of 17 cases. Am J Surg Pathol. 25(1):13-25. dymoma: a prospective study. Lancet Oncol. A benign neoplasm with histopathological featu-
analysis of 153 histologically verified cases. J PMID:11145248 10(3):258-66. PMID:19274783 res of both schwannoma and retiform perineu-
Neurosurg. 86(3):446-55. PMID:9046301 1629. McNatt SA, Gonzalez-Gomez I, Nelson 1645. Merchant TE, Pollack IF, Loeffler JS rioma (benign schwannoma-perineurioma): a
1613. Matthies C, Samii M (1997). Management MD, McComb JG (2005). Synchronous mul- (2010). Brain tumors across the age spectrum: report of six cases of a distinctive soft tissue tu-
of 1000 vestibular schwannomas (acoustic neu- ticentric pleomorphic xanthoastrocytoma: case biology, therapy, and late effects. Semin Radiat mor with a predilection for the fingers. Virchows
romas): clinical presentation. Neurosurgery. report. Neurosurgery. 57(1):E191, discussion Oncol. 20(1 ):58-66. PMID:19959032 Arch. 445(4):347-53. PMID:15322875
40(1):1-9, discussion 9-10. PMID:8971818 E191. PMID:15987556 1646. Mercuri S, Gazzeri R, Galarza M, Espo- 1662. Miettinen M, Shekitka KM, Sobin LH
1614. Matyakhina L, Bei TA, McWhinney SR, 1630. Medhkour A, Traul D, Husain M (2002). sito S, Giordano M (2005). Primary meningeal (2001). Schwannomas in the colon and rec-
Pasini B, Cameron S, Gunawan B, et al. (2007). Neonatal subependymal giant cell ast- pheochromocytoma: case report. J Neurooncol. tum: a clinicopathologic and immunohistoche-
Genetics of camey triad: recurrent losses at rocytoma. Pediatr Neurosurg. 36(5):271-4. 73(2):169-72. PMID:15981108 mical study of 20 cases. Am J Surg Pathol.
chromosome 1 but lack of germline mutations PM ID: 12053047 1647. Merel P, Hoang-Xuan K, Sanson M, 25(7):846-55. PMID:11420455
in genes associated with paragangliomas and 1631. Mei K, Liu A, Allan RW, Wang P, Lane Bijlsma E, Rouleau G, Laurent-Puig P, et al. 1663. Migheli A, Cavalla P, Marino S, Schiffer
References 381
D (1994). A study of apoptosis in normal and 1679. Ming JE, Kaupas ME, Roessler E, Brun- with special reference to its cytogenesis. Neurol R, Gesk S, Madin-Subero Jl, Schaller C, Van
pathologic nervous tissue after in situ end-labe- ner HG, Nance WE, Stratton RF, et al. (1998). Med Chir (Tokyo). 33(7):42<M. PMID7692317 Roost D, et al. (2002). Interphase cytogenetic
ling of DNA strand breaks. J Neuropathol Exp Mutations of PATCHED in holoprosencephaly. 1696. Mobley BC, Roulston D, Shah GV, Bi- analysis of lymphoma-associated chromoso-
Neurol. 53(6):606-16. PMID:7525880 Am J Hum Genet. 63:A140-140. jwaard KE, McKeever PE (2006). Peripheral mal breakpoints in primary diffuse large B-cell
1664. Milbouw G, Born JD, Martin D, Collignon 1680. Mirsattari SM, Chong JJ, Hammond RR, primitive neuroectodermal tumor/Ewing's lymphomas of the central nervous system.
J, Hans P, Reznik M, et al. (1988). Clinical and Megyesi JF, Macdonald DR, Lee DH, et al. sarcoma of the craniospinal vault: case re- J Neuropathol Exp Neurol. 61(10):926-33.
radiological aspects of dysplastic gangliocyto- (2011). Do epileptic seizures predict outcome in ports and review. Hum Pathol. 37(7):845-53. PMID:12387458
ma (Lhermitte-Duclos disease): a report of two patients with oligodendroglioma? Epilepsy Res. PMID:16784984 1711. Moody P, Muriagh K, Piduru S, Brem S,
cases with review of the literature. Neurosur- 94(1-2):39-44. PMID:21315558 1697. Modena P, Lualdi E, Facchinetti F, Galli L, Muriagh R, Rojiani AM (2012). Tumor-to-tumor
gery. 22(1 Pt 1):124-8. PMID:3278250 1681. Mishima K, Nakamura M, Nakamura Teixeira MR, Pilotti S, et al. (2005). SMARCB1/ metastasis: pathology and neuroimaging consi-
1665. Millard NE, Dunkel IJ (2014). Advances H, Nakamura O, Funata N, Shitara N (1992). INI1 tumor suppressor gene is frequently inac- derations. Int J Clin Exp Pathol. 5(4):367-73.
in the management of central nervous system Leptomeningeal dissemination of cerebellar pi- tivated in epithelioid sarcomas. Cancer Res. PMID:22670183
germ cell tumors. Curr Oncol Rep. 16(7):393. locytic astrocytoma. Case report. J Neurosurg. 65(10):4012-9. PMID:15899790 1712. Moran CA, Rush W, Mena H (1997).
PMID:24838613 77(5)788-91. PMID:1403124 1698. Moles KJ, Gowans GC, Gedela S, Bev- Primary spinal paragangliomas: a clinicopa-
1666. Miller CA, Torack RM (1970). Secretory 1682. Mishra T, Goel NA, Goel AH (2014). Pri- ersdorf D, Yu A, Seaver LH, et al. (2012). NF1 thological and immunohistochemical study
ependymoma of the filum terminale. Acta Neu- mary paraganglioma of the spine: A clinicopa- microduplications: identification of seven nonre- of 30 cases. Histopathology. 31(2):167-73.
ropathol. 15(3):240-50. PMID:4193811 thological study of eight cases. J Craniovertebr lated individuals provides further characterizati- PMID:9279569
1667. Miller CR, Dunham CP, Scheithauer BW, Junction Spine. 5(1):20-4. PMID:25013343 on of the phenotype. Genet Med. 14(5):508-14. 1713. Morantz RA, Feigin I, Ransohoff J 3rd
Perry A (2006). Significance of necrosis in gra- 1683. Mistry M, Zhukova N, Merico D, Rako- PMID:22241097 (1976). Clinical and pathological study of 24
ding of oligodendroglial neoplasms: a clinicopa- poulos P, Krishnatry R, Shago M, et al. (2015). 1699. Momota H, Iwami K, Fujii M, Motomura cases of gliosarcoma. J Neurosurg. 45(4):398-
thologic and genetic study of newly diagnosed BRAF mutation and CDKN2A deletion defi- K, Natsume A, Ogino J, et al. (2011). Rhabdoid 408. PMID:956876
high-grade gliomas. J Clin Oncol. 24(34):5419- ne a clinically distinct subgroup of childhood glioblastoma in a child: case report and litera- 1714. Moriguchi S, Yamashita A, Marutsuka
26. PMID:17135643 secondary high-grade glioma. J Clin Oncol. ture review. Brain Tumor Pathol. 28(1):65-70. K, Yoneyama T, Nakano S, Wakisaka S, et al.
1668. Miller S, Rogers HA, Lyon P, Rand V, 33(9):1015-22. PMID:25667294 PMID:21213124 (2006). Atypical extraventricular neurocytoma.
Adamowicz-Brice M, Clifford SC, et al. (2011). 1684. Mitchell A, Scheithauer BW, Ebersold MJ, 1700. Momota H, Narita Y, MaeshimaAM, Miya- Pathol Int. 56(1):25-9. PMID:16398676
Genome-wide molecular characterization of Forbes GS (1991). Intracranial fibromatosis. kita Y, Shinomiya A, Maruyama T, et al. (2010). 1715. Moskowitz SI, Jin T, Prayson RA (2006).
central nervous system primitive neuroectoder- Neurosurgery. 29(1):123-6. PMID:1870673 Prognostic value of immunohistochemical profi- Role of MIB1 in predicting survival in patients
mal tumor and pineoblastoma. Neuro Oncol. 1685. Mitchell A, Scheithauer BW, Unni KK, le and response to high-dose methotrexate the- with glioblastomas. J Neurooncol. 76(2):193-
13(8):866-79. PMID:21798848 Forsyth PJ, Wold LE, McGivney DJ (1993). rapy in primary CNS lymphoma. J Neurooncol. 200. PMID:16234986
1669. Miller S, Ward JH, Rogers HA, Lowe Chordoma and chondroid neoplasms of the 98(3):341-8. PMID:20012911 1716. Moss TH (1984). Observations on
J, Grundy RG (2013). Loss of INI1 protein spheno-occiput. An immunohistochemical 1701. Monje M, Mitra SS, Freret ME, Raveh TB, the nature of subependymoma: an electron
expression defines a subgroup of aggressive study of 41 cases with prognostic and noso- Kim J, Masek M, et al. (2011). Hedgehog-res- microscopic study. Neuropathol Appl Neurobiol.
central nervous system primitive neuroecto- logic implications. Cancer. 72(10):2943-9. ponsive candidate cell of origin for diffuse intrin- 10(1):63-75. PMID:6738805
dermal tumors. Brain Pathol. 23(1):19-27. PMID7693324 sic pontine glioma. Proc Natl Acad Sci U S A . 1717. Mott RT, Goodman BK, Burchette JL,
PMID:22672440 1686. Mittal P, Gupta K, Saggar K, Kaur S 108(11):4453-8. PMID:21368213 Cummings TJ (2005). Loss of chromosome 13
1670. Min HS, Lee JY, Kim SK, Park SH (2013). (2009). Adult medulloblastoma mimicking 1702. Montesinos-Rongen M, Besleaga R, in a case of soft tissue perineurioma. Clin Neu-
Genetic grouping of medulloblastomas by re- Lhermitte-Duclos disease: can diffusion weigh- Heinsohn S, Siebert R, Kabisch H, Wiestler OD, ropathol. 24(2):69-76. PMID:15803806
presentative markers in pathologic diagnosis. ted imaging help? Neurol India. 57(2):203-5. et al. (2004). Absence of simian virus 40 DNA 1718. Mrak RE, Yasargil MG, Mohapatra G, Ea-
Transl Oncol. 6(3):265-72. PMID:23730405 P MID: 19439857 sequences in primary central nervous system rel J Jr, Louis DN (2004). Atypical extraventri-
1671. Min HS, Lee YJ, Park K, Cho BK, Park 1687. Miyagami M, Katayama Y, Nakamura lymphoma in HIV-negative patients. Virchows cular neurocytoma with oligodendroglioma-like
SH (2006). Medulloblastoma: histopathologic S (2000). Clinicopathological study of vas- Arch. 444(5):436-8. PMID:15042369 spread and an unusual pattern of chromosome
and molecular markers of anaplasia and biolo- cular endothelial growth factor (VEGF), p53, 1703. Montesinos-Rongen M, Godlewska 1p and 19q loss. Hum Pathol. 35(9):1156-9.
gic behavior. Acta Neuropathol. 112(1):13-20. and proliferative potential in familial von Hip- E, Brunn A, Wiestler OD, Siebert R, Decked PMID:15343519
PMID:16691420 pel-Lindau disease and sporadic hemangiob- M (2011). Activating L265P mutations of the 1719. Mu Q, Yu J, Qu L, Hu X, Gao H, Liu P,
1672. Min KW, Scheithauer BW (1990). Pi- lastomas. Brain Tumor Pathol. 17(3):111-20. MYD88 gene are common in primary central et al. (2015). Spindle cell oncocytoma of the
neal germinomas and testicular seminoma: a PMID:11310918 nervous system lymphoma. Acta Neuropathol. adenohypophysis: two case repods and a re-
comparative ultrastructural study with special 1688. Miyagi Y, Suzuki SO, Iwaki T, Shima F, Is- 122(6)791-2. PMID:22020631 view of the literature. Mol Med Rep. 12(1):871-
references to early carcinomatous transfor- hido K, Araki T, et al. (2001). Pleomorphic xan- 1704. Montesinos-Rongen M, Hans VH, Eis-Hii- 6. PMID:25777996
mation. Ultrastruct Pathol. 14(6):483-96. thoastrocytoma with predominantly exophytic binger AM, Prinz M, Schaller C, Van Roost D, 1720. Mueller W, Mizoguchi M, Silen E,
PMID:2281547 growth: case report. Surg Neurol. 56(5):330-2. et al. (2001). Human herpes virus-8 is not as- D’Amore K, Nutt CL, Louis DN (2005). Muta-
1673. Min KW, Scheithauer BW (1997). Clear PMID:11750009 sociated with primary central nervous system tions of the PIK3CA gene are rare in human
cell ependymoma: a mimic of oligodendroglio- 1689. Miyamori T, Mizukoshi H, Yamano K, lymphoma in HIV-negative patients. Acta Neu- glioblastoma. Acta Neuropathol. 109(6):654-5.
ma: clinicopathologic and ultrastructural con- Takayanagi N, Sugino M, Hayase H, et al. ropathol. 102(5):489-95. PMID:11699563 PMID:15924252
siderations. Am J Surg Pathol. 21(7):820-6. (1990). Intracranial chondrosarcoma-case 1705. Montesinos-Rongen M, Kuppers R, 1721. Muller C, Adroos N, Lockhat Z, Slavik T,
PMID:9236838 report. Neurol Med Chir (Tokyo). 30(4):263-7. Schluter D, Spieker T, Van Roost D, Schaller Kruger H (2011). Toothy craniopharyngioma:
1674. Min KW, Scheithauer BW, Bauserman SC PMID:1696697 C, et al. (1999). Primary central nervous system a literature review and case repod of cranio-
(1994). Pineal parenchymal tumors: an ultra- 1690. Miyata H, Chiang AC, Vinters HV (2004). lymphomas are derived from germinal-center B pharyngioma with extensive odontogenic diffe-
structural study with prognostic implications. Ul- Insulin signaling pathways in cortical dysplasia cells and show a preferential usage of the V4- rentiation and tooth formation. Childs Nerv Syst.
trastruct Pathol. 18(1-2):69-85. PMID:8191649 and TSC-tubers: tissue microarray analysis. 34 gene segment. Am J Pathol. 155(6):2077- 27(2):323-6. PMID:20922394
1675. Min KW, Seo IS, Song J (1987). Post- Ann Neurol. 56(4):510-9. PMID:15455398 86. PMID:10595937 1722. Mullins KJ, Rubio A, Myers SP, Korones
natal evolution of the human pineal gland. 1691. Miyata H, Ryufuku M, Kubota Y, Ochiai 1706. Montesinos-Rongen M, Schmitz R, Brunn DN, Pilcher WH (1998). Malignant ependymo-
An immunohistochemical study. Lab Invest. T, Niimura K, Hori T (2012). Adult-onset angio- A, Gesk S, Richter J, Hong K, et al. (2010). mas in a patient with Turcot's syndrome: case
57(6):724-8. PMID:3695415 centric glioma of epithelioid cell-predominant Mutations of CARD11 but not TNFAIP3 may ac- repori and management guidelines. Surg Neu-
1676. Minaguchi T, Waite KA, Eng C (2006). type of the mesial temporal lobe suggestive tivate the NF-kappaB pathway in primary CNS rol. 49(3):290-4. PMID:9508117
Nuclear localization of PTEN is regulated by of a rare but distinct clinicopathological subset lymphoma. Acta Neuropathol. 120(4):529-35. 1723. Mur P, Mollejo M, Ruano Y, de Lope AR,
Ca(2+) through a tyrosil phosphorylation-inde- within a spectrum of angiocentric cortical epen- PMID:20544211 Fiano C, Garcia JF, et al. (2013). Codeletion of
pendent conformational modification in major dymal tumors. Neuropathology. 32(5):479-91. 1707. Montesinos-Rongen M, Schmitz R, 1p and 19q determines distinct gene methyla-
vault protein. Cancer Res. 66(24): 11677-82. PMID:22151480 Couris C, Stenzel W, Bechtel D, Niedobitek G, tion and expression profiles in IDH-mutated
PMID:17178862 1692. Mizoguchi M, Nutt CL, Mohapatra G, et al. (2005). Absence of immunoglobulin class oligodendroglial tumors. Acta Neuropathol.
1677. Minehan KJ, Brown PD, Scheithauer Louis DN (2004). Genetic alterations of phos- switch in primary lymphomas of the central 126(2):277-89. PMID:23689617
BW, Krauss WE, Wright MP (2009). Progno- phoinositide 3-kinase subunit genes in human nervous system. Am J Pathol. 166(6):1773-9. 1724. Murali R, Wiesner T, Rosenblum MK,
sis and treatment of spinal cord astrocytoma. glioblastomas. Brain Pathol. 14(4):372-7. PMID:15920162 Bastian BC (2012). GNAQ and GNA11 muta-
Int J Radiat Oncol Biol Phys. 73(3):727-33. PMID:15605984 1708. Montesinos-Rongen M, Schafer E, Sie- tions in melanocytomas of the central nervous
PMID:18687533 1693. Mizuguchi M, Ikeda K, Takashima S bert R, Decked M (2012). Genes regulating system. Acta Neuropathol. 123(3):457-9.
1678. Minehan KJ, Shaw EG, Scheithauer (2000). Simultaneous loss of hamartin and the B cell receptor pathway are recurrently PMID:22307269
BW, Davis DL, Onofrio BM (1995). Spinal tuberin from the cerebrum, kidney and heart mutated in primary central nervous system 1725. Murray JM, Morgello S (2004). Polyo-
cord astrocytoma: pathological and treatment with tuberous sclerosis. Acta Neuropathol. lymphoma. Acta Neuropathol. 124(6):905-6. maviruses and primary central nervous sys-
considerations. J Neurosurg. 83(4):590-5. 99(5):503-10. PMID:10805093 PMID:23138649 tem lymphomas. Neurology. 63(7): 1299-301.
PMID:7674006 1694. Mizuguchi M, Kato M, Yamanouchi H, 1709. Montesinos-Rongen M, Van Roost D, PMID:15477558
1678A. Ming JE, Kaupas ME, Roessler E, Ikeda K, Takashima S (1996). Loss of tuberin Schaller C, Wiestler OD, Decked M (2004). Pri- 1726. Mudhy A, Gonzalez-Agosti C, Cordero E,
Brunner HG, Golabi M, Tekin M, et al. (2002). from cerebral tissues with tuberous sclerosis mary diffuse large B-cell lymphomas of the cen- Pinney D, Candia C, Solomon F, et al. (1998).
Mutations in PATCHED-1, the receptor for and astrocytoma. Ann Neurol. 40(6):941^1. tral nervous system are targeted by aberrant NHE-RF, a regulatory cofactor for Na(+)-H+
SONIC HEDGEHOG, are associated with ho- PMID:9007104 somatic hypermutation. Blood. 103(5):1869-75. exchange, is a common interactor for mer-
loprosencephaly. Hum Genet. 110(4):297-301. 1695. Mizuno J, Iwata K, Takei Y (1993). Im- PMID:14592832 lin and ERM (MERM) proteins. J Biol Chem.
PMID:11941477 munohistochemical study of hemangioblastoma 1710. Montesinos-Rongen M, Zuhlke-Jenisch 273(3):1273-6. PMID:9430655
382 References
1727. Mustafa D, Swagemakers S, French P, paraganglioma: a case report and review of Pleomorphic xanthoastrocytoma in two siblings imaging. J Neurooncol. 121(1):209-15.
Luider TM, van der Spek P, Kremer A, et al. the literature. Neuroradiology. 47(10):753-7. with neurofibromatosis type 1 (NF-1). Clin Neu- PMID:25293439
(2013). Structural and expression differences PMID:16047139 ropathol. 31(1):54-6. PMID:22192706 1779. Nguyen SA, Stechishin OD, Luchman
between the vasculature of pilocytic astrocyto- 1743. Nair S, Fort JA, Yachnis AT, Williams CA 1762. Neelima R, Easwer HV, Kapilamoorthy HA, Lun XQ, Senger DL, Robbins SM, et
mas and glioblastomas. J Neuropathol Exp (2015). Optic nerve pilomyxoid astrocytoma in TR, Hingwala DR, Radhakrishnan VV (2012). al. (2014). Novel MSH6 mutations in treat-
Neurol. 72(12):1171-81. PMID:24226271 a patient with Noonan syndrome. Pediatr Blood Embryonal tumor with multilayered rosettes: ment-naive glioblastoma and anaplastic oli-
1728. Mut M, Schiff D, Shaffrey ME (2005). Cancer. 62(6):1084-6. PMID:25585602 Two case reports with a review of the literature. godendroglioma contribute to temozolomide
Metastasis to nervous system: spinal epidural 1744. Naitoh Y, Sasajima T, Kinouchi H, Mika- Neurol India. 60(1 ):96-9. PMID:22406791 resistance independently of MGMT promoter
and intramedullary metastases. J Neurooncol. wa S, Mizoi K (2002). Medulloblastoma with 1763. Neff BA, Willcox TO Jr, Sataloff RT methylation. Clin Cancer Res. 20(18)4894-
75(1):43-56. PMID:16215815 extensive nodularity: single photon emission (2003). Intralabyrinthine schwannomas. Otol 903. PMID:25078279
1729. Myers MP, Stolarov JP, Eng C, Li J, Wang CT study with iodine-123 metaiodobenzylgua- Neurotol. 24(2):299-307. PMID42621348 1780. Ni HC, Chen SY, Chen L, Lu DH, Fu YJ,
SI, Wigler MH, et al. (1997). P-TEN, the tumor nidine. AJNR Am J Neuroradiol. 23(9):1564-7. 1764. Nelen MR, Kremer H, Konings IB, Schou- Piao YS (2015). Angiocentric glioma: a report of
suppressor from human chromosome 10q23, is PMID:12372749 te F, van Essen AJ, Koch R, et al. (1999). No- nine new cases, including four with atypical his-
a dual-specificity phosphatase. Proc Natl Acad 1745. Najm I, Jehi L, Palmini A, Gonzalez-Mar- vel PTEN mutations in patients with Cowden tological features. Neuropathol Appl Neurobiol.
Sci U S A . 94(17):9052-7. PMID:9256433 tinez J, Paglioli E, Bingaman W (2013). Tem- disease: absence of clear genotype-phenotype 41 (3):333-46. PMID:24861831
1730. Muller HL, Gebhardt U, Teske C, Faldum poral patterns and mechanisms of epilepsy correlations. Eur J Hum Genet. 7(3):267-73. 1781. Ni Y, He X, Chen J, Moline J, Mester J,
A, Zwiener I, Warmuth-Metz M, et al.; Study surgery failure. Epilepsia. 54(5):772-82. PMID40234502 Orloff MS, et al. (2012). Germline SDHx vari-
Committee of KRANIOPHARYNGEOM 2000 PMID:23586531 1765. Nelen MR, Padberg GW, Peeters EA, Lin ants modify breast and thyroid cancer risks in
(2011) . Post-operative hypothalamic lesions 1746. Nakagawa Y, Perentes E, Rubinstein LJ AY, van den Helm B, Frants RR, et al. (1996). Cowden and Cowden-like syndrome via FAD/
and obesity in childhood craniopharyngioma: (1986). Immunohistochemical characterization Localization of the gene for Cowden disease to NAD-dependant destabilization of p53. Hum
results of the multinational prospective trial of oligodendrogliomas: an analysis of multi- chromosome 10q22-23. Nat Genet. 13(1):114- Mol Genet. 21(2):300-10. PMID:21979946
KRANIOPHARYNGEOM 2000 after 3-year ple markers. Acta Neuropathol. 72(1):15-22. 6. PMID:8673088 1782. Ni Y, Zbuk KM, Sadler T, Patocs A,
follow-up. Eur J Endocrinol. 165(1):17-24. PMID:2435103 1766. Nelen MR, van Staveren WC, Pee- Lobo G, Edelman E, et al. (2008). Germline
PMID:21490122 1747. Nakagawa Y, Perentes E, Rubinstein ters EA, Hassel MB, Gorlin RJ, Hamm H, et mutations and variants in the succinate dehy-
1731. Myung JK, Byeon SJ, Kim B, Suh J, Kim LJ (1987). Non-specificity of anti-carbonic al. (1997). Germline mutations in the PTEN/ drogenase genes in Cowden and Cowden-like
SK, Park CK, et al. (2011). Papillary glioneu- anhydrase C antibody as a marker in human MMAC1 gene in patients with Cowden disease. syndromes. Am J Hum Genet. 83(2):261-8.
ronal tumors: a review of clinicopathologic and neurooncology, J Neuropathol Exp Neurol. Hum Mol Genet. 6(8):1383-7. PMID:9259288 PMID:18678321
molecular genetic studies. Am J Surg Pathol. 46(4):451-60. PMID:3110380 1767. Nemes Z (1992). Fibrohistiocytic diffe- 1783. Nieder C, Spanne O, Mehta MP, Grosu
35(12):1794-805. PMID:22020040 1748. Nakama S, Higashi T, Kimura A, Yama- rentiation in capillary hemangioblastoma. Hum AL, Geinitz H (2011). Presentation, patterns of
1732. Myung JK, Cho HJ, Park CK, Chung muro K, Kikkawa I, Hoshino Y (2005). Double Pathol. 23(7):805-10. PMID4351864 care, and survival in patients with brain metas-
CK, Choi SH, Kim SK, et al. (2013). Clinico- myxopapillary ependymoma of the cauda equi- 1768. Nestor SL, Perry A, Kurtkaya O, Abell-AI- tases: what has changed in the last 20 years?
pathological and genetic characteristics of ex- na. J Orthop Sci. 10(5):543-5. PMID:16193371 eff P, Rosemblat AM, Burger PC, et al. (2003). Cancer. 117(11):2505-12. PMID:24048799
traventricular neurocytomas. Neuropathology. 1749. Nakamura M, Chiba K, Matsumoto M, Melanocytic colonization of a meningothelial 1784. Nielsen EH, Feldt-Rasmussen U, Pouls-
33(2):111-21. PMID:22672632 Ikeda E, Toyama Y (2006). Pleomorphic xan- meningioma: histopathological and ultra- gaard L, Kristensen LO, Astrup J, Jorgensen
1733. Mollemann M, Wolter M, Felsberg J, thoastrocytoma of the spinal cord. Case report. structural findings with immunohistochemical JO, et al. (2011). Incidence of craniopharyn-
Collins VP, Reifenberger G (2005). Frequent J Neurosurg Spine. 5(1):72-5. PMID:16850961 and genetic correlation: case report. Neu- gioma in Denmark (n = 189) and estimated
promoter hypermethylation and low expression 1751. Nakamura M, Saeki N, Iwadate Y, Suna- rosurgery. 53(1):211-4, discussion 214-5. world incidence of craniopharyngioma in child-
of the MGMT gene in oligodendroglial tumors. mi K, Osato K, Yamaura A (2000). Neurora- PMID:12823892 ren and adults. J Neurooncol. 104(3):755-63.
Int J Cancer. 113(3):379-85. PMID:15455350 diological characteristics of pineocytoma and 1769. Neumann HP, Eggert HR, Weigel K, Frie- PMID:21336771
1734. Mark SJ, Rubinstein LJ, Kepes JJ, Pe- pineoblastoma. Neuroradiology. 42(7):509-14. dburg H, Wiestler OD, Schollmeyer P (1989). 1785. Nielsen GP, Stemmer-Rachamimov AO,
rentes E, Uphoff DF (1988). Patterns of epithe- PMID:10952183 Hemangioblastomas of the central nervous Ino Y, Moller MB, Rosenberg AE, Louis DN
lial metaplasia in malignant gliomas. II. Squa- 1752. Nakamura M, Watanabe T, Klangby U, system. A 10-year study with special reference (1999). Malignant transformation of neurofi-
mous differentiation of epithelial-like formations Asker C, Wiman K, Yonekawa Y, et al. (2001). to von Hippel-Lindau syndrome. J Neurosurg. bromas in neurofibromatosis 1 is associated
in gliosarcomas and glioblastomas. J Neuropa- p14ARF deletion and methylation in genetic 70(1):24-30. PMID:2909683 with CDKN2A/p16 inactivation. Am J Pathol.
thol Exp Neurol. 47(2)401-18. PMID:3339369 pathways to glioblastomas. Brain Pathol. 1770. Neves S, Mazal PR, Wanschitz J, Rud- 155(6)4879-84. PMID40595918
1735. Nagai S, Kurimoto M, Ishizawa S, 11(2):159-68. PMID:11303791 nay AC, Drlicek M, Czech T, et al. (2001). Pseu- 1786. Nieuwenhuis MH, Kets CM, Murphy-Ryan
Hayashi N, Hamada H, Kamiyama H, et al. 1753. Nakamura M, Watanabe T, Yonekawa dogliomatous growth pattern of anaplastic small M, Yntema HG, Evans DG, Colas C, et al.
(2009). A rare astrocytic tumor with rhabdoid Y, Kleihues P, Ohgaki H (2001). Promoter cell carcinomas metastatic to the brain. Clin (2014). Cancer risk and genotype-phenotype
features. Brain Tumor Pathol. 26(1):19-24. methylation of the DNA repair gene MGMT Neuropathol. 20(1):38-42. PMID41220694 correlations in PTEN hamartoma tumor syndro-
PMID:19408093 in astrocytomas is frequently associated with 1771. Newcomb EW, Madonia WJ, Pisharody me. Fam Cancer. 13(1):57-63. PMID:23934601
1736. Nagaishi M, Kim YH, Mittelbronn M, G:C -> A:T mutations of the TP53 tumor sup- S, Lang FF, Koslow M, Miller DC (1993). A cor- 1787. Niida Y, Stemmer-Rachamimov AO, Lo-
Giangaspero F, Paulus W, Brokinkel B, et al. pressor gene. Carcinogenesis. 22(10):1715-9. relative study of p53 protein alteration and p53 grip M, Tapon D, Perez R, Kwiatkowski DJ, et
(2012) . Amplification of the STOML3, FREM2, PMID:11577014 gene mutation in glioblastoma multiforme. Brain al. (2001). Survey of somatic mutations in tu-
and LHFP genes is associated with mesenchy- 1754. Nakamura M, Yang F, Fujisawa H, Pathol. 3(3):229-35. PMID:8293182 berous sclerosis complex (TSC) hamartomas
mal differentiation in gliosarcoma. Am J Pathol. Yonekawa Y, Kleihues P, Ohgaki H (2000). 1772. Newton HB, Dalton J, Ray-Chaudhury A, suggests different genetic mechanisms for pa-
180(5):1816-23. PMID:22538188 Loss of heterozygosity on chromosome 19 in Gahbauer R, McGregor J (2008). Aggressive thogenesis of TSC lesions. Am J Hum Genet.
1737. Nagaishi M, Paulus W, Brokinkel B, Vital secondary glioblastomas. J Neuropathol Exp papillary glioneuronal tumor: case report and 69(3)493-503. PMID:11468687
A, Tanaka Y, Nakazato Y, et al. (2012). Tran- Neurol. 59(6):539-43. PMID:10850866 literature review. Clin Neuropathol. 27(5):317- 1788. Niiro T, Tokimura H, Hanaya R, Hirano
scriptional factors for epithelial-mesenchymal 1755. Nakamura M, Yonekawa Y, Kleihues P, 24. PM ID: 18808063 H, Fukukura Y, Sugiyma K, et al. (2012). MRI
transition are associated with mesenchymal Ohgaki H (2001). Promoter hypermethylation 1773. Ng HK, Lo ST (1989). Cytokeratin Im- findings in patients with central neurocytomas
differentiation in gliosarcoma. Brain Pathol. of the RB1 gene in glioblastomas. Lab Invest. munoreactivity in gliomas. Histopathology. with special reference to differential diagnosis
22(5):670-6. PMID:22288519 81(1)77-82. PMID:11204276 14(4):359-68. PMID:2472343 from other ventricular tumours near the fora-
1738. Nagaishi M, Yokoo H, Nobusawa S, Fujii 1756. Nakano I (2015). Stem cell signature in 1774. Ng HK, Poon WS (1990). Gliosarcoma of men of Monro. J Clin Neurosci. 19(5):681-6.
Y, Sugiura Y, Suzuki R, et al. (2015). Localized glioblastoma: therapeutic development for a the posterior fossa with features of a malignant PMID:22410173
overexpression of alpha-internexin within no- moving target. J Neurosurg. 122(2):324-30. fibrous histiocytoma. Cancer. 65(5):1161-6. 1789. Nishikawa R, Furnari FB, Lin H, Arap W,
dules in multinodular and vacuolating neuronal PMID:25397368 PMID:2154322 Berger MS, Cavenee WK, et al. (1995). Loss
tumors. Neuropathology. PMID:26073706 1757. Narod SA, Parry DM, Parboosingh J, Le- 1775. Ng HK, Poon WS (1999). Diffuse lepto- of P16INK4 expression is frequent in high
1739. Nagao K, Togawa N, Fujii K, Uchikawa noir GM, Ruttledge M, Fischer G, et al. (1992). meninges! gliomatosis with oligodendroglioma. grade gliomas. Cancer Res. 55(9)4941-5.
H, Kohno Y, Yamada M, et al. (2005). Detecting Neurofibromatosis type 2 appears to be a ge- Pathology. 31(1):59-63. PMID:10212927 PMID:7728764
tissue-specific alternative splicing and disea- netically homogeneous disease. Am J Hum 1776. Ng TH, Fung CF, Ma LT (1990). The pa- 1790. Nishimoto T, Kaya B (2012). Cerebel-
se-associated aberrant splicing of the PTCH Genet. 51(3)486-96. PMID4496982 thological spectrum of desmoplastic infantile lar liponeurocytoma. Arch Pathol Lab Med.
gene with exon junction microarrays. Hum Mol 1758. National Institutes of Health Consensus gangliogliomas. Histopathology. 16(3):235-41. 136(8):965-9. PMID:22849747
Genet. 14(22):3379-88. PMID:16203740 Development Conference (1988). Neurofibro- PMID:2332209 1791. Nishio S, Morioka T, Inamura T, Takes-
1740. Nagao K, Toyoda M, Takeuchi-lnoue K, matosis. Conference statement. Arch Neurol. 1777. Ngeow J, Mester J, Rybicki LA, Ni Y, Milas hita I, Fukui M, Sasaki M, et al. (1998). Radi-
Fujii K, Yamada M, Miyashita T (2005). Identifi- 45(5):575-8. PMID:3128965 M, Eng C (2011). Incidence and clinical charac- ation-induced brain tumours: potential late
cation and characterization of multiple isoforms 1759. Nauen D, Haley L, Lin MT, Perry A, Gian- teristics of thyroid cancer in prospective series complications of radiation therapy for brain tu-
of a murine and human tumor suppressor, nini C, Burger PC, etal. (2015). Molecular Ana- of individuals with Cowden and Cowden-like mours. Acta Neurochir (Wien). 140(8):763-70.
patched, having distinct first exons. Genomics. lysis of Pediatric Oligodendrogliomas Highlights syndrome characterized by germline PTEN, PMID:9810442
85(4):462-71. PMID:15780749 Genetic Differences with Adult Counterparts SDH, or KLLN alterations. J Clin Endocrinol 1792. Nishio S, Takeshita I, Kaneko Y, Fukui M
1741. Nagashima T, Hoshino T, Cho KG (1987). and Other Pediatric Gliomas. Brain Pathol. Metab. 96(12):E2063-71. PMID:21956414 (1992). Cerebral neurocytoma. A new subset of
Proliferative potential of vascular components PMID:26206478 1778. Nguyen R, Dombi E, Akshintala S, Bald- benign neuronal tumors of the cerebrum. Can-
in human glioblastoma multiforme. Acta Neuro- 1760. Nayak L, Abrey LE, Iwamoto FM win A, Widemann BC (2015). Characterization cer. 70(2):529-37. PMID4617603
pathol. 73(3):301-5. PMID:3039783 (2009). Intracranial dural metastases. Cancer. of spinal findings in children and adults with 1793. Nitta H, Hayase H, Moriyama Y, Ya-
1742. Naggara O, Varlet P, Page P, Op- 115(9): 1947-53. PMID49241421 neurofibromatosis type 1 enrolled in a natu- mashima T, Yamashita J (1993). Gliosarcoma
penheim C, Meder JF (2005). Suprasellar 1761. Neal MT, Ellis TL, Stanton CA (2012). ral history study using magnetic resonance of the posterior cranial fossa: MRI findings.
References 383
Neuroradiology. 35(4):279-80. PMID:8492894 49(4):243-54. PMID:24053982 oligodendroglial gliomas. J Neuropathol Exp hypotheses on the etiology of cancer. IARC Sci
1794. Noble M, Wren D, Wolswijk G (1992). The 1810. Noushmehr H, Weisenberger DJ, Diefes Neurol. 64(6):479-89. PMID:15977639 Publ. 157:247-70. PMID:15055300
0-2A(adult) progenitor cell: a glial stem cell of K, Phillips HS, Pujara K, Berman BP, et al.; Can- 1827. Ohgaki H, Kleihues P (2007). Genetic pa- 1844. Olschwang S, Serova-Sinilnikova OM,
the adult central nervous system. Semin Cell cer Genome Atlas Research Network (2010). thways to primary and secondary glioblastoma. Lenoir GM, Thomas G (1998). PTEN germ-line
Biol. 3(6):413-22. PMID:1489973 Identification of a CpG island methylator pheno- Am J Pathol. 170(5):1445-53. PMID:17456751 mutations in juvenile polyposis coli. Nat Genet.
1795. Nobusawa S, Hirato J, Kurihara H, Oga- type that defines a distinct subgroup of glioma. 1828. Ohgaki H, Kleihues P (2009). Genetic 18(1):12-4. PMID:9425889
wa A, Okura N, Nagaishi M, et al. (2014). In- Cancer Cell. 17(5):510-22. PMID:20399149 alterations and signaling pathways in the evo- 1845. Olson JD, Riedel E, DeAngelis LM
tratumoral heterogeneity of genomic imbalance 1811. Numoto RT (1994). Pineal parenchy- lution of gliomas. Cancer Sci. 100(12):2235-41. (2000). Long-term outcome of low-grade oli-
in a case of epithelioid glioblastoma with BRAF mal tumors: cell differentiation and prognosis. PMID:19737147 godendroglioma and mixed glioma. Neurology.
V600E mutation. Brain Pathol. 24(3):239-46. J Cancer Res Clin Oncol. 120(11 ):683-90. 1829. Ohgaki H, Kleihues P (2011). Genetic 54(7):1442-8. PMID:10751254
PMID:24354918 PMID:7525594 profile of astrocytic and oligodendroglial gli- 1846. Olson JM, Breslow NE, Barce J (1993).
1796. Nobusawa S, Orimo K, Horiguchi K, Ikota 1812. Nutt CL, Mani DR, Betensky RA, Ta- omas. Brain Tumor Pathol. 28(3):177-83. Cancer in twins of Wilms tumor patients. Am J
H, Yokoo H, Hirato J, et al. (2014). Embryonal mayo P, Cairncross JG, Ladd C, et al. (2003). PMID:21442241 Med Genet. 47(1):9M. PMID:8396323
tumor with abundant neuropil and true rosettes Gene expression-based classification of ma- 1830. Ohgaki H, Kleihues P (2013). The definiti- 1847. Onda K, Davis RL, Wilson CB, Hoshino T
with only one structure suggestive of an epen- lignant gliomas correlates better with survival on of primary and secondary glioblastoma. Clin (1994). Regional differences in bromodeoxyu-
dymoblastic rosette. Pathol Int. 64(9):472-7. than histological classification. Cancer Res. Cancer Res. 19(4):764-72. PMID:23209033 ridine uptake, expression of Ki-67 protein, and
PMID:25186165 63(7): 1602-7. PMID:12670911 1831. Ojha BK, Sharma MC, Rastogi M, nucleolar organizer region counts in glioblasto-
1797. Nobusawa S, Watanabe T, Kleihues P, 1813. O'Malley S, Weitman D, Olding M, Sek- Chandra A, Husain M, Husain N (2007). Dum- ma multiforme. Acta Neuropathol. 87(6):586-
Ohgaki H (2009). IDH1 mutations as molecular har L (1997). Multiple neoplasms following bbell-shaped paraganglioma of the cervical 93. PMID:8091951
signature and predictive factor of secondary gli- craniospinal irradiation for medulloblastoma in spine in a child. Pediatr Neurosurg. 43(1 ):60-4. 1848. Ongiiru O, Deveci S, Sirin S, Timurkay-
oblastomas. Clin Cancer Res. 15(19):6002-7. a patient with nevoid basal cell carcinoma syn- PMID:17190992 nak E, Giinhan O (2003). Dysembryoplastic
PMID:19755387 drome. Case report. J Neurosurg. 86(2):286-8. 1832. Okada M, Yano H, Hirose Y, Nakayama neuroepithelial tumor in the left lateral vent-
1798. Nobusawa S, Yokoo H, Hirato J, Kakita A, PMID:9010431 N, Ohe N, Shinoda J, etal. (2011). Olig2 is use- ricle. Minim Invasive Neurosurg. 46(5):306-9.
Takahashi H, Sugino T, et al. (2012). Analysis 1814. O’Marcaigh AS, Ledger GA, Roche PC, ful in the differential diagnosis of oligodendrogli- PMID:14628248
of chromosome 19q13.42 amplification in em- Parisi JE, Zimmerman D (1995). Aromatase omas and extraventricular neurocytomas. Brain 1849. Onilude OE, Lusher ME, Lindsey JC,
bryonal brain tumors with ependymoblastic mul- expression in human germinomas with possib- Tumor Pathol. 28(2):157-61. PMID:21312066 Pearson AD, Ellison DW, Clifford SC (2006).
tilayered rosettes. Brain Pathol. 22(5):689-97. le biological effects. J Clin Endocrinol Metab. 1833. Okada Y, Nishikawa R, Matsutani M, Lou- APC and CTNNB1 mutations are rare in spo-
PMID:22324795 80(12):3763-6. PMID:8530631 is DN (2002). Hypomethylated X chromosome radic ependymomas. Cancer Genet Cytogenet.
1799. Noell S, Beschorner R, Bisdas S, Beyer 1815. Oderich GS, Sullivan TM, Bower TC, gain and rare isochromosome 12p in diverse in- 168(2): 158-61. PMID:16843107
U, Weber RG, Fallier-Becker P, et al. (2014). Si- Gloviczki P, Miller DV, Babovic-Vuksanovic D, tracranial germ cell tumors. J Neuropathol Exp 1850. Oosterhuis JW, Stoop H, Honecker F,
multaneous subependymomas in monozygotic et al. (2007). Vascular abnormalities in patients Neurol. 61(6):531-8. PMID:12071636 Looijenga LH (2007). Why human extrago-
female twins: further evidence for a common with neurofibromatosis syndrome type I: clinical 1834. Okamoto Y, Di Patre PL, Burkhard C, nadal germ cell tumours occur in the midline
genetic or developmental disorder background. spectrum, management, and results. J Vase Horstmann S, Jourde B, Fahey M, et al. (2004). of the body: old concepts, new perspectives.
J Neurosurg. 121 (3):570-5. PMID:24655099 Surg. 46(3):475-84. PMID:17681709 Population-based study on incidence, survival Int J Androl. 30(4):256-63, discussion 263-4.
1800. Nolan MA, Sakuta R, Chuang N, Otsubo 1816. Ogiwara H, Dubner S, Shafizadeh S, rates, and genetic alterations of low-grade diffu- PMID:17705807
H, Rutka JT, Snead OC 3rd, et al. (2004). Raizer J, Chandler JP (2011). Spindle cell on- se astrocytomas and oligodendrogliomas. Acta 1851. Orloff MS, Eng C (2008). Genetic and
Dysembryoplastic neuroepithelial tumors cocytoma of the pituitary and pituicytoma: Two Neuropathol. 108(1):49-56. PMID:15118874 phenotypic heterogeneity in the PTEN hamarto-
in childhood: long-term outcome and prog- tumors mimicking pituitary adenoma. Surg Neu- 1835. Okita Y, Narita Y, Miyakita Y, Ohno M, ma tumour syndrome. Oncogene. 27(41):5387-
nostic features. Neurology. 62(12):2270-6. rol Int. 2:116. PMID:21886889 Matsushita Y, Fukushima S, et al. (2012). 97. PMID:18794875
PMID:15210893 1817. Ogura R, Aoki H, Natsumeda M, Shi- IDH 1/2 mutation is a prognostic marker for sur- 1852. Orloff MS, He X, Peterson C, Chen F,
1801. Nonoguchi N, Ohta T, Oh JE, Kim YH, mizu H, Kobayashi T, Saito T, et al. (2013). vival and predicts response to chemotherapy Chen JL, Mester JL, et al. (2013). Germline
Kleihues P, Ohgaki H (2013). TERT promoter Epstein-Barr virus-associated primary cen- for grade II gliomas concomitantly treated with PIK3CA and AKT1 mutations in Cowden and
mutations in primary and secondary gliob- tral nervous system cytotoxic T-cell lym- radiation therapy. Int J Oncol. 41 (4):1325-36. Cowden-like syndromes. Am J Hum Genet.
lastomas. Acta Neuropathol. 126(6):931-7. phoma. Neuropathology. 33(4):436^41. PMID:22825915 92(1):76-80. PMID:23246288
PMID:23955565 PMID:23279449 1836. Olar A, Wani KM, Alfaro-Munoz KD, He- 1853. Ortega A, Nuho M, Walia S, Mukherjee D,
1802. Nora FE, Scheithauer BW (1996). Pri- 1818. Oh D, Prayson RA (1999). Evaluation athcock LE, van Thuijl HF, Gilbert MR, et al. Black KL, Patil CG (2014). Treatment and survi-
mary epithelioid hemangioendothelioma of of epithelial and keratin markers in gliob- (2015). IDH mutation status and role of WHO val of patients harboring histological variants of
the brain. Am J Surg Pathol. 20(6):707-14. lastoma multiforme: an immunohistochemical grade and mitotic index in overall survival in glioblastoma. J Clin Neurosci. 21(10):1709-13.
PMID:8651350 study. Arch Pathol Lab Med. 123(10):917-20. grade ll-lll diffuse gliomas. Acta Neuropathol. PMID:24980627
1803. Norman MG, Harrison KJ, Poskitt KJ, Ka- PMID:10506444 129(4):585-96. PMID:25701198 1854. Ortega-Aznar A, Romero-Vidal FJ, de
lousek DK (1995). Duplication of 9P and hyper- 1819. Oh JE, Ohta T, Nonoguchi N, Satomi K, 1837. Olar A, Wani KM, Sulman EP, Mansouri la Torre J, Castellvi J, Nogues P (2001). Neo-
plasia of the choroid plexus: a pathologic, radio- Capper D, Pierscianek D, et al. (2015). Genetic A, Zadeh G, Wilson CD, et al. (2015). Mitotic natal tumors of the CNS: a report of 9 cases
logic, and molecular cytogenetics study. Pediatr alterations in gliosarcoma and giant cell gliob- Index is an Independent Predictor of Recurren- and a review. Clin Neuropathol. 20(5):181-9.
Pathol Lab Med. 15(1):109-20. PMID:8736601 lastoma. Brain Pathol. PMID:26443480 ce-Free Survival in Meningioma. Brain Pathol. PMID:11594502
1804. Northcott PA, Jones DT, Kool M, Ro- 1820. Oh T, Rutkowski MJ, Safaee M, Sun 25(3):266-75 PMID:25040885 1855. Oruckaptan HH, Berker M, Soylemezoglu
binson GW, Gilbertson RJ, Cho YJ, et al. MZ, Sayegh ET, Bloch O, et al. (2014). Sur- 1838. Oliveira AM, Scheithauer BW, Salomao F, Ozcan OE (2001). Parafalcine chondrosar-
(2012) . Medulloblastomics: the end of the vival outcomes of giant cell glioblastoma: DR, Parisi JE, Burger PC, Nascimento AG coma: an unusual localization for a classical
beginning. Nat Rev Cancer. 12(12):818-34. institutional experience in the management of (2002). Primary sarcomas of the brain and spi- variant. Case report and review of the literature.
PMID:23175120 20 patients. J Clin Neurosci. 21(12):2129-34. nal cord: a study of 18 cases. Am J Surg Pathol. Surg Neurol. 55(3):174-9. PMID:11311919
1805. Northcott PA, Korshunov A, Witt H, Hiel- PMID:25037316 26(8):1056-63. PMID:12170093 1856. Osawa T, Tosaka M, Nagaishi M, Yos-
scher T, Eberhart CG, Mack S, et al. (2011). 1821. Ohba Y, Mochizuki N, Yamashita S, Chan 1839. Oliver TG, Grasfeder LL, Carroll AL, himoto Y (2013). Factors affecting peritumoral
Medulloblastoma comprises four distinct mo- AM, Schrader JW, Hattori S, et al. (2000). Re- Kaiser C, Gillingham CL, Lin SM, et al. (2003). brain edema in meningioma: special histologi-
lecular variants. J Clin Oncol. 29(11):1408-14 gulatory proteins of R-Ras, TC21/R-Ras2, and Transcriptional profiling of the Sonic hedgehog cal subtypes with prominently extensive edema.
PMID:20823417 M-Ras/R-Ras3. J Biol Chem. 275(26):20020-6. response: a critical role for N-myc in proliferati- J Neurooncol. 111(1):49-57. PMID:23104516
1806. Northcott PA, Lee C, ZichnerT, Stutz AM, PMID:10777492 on of neuronal precursors. Proc Natl Acad Sci U 1857. Osborn AG, et al. (2004). Diagnostic Ima-
Erkek S, Kawauchi D, et al. (2014). Enhancer 1822. Ohgaki H, Burger P, Kleihues P (2014). S A. 100(12):7331-6. PMID:12777630 ging Brain, first Salt Lake City. Utah: Amirsys.
hijacking activates GFI1 family oncogenes in Definition of primary and secondary glioblasto- 1840. Oliver TG, Read TA, Kessler JD, Meh- 1858. Osorio JA, Hervey-Jumper SL, Walsh
medulloblastoma. Nature. 511(7510):428-34. ma-response. Clin Cancer Res. 20(7):2013. meti A, Wells JF, Huynh TT, et al. (2005). Loss KM, Clarke JL, Butowski NA, Prados MD, et
PMID:25043047 PMID:24557936 of patched and disruption of granule cell de- al. (2015). Familial gliomas: cases in two pairs
1807. Northcott PA, Shih DJ, Peacock J, Gar- 1823. Ohgaki H, Dessen P, Jourde B, Horst- velopment in a pre-neoplastic stage of medul- of brothers. J Neurooncol. 121(1): 135-40.
zia L, Morrissy AS, Zichner T, et al. (2012). mann S, Nishikawa T, Di Patre PL, et al. (2004). loblastoma. Development. 132(10):2425-39. PMID:25208478
Subgroup-specific structural variation across Genetic pathways to glioblastoma: a populati- PMID:15843415 1859. Ostendorf AP, Gutmann DH, Weisenberg
I, 000 medulloblastoma genomes. Nature. on-based study. Cancer Res. 64(19):6892-9. 1841. Olivier M, Goldgar DE, Sodha N, Oh- JL (2013). Epilepsy in individuals with neurofi-
488(7409):49-56. PMID:22832581 PMID:15466178 gaki H, Kleihues P, Hainaut P, et al. (2003). bromatosis type 1. Epilepsia. 54(10):1810-4.
1808. Northcott PA, Shih DJ, Remke M, Cho YJ, 1824. Ohgaki H, Eibl RH, Schwab M, Rei- Li-Fraumeni and related syndromes: correla- PMID:24032542
Kool M, Hawkins C, et al. (2012). Rapid, reliab- chel MB, Mariani L, Gehring M, et al. (1993). tion between tumor type, family structure, and 1860. Ostertun B, Wolf HK, Campos MG, Matus
le, and reproducible molecular sub-grouping of Mutations of the p53 tumor suppressor gene in TP53 genotype. Cancer Res. 63(20):6643-50. C, Solymosi L, Eiger CE, et al. (1996). Dysem-
clinical medulloblastoma samples. Acta Neuro- neoplasms of the human nervous system. Mol PMID:14583457 bryoplastic neuroepithelial tumors: MR and CT
pathol. 123(4):615-26. PMID:22057785 Carcinog. 8(2):74-80. PMID:8397797 1842. Olivier M, Hollstein M, Hainaut P (2010). evaluation. AJNR Am J Neuroradiol. 17(3):419-
1809. Northrup H, Krueger DA; International 1825. Ohgaki H, Kleihues P (2005). Epidemio- TP53 mutations in human cancers: origins, con- 30. PMID:8881234
Tuberous Sclerosis Complex Consensus Group logy and etiology of gliomas. Acta Neuropathol. sequences, and clinical use. Cold Spring Harb 1861. Ostrom QT, Bauchet L, Davis FG, De-
(2013) . Tuberous sclerosis complex diagno- 109(1 ):93-108. PMID:15685439 Perspect Biol. 2(1):a001008. PMID:20182602 Itour I, Fisher JL, Langer CE, et al. (2014). The
stic criteria update: recommendations of the 1826. Ohgaki H, Kleihues P (2005). Popu- 1843. Olivier M, Hussain SP, Caron de Fro- epidemiology of glioma in adults: a “state of the
2012 linternational Tuberous Sclerosis Com- lation-based studies on incidence, survival mentel C, Hainaut P, Harris CC (2004). TP53 science” review. Neuro Oncol. 16(7):896-913.
plex Consensus Conference. Pediatr Neurol. rates, and genetic alterations in astrocytic and mutation spectra and load: a tool for generating PMID:24842956
384 References
1862. Ostrom QT, de Blank PM, Kruchko C, J, Benelli M, Barbetti L, et al. (2015). Expanding 63 affected individuals and clinical evidence for treatment strategies for central neurocytoma.
Petersen CM, Liao P, Finlay JL, et al. (2015), the mutational spectrum of LZTR1 in schwan- heterogeneity. Am J Med Genet. 52(4):450-61. J Clin Neurosci. 20(9):1193-9. PMID:23810386
Alex’s Lemonade Stand Foundation Infant and nomatosis. Eur J Hum Genet. 23(7):963-8 PMID:7747758 1908. Patel N, Fallah A, Provias J, Jha NK
Childhood Primary Brain and Central Nervous PMID:25335493 1894. Parsa CF, Hoyt CS, Lesser RL, Wein- (2009). Cerebellar liponeurocytoma. Can J
System Tumors Diagnosed in the United States 1878. Pagni CA, Giordana MT, Canavero S stein JM, Strother CM, Muci-Mendoza R, et al. Surg. 52(4):E117-9. PMID:19680499
in 2007-2011. Neuro Oncol. 16 Suppl 10:x1- (1991). Benign recurrence of a pilocytic cere- (2001). Spontaneous regression of optic glio- 1909. Patil S, Perry A, Maccollin M, Dong S,
36. PMID:25542864 bellar astrocytoma 36 years after radical remo- mas: thirteen cases documented by serial neu- Betensky RA, Yeh TH, et al. (2008). Immunohis-
1862A. Ostrom QT, Gittleman H, Farah P, val: case report. Neurosurgery. 28(4):606-9. roimaging, Arch Ophthalmol. 119(4):516-29. tochemical analysis supports a role for INI1/SM-
Ondracek A, Chen Y, Wolinsky Y, et al. (2013). PMID:2034360 PMID:11296017 ARCB1 in hereditary forms of schwannomas,
CBTRUS statistical report: Primary brain and 1879. Pagon RA, Adam MP, Ardinger HH, et 1895. Parsons DW, Jones S, Zhang X, Lin JC, but not in solitary, sporadic schwannomas.
central nervous system tumors diagnosed in al. (1993-2015).GeneReviews® [Internet]. Leary RJ, Angenendt P, et al. (2008). An inte- Brain Pathol. 18(4):517-9. PMID:18422762
the United States in 2006-2010. Neuro Oncol. [Updated 2014 Mar 27], Seattle: University of grated genomic analysis of human glioblasto- 1910. Patil S, Scheithauer BW, Strom RG, Maf-
15 Suppl 2:ii1-56. PMID:24137015 Washington, ma multiforme. Science. 321 (5897):1807-12. ra M, Chicoine MR, Perry A (2011). Malignant
1863. Ostrom QT, Gittleman H, Liao P, Rouse 1880. Pajtler KW, Witt H, Sill M, Jones DT, Ho- PMID:18772396 meningiomas with epithelial (adenocarcino-
C, Chen Y, Dowling J, et al. (2014). CBTRUS vestadt V, Kratochwil F, et al. (2015). Molecular 1896. Partap S, Curran EK, Propp JM, Le ma-like) metaplasia: a study of 3 cases. Neuro-
statistical report: primary brain and central ner- Classification of Ependymal Tumors across All GM, Sainani KL, Fisher PG (2009), Medullob- surgery. 69(4):884-92. PMID:21558975
vous system tumors diagnosed in the United CNS Compartments, Histopathological Grades, lastoma incidence has not changed over time: 1911. Patsalides AD, Atac G, Hedge U, Janik
States in 2007-2011. Neuro Oncol. 16 Suppl and Age Groups. Cancer Cell. 27(5):728-43. a CBTRUS study. J Pediatr Hematol Oncol. J, Grant N, Jaffe ES, et al. (2005). Lymphoma-
4:iv1-63. PMID:25304271 PMID:25965575 31(12):970-1. PMID:19887963 toid granulomatosis: abnormalities of the brain
1864. Ota S, Crabbe DC, Tran TN, Triche TJ, 1881. Pakos EE, Goussia AC, Zina VP, Pitouli 1897. Pascual-Castroviejo I, Pascual-Pascual at MR imaging. Radiology. 237(1 ):265-73.
Shimada H (1993). Malignant rhabdoid tumor, EJ, Tsekeris PG (2005). Multi-focal gliosarco- SI, Viano J, Velazquez-Fragua R, Lopez-Gu- PMID:16100084
A study with two established cell lines. Cancer, ma: a case report and review of the literature. J tierrez JC (2012). Bilateral spinal neurofibromas 1912. Paulli M, Bergamaschi G, Tonon L, Viglio
71 (9):2862-72. PMID:8385567 Neurooncol. 74(3):301-4. PMID:16086111 in patients with neurofibromatosis 1. Brain Dev. A, Rosso R, Facchetti F, et al. (1995). Evidence
1865. Otero JJ, Rowitch D, Vandenberg S 1882. Palma L, Russo A, Celli P (1984). Pro- 34(7):563-9. PMID:21999966 for a polyclonal nature of the cell infiltrate in si-
(2011). OLIG2 is differentially expressed in pe- gnosis of the so-called “diffuse" cerebellar 1898. Pasini B, McWhinney SR, Bei T, Ma- nus histiocytosis with massive lymphadenopa-
diatric astrocytic and in ependymal neoplasms. astrocytoma. Neurosurgery. 15(3):315-7. tyakhina L, Stergiopoulos S, Muchow M, et thy (Rosai-Dorfman disease). Br J Haematol.
J Neurooncol. 104(2):423-38. PMID:21193945 PMID:6483145 al. (2008). Clinical and molecular genetics of 91(2):415-8. PMID:8547085
1866. Ouladan S, Trautmann M, Orouji E, Hart- 1883. Palmero El, Achatz Ml, Ashton-Prolla patients with the Carney-Stratakis syndrome 1913. Paulus W, BayasA, Ott G, RoggendorfW
mann W, Huss S, Buttner R, et al. (2015). Dif- P, Olivier M, Hainaut P (2010). Tumor protein and germline mutations of the genes coding for (1994). Interphase cytogenetics of glioblastoma
ferential diagnosis of solitary fibrous tumors: A 53 mutations and inherited cancer: beyond the succinate dehydrogenase subunits SDHB, and gliosarcoma. Acta Neuropathol. 88(5):420-
study of 454 soft tissue tumors indicating the di- Li-Fraumeni syndrome. Curr Opin Oncol. SDHC, and SDHD. Eur J Hum Genet. 16(1):79- 5. PMID:7847070
agnostic value of nuclear STAT6 relocation and 22(1):64-9. PMID:19952748 88. PMID:17667967 1914. Paulus W, Honegger J, Keyvani K, Fahl-
ALDH1 expression combined with in situ pro- 1884. Panageas KS, Reiner AS, Iwamoto 1899. Pasmant E, Masliah-Planchon J, Levy busch R (1999). Xanthogranuloma of the sellar
ximity ligation assay. Int J Oncol. 46(6):2595- FM, Cloughesy TF, Aldape KD, Rivera AL, et P, Laurendeau I, Ortonne N, Parfait B, et al. region: a clinicopathological entity different from
605. PMID:25901508 al. (2014). Recursive partitioning analysis of (2011). Identification of genes potentially in- adamantinomatous craniopharyngioma. Acta
1867. Owler BK, Makeham JM, Shingde M, prognostic variables in newly diagnosed ana- volved in the increased risk of malignancy in Neuropathol. 97(4):377-82. PMID:10208277
Besser M (2005). Cerebellar liponeurocytoma. plastic oligodendroglial tumors. Neuro Oncol. NF1-microdeleted patients. Mol Med. 17(1- 1915. Paulus W, Jellinger K, Hallas C, Ott G,
J Clin Neurosci. 12(3):326-9. PMID:15851097 16(11):1541-6. PMID:24997140 2):79-87. PMID:20844836 Muller-Hermelink HK (1993). Human herpesvi-
1868. Owonikoko TK, Arbiser J, Zelnak A, Shu 1885. Pantazis G, Harter PN, Capper D, Kohl- 1900. Pasquale G, Maria BA, Vania P, Gas- rus-6 and Epstein-Barr virus genome in primary
HK, Shim H, Robin AM, et al. (2014). Current hof P, Mittelbronn M, Schittenhelm J (2014). tone P, Nicola DL (2009). Cerebellar lipon- cerebral lymphomas. Neurology. 43(8):1591-3.
approaches to the treatment of metastatic brain The embryonic stem cell factor UTF1 serves eurocytoma: an updated follow-up of a case PMID:8394522
tumours. Nat Rev Clin Oncol. 11(4):203-22. as a reliable diagnostic marker for germinomas. presenting histopathological and clinically ag- 1916. Paulus W, Janisch W (1990). Clinicopa-
PMID:24569448 Pathology. 46(3):225-9. PMID:24614704 gressive features. Neurol India. 57(2):194-6. thologic correlations in epithelial choroid plexus
1869. Ozawa T, Brennan CW, Wang L, Squatrito 1886. Papanicolau-Sengos A, Wang-Rodriguez PMID:19439854 neoplasms: a study of 52 cases. Acta Neuropa-
M, Sasayama T, Nakada M, et al. (2010). PDG- J, Wang HY, Lee RR, Wong A, Hansen LA, et al. 1901. Pasquier B, Gasnier F, Pasquier D, Ked- thol. 80(6):635-41. PMID:1703384
FRA gene rearrangements are frequent genetic (2012). Rare case of a primary non-dural cent- dari E, Morens A, Couderc P (1986). Papillary 1917. Paulus W, Lisle DK, Tonn JC, Wolf HK,
events in PDGFRA-amplified glioblastomas. ral nervous system low grade B-cell lymphoma meningioma. Clinicopathologic study of seven Roggendorf W, Reeves SA, et al. (1996). Mo-
Genes Dev. 24(19):2205-18. PMID:20889717 and literature review. Int J Clin Exp Pathol. cases and review of the literature. Cancer. lecular genetic alterations in pleomorphic xan-
1870. Ozek MM, Sav A, Pamir MN, Ozer AF, 5(1 ):89-95. PMID:22295152 58(2):299-305. PMID:3719522 thoastrocytoma. Acta Neuropathol. 91(3):293-
Ozek E, Erzen C (1993). Pleomorphic xan- 1886A. Paraf F, Jothy S, Van Meir EG (1997). 1902. Pasquier B, Pasquier D, N'Golet A, Panh 7. PMID:8834542
thoastrocytoma associated with von Reckling- Brain tumor-polyposis syndrome: two ge- MH, Couderc P (1980). Extraneural metastases 1918. Paulus W, Schlote W, Perentes E, Jacobi
hausen neurofibromatosis. Childs Nerv Syst. netic diseases? J Clin Oncol. 15(7):2744-58. of astrocytomas and glioblastomas: clinicopa- G, Warmuth-Metz M, Roggendorf W (1992).
9(1 ):39-42. PMID:8481944 PMID:9215849 thological study of two cases and review of li- Desmoplastic supratentorial neuroepithelial
1871. Ozolek JA, Finkelstein SD, Couce ME 1887. Parham DM, Weeks DA, Beckwith JB terature. Cancer. 45(1):112-25. PMID:6985826 tumours of infancy. Histopathology. 21(1):43-9.
(2004). Gliosarcoma with epithelial differen- (1994). The clinicopathologic spectrum of puta- 1903. Pasquier B, Peoc'H M, Fabre-Bocquen- PMID:1634201
tiation: immunohistochemical and molecular tive extrarenal rhabdoid tumors. An analysis tin B, Bensaadi L, Pasquier D, Hoffmann D, et 1919. Paulus W, Slowik F, Jellinger K (1991).
characterization. A case report and review of 42 cases studied with immunohistochemis- al. (2002). Surgical pathology of drug-resistant Primary intracranial sarcomas: histopatho-
of the literature. Mod Pathol. 17(6):739-45. try or electron microscopy. Am J Surg Pathol. partial epilepsy. A 10-year-experience with a logical features of 19 cases. Histopathology.
PMID:15148503 18(10):1010-29. PMID:8092393 series of 327 consecutive resections. Epileptic 18(5):395-402. PMID:1715839
1872. Ozoren N, El-Deiry WS (2003). Cell sur- 1888. Park CK, Phi JH, Park SH (2015). Glial Disord. 4(2):99-119. PMID:12105073 1920. Pearce MS, Salotti JA, Little MP,
face Death Receptor signaling in normal and tumors with neuronal differentiation. Neurosurg 1904. Pasquier B, Peoc’h M, Morrison AL, Gay McHugh K, Lee C, Kim KP, et al. (2012). Ra-
cancer cells. Semin Cancer Biol. 13(2):135-47. Clin N Am. 26(1):117-38. PMID:25432191 E, Pasquier D, Grand S, et al. (2002). Chordoid diation exposure from CT scans in childhood
PMID:12654257 1889. Park DH, Park YK, Oh Jl, Kwon TH, glioma of the third ventricle: a report of two and subsequent risk of leukaemia and brain
1873. Padberg GW, Schot JD, Vielvoye GJ, Chung HS, Cho HD, et al. (2002). Oncocytic new cases, with further evidence supporting tumours: a retrospective cohort study. Lancet.
Bots GT, de Beer FC (1991). Lhermitte-Duclos paraganglioma of the cauda equina in a child. an ependymal differentiation, and review of the 380(9840):499-505. PMID:22681860
disease and Cowden disease: a single Case report and review of the literature. Pediatr literature. Am J Surg Pathol. 26(10):1330-42. 1921. Pedersen M, Ktisters-Vandevelde HV,
phakomatosis. Ann Neurol. 29(5):517-23. Neurosurg. 36(5):260-5. PMID:12053045 PMID:12360048 Viros A, Groenen PJ, Sanchez-Laorden B,
PMID:1859181 1890. Park JS, Park H, Park S, Kim SJ, Seol 1905. Passone E, Pizzolitto S, D’Agostini S, Gilhuis JH, et al. (2013). Primary melanoma
1874. Padovani L, Colin C, Fernandez C, HJ, Ko YH (2013). Primary central nervous sys- Skrap M, Gardiman MP, Nocerino A, et al. of the CNS in children is driven by congenital
Maues de Paula A, Mercurio S, Scavarda D, tem ALK positive anaplastic large cell lympho- (2006). Non-anaplastic pleomorphic xanthoast- expression of oncogenic NRAS in melanocytes.
et al. (2012). Search for distinctive markers in ma with predominantly leptomeningeal invol- rocytoma with neuroradiological evidences of Cancer Discov. 3(4):458-69. PMID:23303902
DNT and cortical grade II glioma in children: vement in an adult. Yonsei Med J. 54(3):791-6. leptomeningeal dissemination. Childs Nerv 1922. Pekmezci M, Louie J, Gupta N, Bloomer
same clinicopathological and molecular enti- PMID:23549832 Syst. 22(6):614-8. PMID:16369851 MM, Tihan T (2010). Clinicopathological cha-
ties? Curr Top Med Chem. 12(15):1683-92. 1891. Parker M, Mohankumar KM, Punchi- 1905A. Pastorino L, Ghiorzo P, Nasti S, Battis- racteristics of adamantinomatous and papillary
PMID:22978341 hewa C, Weinlich R, Dalton JD, Li Y, et al. tuzzi L, Cusano R, Marzocchi C, et al. (2009). craniopharyngiomas: University of California,
1875. Paek SH, Kim SH, Chang KH, Park CK, (2014). C11orf95-RELA fusions drive oncoge- Identification of a SUFU germline mutation in a San Francisco experience 1985-2005. Neu-
Kim JE, Kim DG, et al. (2005). Microcystic nic NF-KB signalling in ependymoma. Nature. family with Gorlin syndrome. Am J Med Genet rosurgery. 67(5):1341-9, discussion 1349.
meningiomas: radiological characteristics of 16 506(7489):451-5. PMID:24553141 A. 149A(7):1539-43. PMID:19533801 PMID:20871436
cases. Acta Neurochir (Wien). 147(9):965-72, 1892. Parkin DM, Whelan SL, Ferlay J, Teppo 1906. Patel AP, Tirosh I, Trombetta JJ, Shalek 1923. Pekmezci M, Perry A (2013), Neuropa-
discussion 972. PMID:16028111 L, Thomas DB (2003). Cancer Incidence in Five AK, Gillespie SM, Wakimoto H, et al. (2014). thology of brain metastases. Surg Neurol Int. 4
1876. Paek SH, Shin HY, Kim JW, Park SH, Son Continents. IARC Scientific Publications. Volu- Single-cell RNA-seq highlights intratumoral Suppl 4:S245-55. PMID:23717796
JH, Kim DG (2010). Primary culture of central me 155. Lyon: IARC Press. heterogeneity in primary glioblastoma. Science. 1924. Pekmezci M, Reuss DE, Hirbe AC, Da-
neurocytoma: a case report. J Korean Med Sci. 1893. Parry DM, Eldridge R, Kaiser-Kupfer Ml, 344(6190):1396-401. PMID:24925914 hiya S, Gutmann DH, von Deimling A, et al.
25(5):798-803. PMID:20436722 Bouzas EA, Pikus A, Patronas N (1994). Neuro- 1907. Patel DM, Schmidt RF, Liu JK (2013). (2015). Morphologic and immunohistochemical
1877. Paganini I, Chang VY, Capone GL, Vitte fibromatosis 2 (NF2): clinical characteristics of Update on the diagnosis, pathogenesis, and features of malignant peripheral nerve sheath
References 385
tumors and cellular schwannomas. Mod Pathol, rhabdoid meningiomas. Mod Pathol. 18(7):951- in patients with neurofibromatosis type I. J histopathological, and molecular characteri-
28(2): 187-200. PMID:25189642 8. PMID:15761491 Pediatr Hematol Oncol. 33(5):e198-201. stics of medulloblastomas in the prospective
1925. Pels H, Montesinos-Rongen M, Schal- 1942. Perry A, Giannini C, Raghavan R, Scheit- PMID:21572348 HIT2000 multicenter clinical trial cohort. Acta
ler C, Schlegel U, Schmidt-Wolf IG, Wiestler hauer BW, Banerjee R, Margraf L, et al. (2001). 1958. Petitjean A, Mathe E, Kato S, Ishioka C, Neuropathol. 128(1 ):137-49. PMID:24791927
OD, et al. (2005). VH gene analysis of primary Aggressive phenotypic and genotypic features Tavtigian SV, Hainaut P, et al. (2007). Impact 1973. Pietsch T, Waha A, Koch A, Kraus J, Alb-
CNS lymphomas, J Neurol Sci. 228(2):143-7. in pediatric and NF2-associated meningio- of mutant p53 functional properties on TP53 recht S, Tonn J, et al. (1997). Medulloblastomas
PMID:15694195 mas: a clinicopathologic study of 53 cases. J mutation patterns and tumor phenotype: les- of the desmoplastic variant carry mutations of
1926. Pels H, Schlegel U (2006). Primary Neuropathol Exp Neurol. 60( 10):994-1003. sons from recent developments in the IARC the human homologue of Drosophila patched.
central nervous system lymphoma. Curr Treat PMID:11589430 TP53 database. Hum Mutat. 28(6):622-9. Cancer Res. 57(11):2085-8. PMID:9187099
Options Neurol. 8(4):346-57. PMID:16942677 1943. Perry A, Giannini C, Scheithauer BW, PMID:17311302 1974. Pietsch T, Wohlers I, Goschzik T, Dre-
1927. Pencalet P, Maixner W, Sainte-Rose C, Rojiani AM, Yachnis AT, Seo IS, et al. (1997). 1959. Peyre M, Bah A, Kalamarides M (2012). schmann V, Denkhaus D, Dorner E, et al.
Lellouch-Tubiana A, Cinalli G, Zerah M, et al. Composite pleomorphic xanthoastrocytoma Multifocal choroid plexus papillomas: case (2014). Supratentorial ependymomas of child-
(1999). Benign cerebellar astrocytomas in child- and ganglioglioma: report of four cases and report. Acta Neurochir (Wien). 154(2):295-9. hood carry C11orf95-RELA fusions leading to
ren. J Neurosurg. 90(2):265-73. PMID:9950497 review of the literature. Am J Surg Pathol. PMID:21953479 pathological activation of the NF-KB signaling
1928. Per H, Konta§ O, Kumanda? S, Kurtsoy A 21(7)763-71. PMID:9236832 1960. Peyre M, Stemmer-Rachamimov A, pathway. Acta Neuropathol. 127(4):609-11,
(2009). A report of a desmoplastic non-infantile 1944. Perry A, Kurtkaya-Yapicier O, Scheit- Clermont-Taranchon E, Quentin S, El-Taraya PMID:24562983
ganglioglioma in a 6-year-old boy with review hauer BW, Robinson S, Prayson RA, Klein- N, Walczak C, et al. (2013). Meningioma pro- 1975. Pignatti F, van den Bent M, Curran D, De-
of the literature. Neurosurg Rev. 32(3):369-74, schmidt-DeMasters BK, et al. (2005). Insights gression in mice triggered by Nf2 and Cdkn2ab bruyne C, Sylvester R, Therasse P, et al.; Euro-
discussion 374. PMID:19280238 into meningioangiomatosis with and without inactivation. Oncogene. 32(36):4264-72. pean Organization for Research and Treatment
1929. Peraud A, Ansari H, Bise K, Reulen HJ meningioma: a clinicopathologic and genetic PMID:23045274 of Cancer Brain Tumor Cooperative Group;
(1998). Clinical outcome of supratentorial ast- series of 24 cases with review of the literature. 1961. Pfister S, Janzarik WG, Remke M, Ernst European Organization for Research and Tre-
rocytoma WHO grade II. Acta Neurochir (Wien). Brain Pathol. 15(1):55-65. PMID:15779237 A, Werft W, Becker N, et al. (2008). BRAF gene atment of Cancer Radiotherapy Cooperative
140(12):1213-22. PMID:9932120 1945. Perry A, Lusis EA, Gutmann DH (2005). duplication constitutes a mechanism of MAPK Group (2002). Prognostic factors for survival in
1930. Peraud A, Kreth FW, Wiestler OD, Klei- Meningothelial hyperplasia: a detailed clinico- pathway activation in low-grade astrocytomas. adult patients with cerebral low-grade glioma.
hues P, Reulen HJ (2002). Prognostic impact of pathologic, immunohistochemical and genetic J Clin Invest. 118(5):1739-49. PMID:18398503 J Clin Oncol. 20(8):2076-84. PMID:11956268
TP53 mutations and P53 protein overexpres- study of 11 cases. Brain Pathol. 15(2):109-15. 1962. Pfister S, Remke M, Castoldi M, Bai AH, 1976. Pimentel J, Barroso C, Miguens J, Firmo
sion in supratentorial WHO grade II astrocyto- PMID:15912882 Muckenthaler MU, Kulozik A, et al. (2009). C, Antunes JL (2009). Papillary glioneuronal tu-
mas and oligoastrocytomas. Clin Cancer Res. 1946. Perry A, Miller CR, Gujrati M, Scheithau- Novel genomic amplification targeting the mor-prognostic value of the extension of surgi-
8(5):1117-24. PMID:12006527 er BW, Zambrano SC, Jost SC, et al. (2009). microRNA cluster at 19q13.42 in a pediatric cal resection. Clin Neuropathol. 28(4):287-94.
1931. Peraud A, Watanabe K, Plate KH, Yone- Malignant gliomas with primitive neuroectoder- embryonal tumor with abundant neuropil and PMID:19642508
kawa Y, Kleihues P, Ohgaki H (1997). p53 muta- mal tumor-like components: a clinicopathologic true rosettes. Acta Neuropathol. 117(4):457-64. 1977. Pimentel J, Silva R, Pimentel T (2003).
tions versus EGF receptor expression in giant and genetic study of 53 cases. Brain Pathol. PMID:19057917 Primary malignant rhabdoid tumors of the cen-
cell glioblastomas. J Neuropathol Exp Neurol. 19(1 ):81-90. PMID:18452568 1963. Phi JH, Koh EJ, Kim SK, Park SH, Cho tral nervous system: considerations about two
56(11 ):1236-41. PMID:9370234 1947. Perry A, Roth KA, Banerjee R, Fuller BK, Wang KC (2011). Desmoplastic infantile as- cases of adulthood presentation. J Neurooncol.
1932. Peraud A, Watanabe K, Schwechheimer CE, Gutmann DH (2001). NF1 deletions in trocytoma: recurrence with malignant transfor- 61(2):121-6. PMID:12622450
K, Yonekawa Y, Kleihues P, Ohgaki H (1999). S-100 protein-positive and negative cells of mation into glioblastoma: a case report. Childs 1978. Pinna V, Lanari V, Daniele P, Consoli
Genetic profile of the giant cell glioblastoma. sporadic and neurofibromatosis 1 (NF1)-asso- Nerv Syst. 27(12):2177-81. PMID:21947035 F, Agolini E, Margiotti K, et al. (2015). p.Ar-
Lab Invest. 79(2):123-9. PMID:10068201 ciated plexiform neurofibromas and malignant 1964. Phi JH, Park SH, Chae JH, Hong KH, g1809Cys substitution in neurofibromin is asso-
1933. Perentes E, Rubinstein LJ, Herman MM, peripheral nerve sheath tumors. Am J Pathol. Park SS, Kang JH, et al. (2008). Congenital ciated with a distinctive NF1 phenotype without
Donoso LA (1986). S-antigen immunoreactivity 159(1):57-61. PMID:11438454 subependymal giant cell astrocytoma: clinical neurofibromas. Eur J Hum Genet. 23(8):1068-
in human pineal glands and pineal parenchymal 1948. Perry A, Scheithauer BW, Macaulay considerations and expression of radial glial 71. PMID:25370043
tumors. A monoclonal antibody study. Acta Neu- RJ, Raffel C, Roth KA, Kros JM (2002). Oligo- cell markers in giant cells. Childs Nerv Syst, 1979. Pinto Gama HP, da Rocha AJ, Braga FT,
ropathol. 71 (3-4):224-7. PMID:3541480 dendrogliomas with neurocytic differentiation. A 24( 12): 1499-503. PMID:18629509 da Silva CJ, Maia AC Jr, de Campos Meirelles
1934. Perilongo G, Carollo C, Salviati L, Murgia report of 4 cases with diagnostic and histoge- 1965. Phillips CL, Miles L, Jones BV, Sutton RG, et al. (2006). Comparative analysis of MR
A, Pillon M, Basso G, etal. (1997). Diencephalic netic implications. J Neuropathol Exp Neurol. M, Crone K, Fouladi M (2011). Medulloblasto- sequences to detect structural brain lesions in
syndrome and disseminated juvenile pilocytic 61(11):947-55. PMID:12430711 ma with melanotic differentiation: case report tuberous sclerosis. Pediatr Radiol. 36(2):119-
astrocytomas of the hypothalamic-optic chiasm 1949. Perry A, Scheithauer BW, Nascimento and review of the literature. J Neurooncol. 25. PM ID: 16283285
region. Cancer. 80(1):142-6. PMID:9210720 AG (1997). The immunophenotypic spectrum 103(3)759-64. PMID:20953660 1980. Piotrowski A, Xie J, Liu YF, Poplawski
1935. Perkins SM, Mitra N, Fei W, Shinohara of meningeal hemangiopericytoma: a com- 1966. Phillips JJ, Misra A, Feuerstein BG, AB, Gomes AR, Madanecki P, et al. (2014).
ET (2012). Patterns of care and outcomes of parison with fibrous meningioma and solitary Kunwar S, Tihan T (2010). Pituicytoma: cha- Germline loss-of-function mutations in LZTR1
patients with pleomorphic xanthoastrocytoma: fibrous tumor of meninges. Am J Surg Pathol. racterization of a unique neoplasm by histolo- predispose to an inherited disorder of multi-
a SEER analysis. J Neurooncol. 110(1):99-104. 21 (11 ):1354-60. PMID:9351573 gy, immunohistochemistry, ultrastructure, and ple schwannomas. Nat Genet. 46(2):182-7.
PMID:22843450 1950. Perry A, Scheithauer BW, Stafford SL, array-based comparative genomic hybridiz- PMID:24362817
1936. Perreault S, Ramaswamy V, Achrol AS, Abell-Aleff PC, Meyer FB (1998). "Rhabdoid" ation. Arch Pathol Lab Med. 134(7):1063-9. 1981. Pirini MG, Mascalchi M, Salvi F, Tassinari
Chao K, Liu TT, Shih D, et al. (2014). MRI sur- meningioma: an aggressive variant. Am J Surg PMID:20586639 CA, Zanella L, Bacchini P, et al. (2003). Primary
rogates for molecular subgroups of medullob- Pathol. 22( 12): 1482-90. PMID:9850174 1967. Picard D, Miller S, Hawkins CE, Bouffet diffuse meningeal melanomatosis: radiolo-
lastoma. AJNR Am J Neuroradiol. 35(7):1263- 1951. Perry A, Scheithauer BW, Stafford SL, E, Rogers HA, Chan TS, et al. (2012). Markers gic-pathologic correlation. AJNR Am J Neurora-
9. PMID:24831600 Lohse CM, Wollan PC (1999). “Malignancy” in of survival and metastatic potential in childhood diol. 24(1 ):115-8. PMID:12533338
1937. Perry A, Aldape KD, George DH, Bur- meningiomas: a clinicopathologic study of 116 CNS primitive neuro-ectodermal brain tumours: 1982. Pirotte B, Krischek B, Levivier M, Bolyn
ger PC (2004). Small cell astrocytoma: an patients, with grading implications. Cancer. an integrative genomic analysis. Lancet Oncol. S, Brucher JM, Brotchi J (1998). Diagnostic
aggressive variant that is dinicopathologically 85(9):2046-56. PMID:10223247 13(8):838-48. PMID:22691720 and microsurgical presentation of intracra-
and genetically distinct from anaplastic oli- 1952. Perry A, Stafford SL, Scheithauer BW, 1968. Pickuth D, Leutloff U (1996). Computed nial angiolipomas. Case report and review
godendroglioma. Cancer. 101(10):2318-26. Suman VJ, Lohse CM (1997). Meningioma gra- tomography and magnetic resonance ima- of the literature. J Neurosurg. 88(1):129-32.
PMID:15470710 ding: an analysis of histologic parameters. Am ging findings in primitive neuroectodermal PMID:9420085
1938. Perry A, Banerjee R, Lohse CM, Klein- J Surg Pathol. 21(12):1455-65. PMID:9414189 tumours in adults. Br J Radiol. 69(817):1-5. 1983. Pitche P, Ategbo S, Gbadoe A, Bassu-
schmidt-DeMasters BK, Scheithauer BW 1953. Perry A, Stafford SL, Scheithauer BW, PMID:8785615 ka-Parent A, Mouzou B, Tchangai'-Walla K
(2002). A role for chromosome 9p21 deletions in Suman VJ, Lohse CM (1998). The prognostic 1969. Pierallini A, Bonamini M, Pantano P, Pal- (1997). [Bullous toxidermatosis and HIV infecti-
the malignant progression of meningiomas and significance of MIB-1, p53, and DNA flow cyto- meggiani F, Raguso M, Osti MF, et al. (1998). on in hospital environment in Lome (Togo)]. Bull
the prognosis of anaplastic meningiomas. Brain metry in completely resected primary meningi- Radiological assessment of necrosis in gliob- Soc Pathol Exot. 90(3):186-8. PMID:9410257
Pathol. 12(2):183-90. PMID:11958372 omas. Cancer. 82(11):2262-9. PMID:9610708 lastoma: variability and prognostic value. Neu- 1984. Pizer BL, Moss T, Oakhill A, Webb D,
1939. Perry A, Burton SS, Fuller GN, Robinson 1954. Persson Al, Petritsch C, Swartling FJ, Its- roradiology. 40(3):150-3. PMID:9561517 Coakham HB (1995). Congenital astroblasto-
CA, Palmer CA, Resch L, et al. (2010). Oligo- ara M, Sim FJ, Auvergne R, et al. (2010). Non- 1970. Piercecchi-Marti MD, Mohamed H, ma: an immunohistochemical study. Case re-
dendroglial neoplasms with ganglioglioma-like stem cell origin for oligodendroglioma. Cancer Liprandi A, Gambarelli D, Grisoli F, Pellissier port. J Neurosurg. 83(3):550-5. PMID7545227
maturation: a diagnostic pitfall. Acta Neuropa- Cell. 18(6):669-82. PMID:21156288 JF (2002). Intracranial meningeal melanocyto- 1985. Pizzuti A, Bottillo I, Inzana F, Lanari V,
thol. 120(2):237-52. PMID:20464403 1955. Persu A, Hamoir M, Gregoire V, Garin ma associated with ipsilateral nevus of Ota. Buttarelli F, Torrente I, etal. (2011). Familial spi-
1940. Perry A, Cai DX, Scheithauer BW, Swan- P, Duvivier E, Reychler H, et al. (2008). High Case report. J Neurosurg. 96(3):619-23. nal neurofibromatosis due to a multiexonic NF1
son PE, Lohse CM, Newsham IF, et al. (2000). prevalence of SDHB mutations in head and PMID:11883852 gene deletion. Neurogenetics. 12(3):233-40.
Merlin, DAL-1, and progesterone receptor ex- neck paraganglioma in Belgium. J Hypertens. 1971. Pierron G, Tirade F, Lucchesi C, Reynaud PMID:21365283
pression in clinicopathologic subsets of menin- 26(7):1395-401. PMID:18551016 S, Ballets, Cohen-GogoS, etal. (2012). Anew 1986. Plank TL, Logginidou H, Klein-Szanto A,
gioma: a correlative immunohistochemical 1956. Burger PC (2009). Smears and Frozen subtype of bone sarcoma defined by BCOR- Henske EP (1999). The expression of hamar-
study of 175 cases. J Neuropathol Exp Neurol. Sections in Surgical Neuropathology. Baltimore CCNB3 gene fusion. Nat Genet. 44(4):461-6. tin, the product of the TSC1 gene, in normal
59(10):872-9. PMID:11079777 (MD): PB Medical Publishing. PMID:22387997 human tissues and in TSC1- and TSC2-linked
1941. Perry A, Fuller CE, Judkins AR, Dehner 1957. Peters KB, Cummings TJ, Gururangan 1972. Pietsch T, Schmidt R, Remke M, angiomyolipomas. Mod Pathol. 12(5):539-45.
LP, Biegel JA (2005). INI1 expression is re- S (2011). Transformation of juvenile pilocytic Korshunov A, Hovestadt V, Jones DT, et al. PMID:10349994
tained in composite rhabdoid tumors, including astrocytoma to anaplastic pilocytic astrocytoma (2014). Prognostic significance of clinical, 1987. Plank TL, Yeung RS, Henske EP (1998).
386 References
Hamartin, the product of the tuberous sclerosis C, Tinguely M, Jouvet A, Ferreri AJ, et al.; Inter- Pathol. 3(1):11-8. PMID:9990108 2038. Prevot S, Bienvenu L, Vaillant JC, de
1 (TSC1) gene, interacts with tuberin and ap- national Extranodal Lymphoma Study Group 2021. Prayson RA (1999). Composite ganglio- Saint-Maur PP (1999). Benign schwannoma
pears to be localized to cytoplasmic vesicles. (2007). Reactive perivascular T-cell infiltrate glioma and dysembryoplastic neuroepithelial of the digestive tract: a clinicopathologic and
Cancer Res. 58(21 ):4766-70. PMID:9809973 predicts survival in primary central nervous tumor. Arch Pathol Lab Med. 123(3):247-50. immunohistochemical study of five cases, in-
1988. Plate KH, Breier G, Weich HA, Risau W system B-cell lymphomas. Br J Haematol. PMID:10086515 cluding a case of esophageal tumor. Am J Surg
(1992). Vascular endothelial growth factor is a 138(3):316-23. PMID:17555470 2022. Prayson RA (2000). Papillary glioneuron- Pathol. 23(4):431-6. PMID:10199472
potential tumour angiogenesis factor in human 2005. Ponzoni M, Bonetti F, Poliani PL, Vermi al tumor. Arch Pathol Lab Med. 124(12):1820- 2038A. Prieto-Granada CN, Wiesner T, Mes-
gliomas in vivo. Nature. 359(6398):845-8. W, Bottelli C, Dolcetti R, et al. (2011). Cen- 3. PMID:11100065 sina JL, Jungbluth AA, Chi P, Antonescu CR
PMID:1279432 tral nervous system marginal zone B-cell 2023. Prayson RA (2012). Pleomorphic xan- (2015). Loss of H3K27me3 Expression Is a
1989. Plate KH, Scholz A, Dumont DJ (2012). lymphoma associated with Chlamydophila thoastrocytoma arising in neurofibromato- Highly Sensitive Marker for Sporadic and Ra-
Tumor angiogenesis and anti-angiogenic thera- psittaci infection. Hum Pathol. 42(5):738-42. sis Type 1. Clin Neuropathol. 31(3):152-4. diation-induced MPNST. Am J Surg Pathol.
py in malignant gliomas revisited. Acta Neuro- PMID:21239044 PMID:22551920 [Epub ahead of print] PMID:26645727
pathol. 124(6):763-75. PMID:23143192 2006. Ponzoni M, Ferreri AJ, Campo E, Fac- 2024. Prayson RA, Castilla EA, Hembury TA, 2039. Probst-Cousin S, Bergmann M, Schroder
1990. Plotkin SR, Blakeley JO, Evans DG, Ha- chetti F, Mazzucchelli L, Yoshino T, et al. Liu W, Noga CM, Prok AL (2003). Interobser- R, Kuchelmeister K, Schmid KW, Ernestus RJ,
nemann CO, Hulsebos TJ, Hunter-Schaedle (2007). Definition, diagnosis, and management ver variability in determining MIB-1 labeling in- et al. (1996). Ki-67 and biological behaviour in
K, et al. (2013). Update from the 2011 Inter- of intravascular large B-cell lymphoma: propo- dices in oligodendrogliomas. Ann Diagn Pathol. meningeal haemangiopericytomas. Histopatho-
national Schwannomatosis Workshop: From sals and perspectives from an international con- 7(1 ):9-13. PM ID:12616468 logy. 29(1 ):57-61. PMID:8818695
genetics to diagnostic criteria. Am J Med Genet sensus meeting. J Clin Oncol. 25(21):3168-73. 2025. Prayson RA, Chahlavi A, Luciano M 2040. Proescholdt MA, Mayer C, Kubitza
A. 161A(3):405-16. PMID:23401320 PMID:17577023 (2004). Cerebellar paraganglioma. Ann Diagn M, Schubert T, Liao SY, Stanbridge EJ, et al.
1991. Plowman PN, Pizer B, Kingston JE 2007. Popova SN, Bergqvist M, Dimberg A, Pathol. 8(4):219-23. PMID:15290673 (2005). Expression of hypoxia-inducible carbo-
(2004). Pineal parenchymal tumours: II. On Edqvist PH, Ekman S, Hesselager G, et al. 2026. Prayson RA, Estes ML (1992). Dysem- nic anhydrases in brain tumors. Neuro Oncol.
the aggressive behaviour of pineoblastoma in (2014). Subtyping of gliomas of various WHO bryoplastic neuroepithelial tumor. Am J Clin 7(4):465-75. PMID.16212811
patients with an inherited mutation of the RB1 grades by the application of immunohisto- Pathol. 97(3):398-401. PMID:1543164 2041. Pruchon E, Chauveinc L, Sabatier L,
gene. Clin Oncol (R Coll Radiol). 16(4):244-7. chemistry. Histopathology. 64(3):365-79. 2027. Prayson RA, Khajavi K, Comair YG Dutrillaux AM, Ricoul M, Delattre JY, et al.
PMID:15214647 PMID:24410805 (1995). Cortical architectural abnormalities (1994). A cytogenetic study of 19 recurrent gli-
1992. Podsypanina K, Ellenson LH, Nemes A, 2008. Poppleton H, Gilbertson RJ (2007). Stem and MIB1 Immunoreactivity in gangliogliomas: omas. Cancer Genet Cytogenet. 76(2):85-92.
Gu J, Tamura M, Yamada KM, et al. (1999). cells of ependymoma. Br J Cancer. 96(1):6-10. a study of 60 patients with intracranial tumors. PMID:7923073
Mutation of Pten/Mmac1 in mice causes neo- PMID:17179988 J Neuropathol Exp Neurol. 54(4):513-20. 2042. Pugh TJ, Weeraratne SD, Archer TC, Po-
plasia in multiple organ systems. Proc Natl 2009. Poremba C, Dockhorn-Dworniczak PMID:7541447 meranz Krummel DA, Auclair D, Bochicchio J, et
Acad Sci U S A . 96(4):1563-8. PMID:9990064 B, Merritt V, Li CY, Heidi G, Tauber PF, et al. 2028. Prayson RA, Suh JH (1999). Subepen- al. (2012). Medulloblastoma exome sequencing
1993. Pohl U, Cairncross JG, Louis DN (1999). (1993). Immature teratomas of different origin dymomas: clinicopathologic study of 14 tumors, uncovers subtype-specific somatic mutations.
Homozygous deletions of the CDKN2C/ carried by a pregnant mother and her fetus. including comparative MIB-1 immunohisto- Nature. 488(7409):106-10. PMID:22820256
p18INK4C gene on the short arm of chromo- Diagn Mol Pathol. 2(2):131-6. PMID:8269278 chemical analysis with other ependymal neo- 2043. Pulido R, Baker SJ, Barata JT, Carracedo
some 1 in anaplastic oligodendrogliomas. Brain 2010. Portela A, Esteller M (2010). Epigenetic plasms. Arch Pathol Lab Med. 123(4):306-9. A, Cid VJ, Chin-Sang ID, et al. (2014). A uni-
Pathol. 9(4):639-43. PMID:10517502 modifications and human disease. Nat Biotech- PMID10320142 fied nomenclature and amino acid numbering
1994. Pollack IF, Claassen D, al-Shboul Q, Ja- nol. 28(10):1057-68. PMID:20944598 2029. Preston DL, Ron E, Yonehara S, Kobuke for human PTEN. Sci Signal. 7(332):pe15.
nosky JE, Deutsch M (1995). Low-grade glio- 2011. Portela-Oliveira E, Torres US, Lancellotti T, Fujii H, Kishikawa M, et al. (2002). Tumors of PMID:24985344
mas of the cerebral hemispheres in children: an CL, Souza AS, Ferraz-Filho JR (2014). Solid the nervous system and pituitary gland associa- 2044. Pummi KP, Aho HJ, Laato MK, Peltonen
analysis of 71 cases. J Neurosurg. 82(4):536- intraventricular papillary glioneuronal tumor: ted with atomic bomb radiation exposure. J Natl JT, Peltonen SA (2006). Tight junction proteins
47. PMID:7897512 magnetic resonance imaging findings with Cancer Inst. 94(20):1555-63. PMID:12381708 and perineurial cells in neurofibromas. J Histo-
1995. Pollack IF, Hoffman HJ, Humphreys RP, histopathological correlation. Pediatr Neurol. 2030. Preuss M, Christiansen H, Merkenschla- chem Cytochem. 54(1):53-61. PMID:16087703
Becker L (1993). The long-term outcome after 50(2):199-200. PMID:24314675 ger A, Hirsch FW, Kiess W, Muller W, et al. 2045. Purav P, Ganapathy K, Mallikarjuna VS,
surgical treatment of dorsally exophytic brain- 2012. Poulgrain K, Gurgo R, Winter C, Ong (2015). Disseminated oligodendroglial cell-like Annapurneswari S, Kalyanaraman S, Reginald
stem gliomas. J Neurosurg. 78(6):859-63. B, Lau Q (2011). Papillary tumour of the pi- leptomeningeal tumors: preliminary diagnostic J, et al. (2005). Rosai-Dorfman disease of
PMID:8487066 neal region. J Clin Neurosci. 18(8):1007-17. and therapeutic results for a novel tumor entity. the central nervous system. J Clin Neurosci.
1996. Pollack IF, Hurtt M, Pang D, Albright AL PMID:21658955 J Neurooncol. 12(6):656-9. PMID:16099162
(1994). Dissemination of low grade intracranial 2013. Powell SZ, Yachnis AT, Rorke LB, Rojiani 2031. Preusser M, Budka H, Rossler K, Hain- 2046. Purdy E, Johnston DL, Bartels U, Fryer
astrocytomas in children. Cancer. 73(11):2869- AM, Eskin TA (1996). Divergent differentiation fellner JA (2007). OLIG2 is a useful immunohis- C, Carret AS, Crooks B, et al. (2014). Ependy-
78. PMID.8194029 in pleomorphic xanthoastrocytoma. Evidence tochemical marker in differential diagnosis of moma in children under the age of 3 years: a re-
1997. Poliak A, Friede RL (1977). Fine structure for a neuronal element and possible relations- clear cell primary CNS neoplasms. Histopatho- port from the Canadian Pediatric Brain Tumour
of medulloepithelioma. J Neuropathol Exp Neu- hip to ganglion cell tumors. Am J Surg Pathol. logy. 50(3):365-70. PMID:17257132 Consortium. J Neurooncol. 117(2):359-64.
rol. 36(4):712-25. PMID:886367 20(1 ):80-5. PMID:8540612 2032. Preusser M, Capper D, Ilhan-Mutlu A, PMID:24532240
1998. Pollock E, Ford-Jones EL, Corey M, 2014. Prabhu VC, Brown HG (2005). The pa- Berghoff AS, Birner P, Bartsch R, et al. (2012). 2047. Qian H, Lin S, Zhang M, Cao Y (2012).
Barker G, Mindorff CM, Gold R, et al. (1991). thogenesis of craniopharyngiomas. Childs Nerv Brain metastases: pathobiology and emer- Surgical management of intraventricular central
Use of the Pediatric Risk of Mortality score to Syst. 21 (8-9):622-7. PMID:15965669 ging targeted therapies. Acta Neuropathol. neurocytoma: 92 cases. Acta Neurochir (Wien).
predict nosocomial infection in a pediatric in- 2015. Prabowo AS, Iyer AM, Veersema TJ, 123(2):205-22. PMID:22212630 154(11):1951-60. PMID:22941394
tensive care unit. Crit Care Med. 19(2):160-5. Anink JJ, Schouten-van Meeteren AY, Spliet 2033. Preusser M, Dietrich W, Czech T, Pray- 2048. Qin W, Chan JA, Vinters HV, Mathern
PMID:1989753 WG, et al. (2014). BRAF V600E mutation is er D, Budka H, Hainfellner JA (2003). Roset- GW, Franz DN, Taillon BE, et al. (2010). Ana-
1999. Polydorides AD, Rosenblum MK, Edgar associated with mTOR signaling activation in te-forming glioneuronal tumor of the fourth lysis of TSC cortical tubers by deep sequencing
MA (2007). Metastatic renal cell carcinoma to glioneuronal tumors. Brain Pathol. 24(1):52-66. ventricle. Acta Neuropathol. 106(5):506-8. of TSC1, TSC2 and KRAS demonstrates that
hemangioblastoma in von Hippel-Lindau di- PMID:23941441 PMID:12915951 small second-hit mutations in these genes are
sease. Arch Pathol Lab Med. 131(4):641-5. 2016. Prabowo AS, van Thuijl HF, Scheinin I, 2034. Preusser M, Hoeftberger R, Woehrer rare events. Brain Pathol. 20(6):1096-105.
PMID:17425399 Sie D, van Essen HF, Iyer AM, et al. (2015). A, Gelpi E, Kouwenhoven M, Kros JM, et PMID:20633017
2000. Pomeroy SL, Tamayo P, Gaasenbeek Landscape of chromosomal copy number aber- al. (2012). Prognostic value of Ki67 index in 2049. Qin Y, Yao L, King EE, Buddavarapu K,
M, Sturla LM, Angelo M, McLaughlin ME, et rations in gangliogliomas and dysembryoplastic anaplastic oligodendroglial tumours-a trans- Lend RE, Chocron ES, et al. (2010). Germline
al. (2002). Prediction of central nervous sys- neuroepithelial tumours. Neuropathol Appl Neu- lational study of the European Organization mutations in TMEM127 confer susceptibility to
tem embryonal tumour outcome based on robiol. 41 (6):743-55. PMID:25764012 for Research and Treatment of Cancer Brain pheochromocytoma. Nat Genet. 42(3):229-33.
gene expression. Nature. 415(6870):436-42. 2017. Prajapati HJ, Vincentelli C, Hwang SN, Tumor Group. Histopathology. 60(6):885-94. PMID:20154675
PMID:11807556 Voloschin A, Crocker I, Dehkharghani S (2014). PMID:22335622 2050. Qu M, Olofsson T, Sigurdardottir S, You
2001. Pomper MG, Passe TJ, Burger PC, Primary CNS natural killer/T-cell lymphoma of 2035. Preusser M, Hoischen A, Novak K, Czech C, Kalimo H, Nister M, et al. (2007). Genetically
Scheithauer BW, Brat DJ (2001). Chordoid gli- the nasal type presenting in a woman: case re- T, Prayer D, Hainfellner JA, et al. (2007). Angio- distinct astrocytic and oligodendroglial compo-
oma: a neoplasm unique to the hypothalamus port and review of the literature. J Clin Oncol. centric glioma: report of clinico-pathologic and nents in oligoastrocytomas. Acta Neuropathol.
and anterior third ventricle. AJNR Am J Neuro- 32(8):e26-9. PMID:24419127 genetic findings in 8 cases. Am J Surg Pathol. 113(2): 129-36. PMID:17031656
radiol. 22(3):464-9. PMID:11237967 2018. Prayer D, Grois N, Prosch H, Gadner H, 31(11 ):1709-18. PMID:18059228 2051. Quillien V, Lavenu A, Karayan-Tapon
2002. Pompili A, Calvosa F, Caroli F, Mastroste- Barkovich AJ (2004). MR imaging presentation 2036. Preusser M, Laggner U, Haberler C, L, Carpentier C, Labussiere M, Lesimple T,
fano R, Occhipinti E, Raus L, et al. (1993). The of intracranial disease associated with Langer- Heinzl H, Budka H, Hainfellner JA (2006). Com- et al. (2012). Comparative assessment of 5
transdural extension of gliomas. J Neurooncol. hans cell histiocytosis. AJNR Am J Neuroradiol. parative analysis of NeuN immunoreactivity in methods (methylation-specific polymerase
15(1):67-74. PMID:8455064 25(5):880-91. PMID:15140741 primary brain tumours: conclusions for rational chain reaction, MethyLight, pyrosequencing,
2003. Ponzoni M, Arrigoni G, Gould VE, Del 2019. Prayson RA (1997). Myxopapillary epen- use in diagnostic histopathology. Histopatholo- methylation-sensitive high-resolution mel-
Curto B, Maggioni M, Scapinello A, et al. dymomas: a clinicopathologic study of 14 cases gy. 48(4):438-44. PMID:16487366 ting, and immunohistochemistry) to analyze
(2000). Lack of CD 29 (betal integrin) and CD including MIB-1 and p53 Immunoreactivity. Mod 2037. Preusser M, Woehrer A, Koperek O, 06-methylguanine-DNA-methyltranferase in
54 (ICAM-1) adhesion molecules in intravascu- Pathol. 10(4):304-10. PMID:9110291 Rottenfusser A, Dieckmann K, Gatterbauer B, a series of 100 glioblastoma patients. Cancer.
lar lymphomatosis. Hum Pathol. 31(2):220-6. 2020. Prayson RA (1999). Clinicopathologic et al. (2010). Primary central nervous system 118(17):4201-11. PMID:22294349
PMID:10685637 study of 61 patients with ependymoma inclu- lymphoma: a clinicopathological study of 75 ca- 2052. Rades D, Fehlauer F, Lamszus K,
2004. Ponzoni M, Berger F, Chassagne-Clement ding MIB-1 immunohistochemistry. Ann Diagn ses. Pathology. 42(6):547-52. PMID:20854073 Schild SE, Hagel C, Westphal M, et al. (2005).
References 387
Well-differentiated neurocytoma: what is 110(20):8188-93. PMID:23633565 PMID:8504413 2101. Resta N, Lauriola L, Puca A, Susca FC,
the best available treatment? Neuro Oncol. 2069. Raney RB, Ater JL, Herman-Liu A, Leeds 2085. Reifenberger G, Louis DN (2003). Oligo- Albanese A, Sabatino G, et al. (2006). Gang-
7(1):77-83. PMID:15701284 NE, Cleary KR, Womer RB, et al. (1994). Pri- dendroglioma: toward molecular definitions in lioglioma arising in a Peutz-Jeghers patient: a
2053. Rades D, Schild SE, Fehlauer F (2004). mary intraspinal soft-tissue sarcoma in child- diagnostic neuro-oncology. J Neuropathol Exp case report with molecular implications. Acta
Prognostic value of the MIB-1 labeling index for hood: report of two cases with a review of the Neurol. 62(2):111-26. PMID:12578221 Neuropathol. 112(1):106-11. PMID:16733653
central neurocytomas. Neurology. 62(6):987-9. literature. Med Pediatr Oncol. 23(4):359-64. 2086. Reifenberger G, Reifenberger J, Ichimura 2102. Reuss DE, Habel A, Hagenlocher C,
PMID:15037708 PMID:8058008 K, Meltzer PS, Collins VP (1994). Amplification Mucha J, Ackermann U, Tessmer C, et al.
2054. Radke J, Gehlhaar C, Lenze D, Capper 2070. Rankine AJ, Filion PR, Platten MA, of multiple genes from chromosomal region (2014). Neurofibromin specific antibody diffe-
D, Bock A, Heppner FL, et al. (2015). The evo- Spagnolo DV (2004). Perineurioma: a clinico- 12q13-14 in human malignant gliomas: preli- rentiates malignant peripheral nerve sheath
lution of the anaplastic cerebellar liponeurocyto- pathological study of eight cases. Pathology. minary mapping of the amplicons shows prefe- tumors (MPNST) from other spindie cell neo-
ma: case report and review of the literature. Clin 36(4):309-15. PMID:15370128 rential involvement of CDK4, SAS, and MDM2. plasms. Acta Neuropathol. 127(4):565-72.
Neuropathol. 34(1):19-25. PMID:25250652 2071. Raoux D, Duband S, Forest F, Trombert Cancer Res. 54(16):4299-303. PMID:8044775 PMID:24464231
2055. Raffel C, Jenkins RB, Frederick L, FHebrink B, Chambonniere ML, Dumollard JM, et al. 2087. Reifenberger G, Szymas J, Wechsler W 2103. Reuss DE, Mamatjan Y, Schrimpf D,
D, Alderete B, Fults DW, et al. (1997). Sporadic (2010). Primary central nervous system lym- (1987). Differential expression of glial- and neu- Capper D, Hovestadt V, Kratz A, et al. (2015).
medulloblastomas contain PTCH mutations. phoma: immunohistochemical profile and prog- ronal-associated antigens in human tumors of IDH mutant diffuse and anaplastic astrocyto-
Cancer Res. 57(5):842-5. PMID:9041183 nostic significance. Neuropathology. 30(3):232- the central and peripheral nervous system. Acta mas have similar age at presentation and
2056. Ragel BT, Osborn AG, Whang K, Town- 40. PMID:19925562 Neuropathol. 74(2):105-23. PMID:3314309 little difference in survival: a grading problem
send JJ, Jensen RL, Couldwell WT (2006). 2072. Rasheed BK, McLendon RE, Friedman 2088. Reifenberger G, Weber RG, Riehmer V, for WHO. Acta Neuropathol. 129(6):867-73.
Subependymomas: an analysis of clinical and HS, Friedman AH, Fuchs HE, Bigner DD, et Kaulich K, Willscher E, Wirth H, et al.; German PMID:25962792
imaging features. Neurosurgery. 58(5):881-90, al. (1995). Chromosome 10 deletion map- Glioma Network (2014). Molecular characteriza- 2104. Reuss DE, Piro RM, Jones DT, Simon
discussion 881-90. PMIDM6639322 ping in human gliomas: a common deletion tion of long-term survivors of glioblastoma using M, Ketter R, Kool M, et al. (2013). Secretory
2057. Raghavan R, Balani J, Perry A, Margraf region in 10q25. Oncogene. 10(11 ):2243-6. genome- and transcriptome-wide profiling. Int J meningiomas are defined by combined KLF4
L, Vono MB, Cai DX, et al, (2003). Pediatric PMID:7784070 Cancer. 135(8):1822-31. PMID:24615357 K409Q and TRAF7 mutations. Acta Neuropa-
oligodendrogliomas: a study of molecular al- 2073. Rauen KA (2013). The RASopathies. 2089. Reifenberger G, Weber T, Weber RG, thol. 125(3):351-8. PMID:23404370
terations on 1p and 19q using fluorescence in Annu Rev Genomics Hum Genet, 14:355-69. Wolter M, Brandis A, Kuchelmeister K, et al. 2105. Reuss DE, Sahm F, Schrimpf D, Wiestler
situ hybridization. J Neuropathol Exp Neurol. PMID:23875798 (1999). Chordoid glioma of the third ventricle: B, Capper D, Koelsche C, et al. (2015). ATRX
62(5):530-7. PMID:12769192 2074. Rauhut F, Reinhardt V, Budach V, Wie- immunohistochemical and molecular genetic and IDH1-R132H immunohistochemistry with
2058. Raghavan R, Dickey WT Jr, Margraf LR, demayer H, Nau HE (1989). Intramedullary pi- characterization of a novel tumor entity. Brain subsequent copy number analysis and IDH
White CL 3rd, Coimbra C, Hynan LS, et al. locytic astrocytomas-a clinical and morphologi- Pathol. 9(4):617-26. PMID:10517500 sequencing as a basis for an “integrated" dia-
(2000). Proliferative activity in craniopharyngi- cal study after combined surgical and photon or 2090. Reifenberger J, Reifenberger G, Ichimura gnostic approach for adult astrocytoma, oligo-
omas: clinicopathological correlations in adults neutron therapy. Neurosurg Rev. 12(4):309-13. K, Schmidt EE, Wechsler W, Collins VP (1996). dendroglioma and glioblastoma. Acta Neuropa-
and children. Surg Neurol. 54(3):241-7, discus- PMID:2594208 Epidermal growth factor receptor expressi- thol. 129(1 ):133-46. PMID:25427834
sion 248. PMID:11118571 2075. Rausch T, Jones DT, Zapatka M, Stiitz on in oligodendroglial tumors. Am J Pathol. 2106. Reyes-Mugica M, Chou P, Byrd S, Ray
2059. Raghavan R, Steart PV, Weller RO AM, Zichner T, Weischenfeldt J, et al. (2012). 149(1 ):29-35. PMID:8686753 V, Castelli M, Gattuso P, et al. (1993). Nevome-
(1990). Cell proliferation patterns in the diag- Genome sequencing of pediatric medullob- 2091. Reifenberger J, Reifenberger G, Liu L, lanocytic proliferations in the central nervous
nosis of astrocytomas, anaplastic astrocytomas lastoma links catastrophic DN A rearrangements James CD, Wechsler W, Collins VP (1994). system of children. Cancer. 72(7):2277-85.
and glioblastoma multiforme: a Ki-67 study. with TP53 mutations. Cell. 148(1-2):59-71. Molecular genetic analysis of oligodendroglial PMID:8374887
Neuropathol Appl Neurobiol. 16(2):123-33. PMID:22265402 tumors shows preferential allelic deletions on 2108. Rezai AR, Woo HH, Lee M, Cohen H,
PMID:2161084 2076. Rawlinson DG, Herman MM, Rubinstein 19q and 1p. Am J Pathol. 145(5): 1175-90. Zagzag D, Epstein FJ (1996). Disseminated
2060. Raghunathan A, Wani K, Armstrong TS, LJ (1973). The fine structure of a myxopapillary PMID:7977648 ependymomas of the central nervous system. J
Vera-Bolanos E, Fouladi M, Gilbertson R, et al.; ependymoma of the filum terminale. Acta Neu- 2092. Reifenberger J, Ring GU, Gies U, Cob- Neurosurg. 85(4):618-24. PMID:8814165
Collaborative Ependymoma Research Network ropathol. 25(1):1-13. PMID:4727729 bers L, Oberstrass J, An HX, et al. (1996). Ana- 2109. Rhiew RB, Manjila S, Lozen A, Guthikon-
(2013). Histological predictors of outcome in 2077. Ray WZ, Blackburn SL, Casavilca-Zam- lysis of p53 mutation and epidermal growth fac- da M, Sood S, Kupsky WJ (2010). Leptomenin-
ependymoma are dependent on anatomic site brano S, Barrionuevo C, Orrego JE, Heinicke tor receptor amplification in recurrent gliomas geal dissemination of a pediatric neoplasm with
within the central nervous system. Brain Pathol. H, et al. (2009). Clinicopathologic features of re- with malignant progression. J Neuropathol Exp 1p19q deletion showing mixed immunohis-
23(5):584-94. PMID:23452038 current dysembryoplastic neuroepithelial tumor Neurol. 55(7):822-31. PMID:8965097 tochemical features of an oligodendroglioma
2061. Rainho CA, Rogatto SR, de Moraes and rare malignant transformation: a report of 5 2093. Reis F, Faria AV, Zanardi VA, Menezes and neurocytoma. Acta Neurochir (Wien).
LC, Barbieri-Neto J (1992). Cytogenetic study cases and review of the literature. J Neuroon- JR, Cendes F, Queiroz LS (2006). Neuroi- 152(8):1425-9. PMID:20446099
of a pineocytoma. Cancer Genet Cytogenet. col. 94(2):283-92. PMID:19267228 maging in pineal tumors. J Neuroimaging. 2110. Rhodes RH, Cole M, Takaoka Y, Roess-
64(2):127-32. PMID:1486561 2078. Raymond AA, Halpin SF, Alsanjari N, 16(1):52-8. PMID:16483277 mann U, Cotes EE, Simon J (1994). Intra-
2062. Rainov NG, Lubbe J, Renshaw J, Prit- Cook MJ, Kitchen ND, Fish DR, et al. (1994). 2094. Reis RM, Hara A, Kleihues P, Ohgaki ventricular cerebral neuroblastoma. Analysis
chard-Jones K, Luthy AR, Aguzzi A (1995). Dysembryoplastic neuroepithelial tumor. Fea- H (2001). Genetic evidence of the neoplastic of subtypes and comparison with hemisphe-
Association of Wilms’ tumor with primary brain tures in 16 patients. Brain. 117(Pt 3):461-75. nature of gemistocytes in astrocytomas. Acta ric neuroblastoma. Arch Pathol Lab Med.
tumor in siblings. J Neuropathol Exp Neurol. PMID:8032857 Neuropathol. 102(5):422-5. PMID:11699553 118(9):897-911. PMID:8080360
54(2):214-23. PMID:7876889 2079. Raza SM, Lang FF, Aggarwal BB, Fuller 2095. Reis RM, Konu-Lebleblicioglu D, Lopes 2111. Ribeiro RC, Sandrini F, Figueiredo B,
2063. Raisanen J, Biegel JA, Hatanpaa KJ, GN, Wildrick DM, Sawaya R (2002). Necrosis JM, Kleihues P, Ohgaki H (2000). Genetic pro- Zambetti GP, Michalkiewicz E, Lafferty AR, et
Judkins A, White CL, Perry A (2005). Chromo- and glioblastoma: a friend or a foe? A review file of gliosarcomas. Am J Pathol. 156(2):425- al. (2001). An inherited p53 mutation that con-
some 22q deletions in atypical teratoid/rhab- and a hypothesis. Neurosurgery. 51(1):2-12, 32. PMID:10666371 tributes in a tissue-specific manner to pediatric
doid tumors in adults. Brain Pathol. 15(1):23-8. discussion 12-3. PMID:12182418 2096. Reis-Filho JS, Faoro LN, Carrilho C, adrenal cortical carcinoma. Proc Natl Acad Sci
PMID:15779233 2080. Read TA, Fogarty MP, Markant SL, Bleggi-Torres LF, Schmitt FC (2000). Evaluati- U S A . 98(16):9330-5. PMID:11481490
2064. Raja Al, Yeaney GA, Jakacki Rl, Ha- McLendon RE, Wei Z, Ellison DW, et al. on of cell proliferation, epidermal growth factor 2112. Ribeiro S, Napoli I, White IJ, Parrinello
milton RL, Pollack IF (2008). Extraventricular (2009). Identification of CD15 as a marker for receptor, and bcl-2 immunoexpression as prog- S, Flanagan AM, Suter U, et al. (2013). Injury
neurocytoma in neurofibromatosis Type 1: tumor-propagating cells in a mouse model of nostic factors for patients with World Health Or- signals cooperate with Nf1 loss to relieve
case report. J Neurosurg Pediatr. 2(1):63-7. medulloblastoma. Cancer Cell. 15(2):135-47. ganization grade 2 oligodendroglioma. Cancer. the tumor-suppressive environment of adult
PMID:18590398 PMID:19185848 88(4):862-9. PMID:10679656 peripheral nerve. Cell Rep. 5(1):126-36.
2065. Rajan B, Ashley S, Gorman C, Jose CC, 2081. Reardon W, Zhou XP, Eng C (2001). A 2097. Reithmeier T, Gumprecht H, Stolzle A, PMID:24075988
Horwich A, Bloom HJ, et al. (1993). Cranio- novel germline mutation of the PTEN gene in Lumenta CB (2000). Intracerebral paragang- 2113. Ricci A Jr, Parham DM, Woodruff JM,
pharyngioma-a long-term results following limi- a patient with macrocephaly, ventricular dilata- lioma. Acta Neurochir (Wien). 142(9):1063-6. Callihan T, Green A, Erlandson RA (1984).
ted surgery and radiotherapy. Radiother Oncol. tion, and features of VATER association. J Med PMID:11086818 Malignant peripheral nerve sheath tumors ari-
26(1):1-10. PMID:8438080 Genet. 38(12):820-3. PMID:11748304 2098. Remke M, Ramaswamy V, Peacock J, sing from ganglioneuromas. Am J Surg Pathol.
2066. Rajaram V, Brat DJ, Perry A (2004). 2082. Reddy AT, Janss AJ, Phillips PC, Weiss Shih DJ, Koelsche C, Northcott PA, et al. (2013). 8(1):19-29. PMID:6696163
Anaplastic meningioma versus meningeal he- HL, Packer RJ (2000). Outcome for children TERT promoter mutations are highly recurrent 2114. Rickard KA, Parker JR, Vitaz TW, Plaga
mangiopericytoma: immunohistochemical and with supratentorial primitive neuroectoder- in SHH subgroup medulloblastoma. Acta Neu- AR, Wagner S, Parker JC Jr (2011). Papillary
genetic markers. Hum Pathol. 35(11):1413-8. mal tumors treated with surgery, radiation, ropathol. 126(6):917-29. PMID:24174164 tumor of the pineal region: two case studies
PMID:15668900 and chemotherapy. Cancer. 88(9):2189-93. 2099. Rencic A, Gordon J, Otte J, Curtis M, and a review of the literature. Ann Clin Lab Sci.
2067. Raju GP, Urion DK, Sahin M (2007). PMID:10813733 Kovatich A, Zoltick P, et al. (1996). Detection 41 (2):174-81. PMID:21844577
Neonatal subependymal giant cell astrocytoma: 2083. Reifenberger G, Kaulich K, Wiestler OD, of JC virus DNA sequence and expression of 2115. Rickert CH, Hasselblatt M (2006). Cyto-
new case and review of literature. Pediatr Neu- Blümcke I (2003). Expression of the CD34 an- the viral oncoprotein, tumor antigen, in brain of genetic features of ependymoblastomas. Acta
rol. 36(2):128-31. PMID:17275668 tigen in pleomorphic xanthoastrocytomas. Acta immunocompetent patient with oligoastrocyto- Neuropathol. 111(6):559-62. PMID:16718352
2068. Ramkissoon LA, Horowitz PM, Craig JM, Neuropathol. 105(4):358-64. PMID:12624789 ma. Proc Natl Acad Sci U S A . 93(14):7352-7. 2116. Rickert CH, Paulus W (2001). Epidemio-
Ramkissoon SH, Rich BE, Schumacher SE, et 2084. Reifenberger G, Liu L, Ichimura K, PMID:8692997 logy of central nervous system tumors in child-
al. (2013). Genomic analysis of diffuse pediatric Schmidt EE, Collins VP (1993). Amplification 2100. Reni M, Ferreri AJ, Zoldan MC, Villa E hood and adolescence based on the new WHO
low-grade gliomas identifies recurrent oncoge- and overexpression of the MDM2 gene in a (1997). Primary brain lymphomas in patients classification. Childs Nerv Syst. 17(9):503-11.
nic truncating rearrangements in the transcrip- subset of human malignant gliomas without with a prior or concomitant malignancy. J Neu- PMID:11585322
tion factor MYBL1. Proc Natl Acad Sci U S A. p53 mutations. Cancer Res. 53(12):2736-9. rooncol. 32(2):135-42. PMID:9120542 2117. Rickert CH, Paulus W (2001). Tumors
388 References
of the choroid plexus. Microsc Res Tech. Central neurocytoma. A clinicopathological, C, Bryant SC, Jenkins RB (2008). Epithelial and radiologic and histopathologic features. Neuro-
52(1): 104-11. PMID:11135453 immunohistochemical and ultrastructural study pseudoepithelial differentiation in glioblastoma radiol J. 26(6):639-48. PMID:24355182
2118. Rickert CH, Paulus W (2002), Genetic of 7 cases. Pathol Res Pract. 191(2):100-11. and gliosarcoma: a comparative morpho- 2167. Romero-Rojas AE, Melo-Uribe MA, Ba-
characterisation of granular cell tumours. Acta PMID:7567679 logic and molecular genetic study. Cancer. rajas-Solano PA, Chinchilla-Olaya SI, Escobar
Neuropathol. 103(4):309-12. PMID:11904749 2135. Roberts AE, Allanson JE, Tartaglia M, 113(10):2779-89. PMID:18816605 LI, Hernandez-Walteros DM (2011). Spindle
2119. Rickert CH, Paulus W (2002). No chro- Gelb BD (2013). Noonan syndrome. Lancet. 2152. Rodriguez FJ, Scheithauer BW, Jenkins cell oncocytoma of the adenohypophysis. Brain
mosomal imbalances detected by comparative 381 (9863):333-42. PMID:23312968 R, Burger PC, Rudzinskiy P, Vlodavsky E, et Tumor Pathol. 28(4):359-64. PMID:21833579
genomic hybridisation in a case of fetal imma- 2136. Roberts CW, Biegel JA (2009). The al. (2007). Gliosarcoma arising in oligodendro- 2168. Roncaroli F, Riccioni L, Cerati M, Ca-
ture teratoma. Childs Nerv Syst. 18(11 ):639-43. role of SMARCB1/INI1 in development of rh- glial tumors (“oligosarcoma"): a clinicopatho- pella C, Calbucci F, Trevisan C, et al. (1997).
PMID:12420126 abdoid tumor. Cancer Biol Ther. 8(5):412-6. logic study. Am J Surg Pathol. 31 (3):351-62. Oncocytic meningioma. Am J Surg Pathol.
2120. Rickert CH, Paulus W (2004). Compa- PMID:19305156 PMID:17325476 21(4):375-82. PMID:9130983
rative genomic hybridization in central and 2137. Roberts CW, Orkin SH (2004). The SWI/ 2153. Rodriguez FJ, Scheithauer BW, Perry 2169. Roncaroli F, Scheithauer BW, Cenacchi
peripheral nervous system tumors of childhood SNF complex-chromatin and cancer. Nat Rev A, Oliveira AM, Jenkins RB, Oviedo A, et al. G, Horvath E, Kovacs K, Lloyd RV, et al. (2002).
and adolescence. J Neuropathol Exp Neurol. Cancer. 4(2)433^12. PMID:14964309 (2008). Ependymal tumors with sarcomatous ‘Spindle cell oncocytoma' of the adenohypophy-
63(5):399-417. PMID:15198120 2138. Roberts RO, Lynch CF, Jones MP, Hart change (“ependymosarcoma”): a dinicopatho- sis: a tumor of folliculostellate cells? Am J Surg
2121. Rickert CH, Simon R, Bergmann M, MN (1991). Medulloblastoma: a population-ba- logic and molecular cytogenetic study. Am J Pathol. 26(8):1048-55. PMID:12170092
Dockhorn-Dwomiczak B, Paulus W (2000). sed study of 532 cases. J Neuropathol Exp Surg Pathol. 32(5):699-709. PMID:18347506 2170. Rong Y, Durden DL, Van Meir EG, Brat
Comparative genomic hybridization in pineal Neurol. 50(2):134-44. PMID:2010773 2154. Rodriguez FJ, Scheithauer BW, Robbins DJ (2006). 'Pseudopalisading' necrosis in gli-
germ cell tumors. J Neuropathol Exp Neurol. 2139. Robertson RP (2011 ).Translational En- PD, Burger PC, Hessler RB, Perry A, et al. oblastoma: a familiar morphologic feature that
59(9):815-21. PMID:11005262 docrinology & Metabolism. Neoplasia Update (2007). Ependymomas with neuronal differenti- links vascular pathology, hypoxia, and angioge-
2122. Rickert CH, Simon R, Bergmann M, Chevy Chase, Maryland 20815: The Endocrine ation: a morphologic and immunohistochemical nesis. J Neuropathol Exp Neurol. 65(6):529-39.
Dockhorn-Dworniczak B, Paulus W (2001). Society. spectrum. Acta Neuropathol. 113(3):313-24. PMID:16783163
Comparative genomic hybridization in pineal 2140. Robin YM, Guillou L, Michels JJ, Coindre PMID:17061076 2171. Rorke LB (1983), The cerebellar me-
parenchymal tumors. Genes Chromosomes JM (2004). Human herpesvirus 8 immunos- 2155. Rodriguez FJ, Scheithauer BW, Tsuno- dulloblastoma and its relationship to primitive
Cancer. 30(1):99-104. PMID:11107183 taining: a sensitive and specific method for da S, Kovacs K, Vidal S, Piepgras DG (2007). neuroectodermal tumors. J Neuropathol Exp
2123. Rickert CH, Wiestler OD, Paulus W diagnosing Kaposi sarcoma in paraffin-embed- The spectrum of malignancy in craniopharyn- Neurol. 42(1):1-15. PMID:6296325
(2002). Chromosomal imbalances in choroid ded sections. Am J Clin Pathol. 121(3):330-4. gioma. Am J Surg Pathol. 31(7):1020-8. 2172. Rorke LB, Packer RJ, Biegel JA (1996).
plexus tumors. Am J Pathol. 160(3):1105-13. PMID:15023036 PMID:17592268 Central nervous system atypical teratoid/
PMID:11891207 2141. Robinson DR, Wu YM, Kalyana-Sunda- 2156. Rodriguez FJ, Schniederjan MJ, Nico- rhabdoid tumors of infancy and childhood: de-
2124. Rickman DS, Bobek MP, Misek DE, Kuick ram S, Cao X, Lonigro RJ, Sung YS, et al. laides T, Tihan T, Burger PC, Perry A (2015). finition of an entity. J Neurosurg. 85(1):56-65.
R, Blaivas M, Kurnit DM, et al. (2001). Distincti- (2013). Identification of recurrent NAB2-STAT6 High rate of concurrent BRAF-KIAA1549 gene PMID:8683283
ve molecular profiles of high-grade and low-gra- gene fusions in solitary fibrous tumor by inte- fusion and 1p deletion in disseminated oligo- 2173. Rosai J, Parkash V, Reuter V (1994). In-
de gliomas based on oligonucleotide microar- grative sequencing. Nat Genet. 45(2):180-5. dendroglioma-like leptomeningeal neoplasms vited Review: The Origin of Mediastinal Germ
ray analysis. Cancer Res. 61(18):6885-91. PMID:23313952 (DOLN). Acta Neuropathol. 129(4):609-10. Cell Tumors. Int J Surg Pathol. 2:73-8.
PMID: 11559565 2142. Robinson G, Parker M, Kranenburg TA, PMID:25720745 2174. Rosemberg S, Fujiwara D (2005). Epi-
2125. Riegert-Johnson DL, Gleeson FC, Ro- Lu C, Chen X, Ding L, etal. (2012). Novel muta- 2157. Rodriguez FJ, Tihan T, Lin D, McDonald demiology of pediatric tumors of the nervous
berts M, Tholen K, Youngborg L, Bullock M, tions target distinct subgroups of medulloblasto- W, Nigro J, Feuerstein B, et al. (2014). Clinico- system according to the WHO 2000 classifi-
et al. (2010). Cancer and Lhermitte-Dudos ma. Nature. 488(7409):43-8. PMID:22722829 pathologic features of pediatric oligodendroglio- cation: a report of 1,195 cases from a single
disease are common in Cowden syndrome 2143. Robinson GW, Orr BA, Wu G, Gur- mas: a series of 50 patients. Am J Surg Pathol. institution. Childs Nerv Syst. 21(11):940-4.
patients. Hered Cancer Clin Pract. 8(1 ):6. urangan S, Lin T, Qaddoumi I, et al. (2015). 38(8): 1058-70. PMID:24805856 PMID:16044344
PMID:20565722 Vismodegib Exerts Targeted Efficacy Against 2158. Rodriguez HA, Berthrong M (1966). Mul- 2175. Rosemberg S, Vieira GS (1998). [Dysem-
2126. Riemenschneider MJ, Reifenberger G Recurrent Sonic Hedgehog-Subgroup Medul- tiple primary intracranial tumors in von Reck- bryoplastic neuroepithelial tumor. An epidemio-
(2009). Molecular neuropathology of gliomas. loblastoma: Results From Phase II Pediatric linghausen’s neurofibromatosis. Arch Neurol. logical study from a single institution], Arq Neu-
Int J Mol Sci. 10(1):184-212. PMID:19333441 Brain Tumor Consortium Studies PBTC-025B 14(5)467-75. PMID4957904 ropsiquiatr. 56(2):232-6. PMID:9698733
2127. Riemersma SA, Jordanova ES, Schop and PBTC-032. J Clin Oncol. 33(24):2646-54. 2159. Rodriguez LA, Edwards MS, Levin VA 2176. Rosenberg AS, Langee CL, Stevens
RF, Philippo K, Looijenga LH, Schuuring E, et PMID:26169613 (1990). Management of hypothalamic gliomas GL, Morgan MB (2002). Malignant peripheral
al. (2000). Extensive genetic alterations of the 2144. Roche PH, Figarella-Branger D, Regis in children: an analysis of 33 cases. Neu- nerve sheath tumor with perineurial differentia-
HLA region, including homozygous deletions J, Peragut JC (1996). Cauda equina parag- rosurgery. 26(2):242-6, discussion 246-7. tion: “malignant perineurioma". J Cutan Pathol.
of HLA class II genes in B-cell lymphomas anglioma with subsequent intracranial and PMID:2308672 29(6):362-7. PMID:12135468
arising in immune-privileged sites. Blood. intraspinal metastases. Acta Neurochir (Wien). 2160. Roerig P, Nessling M, Radlwimmer 2177. Rosenberg DS, Demarquay G, Jouvet
96(10):3569-77. PMID:11071656 138(4):475-9. PMID:8738400 B, Joos S, Wrobel G, Schwaenen C, et al. A, Le Bars D, Streichenberger N, Sindou M,
2128. Riemersma SA, Oudejans JJ, Vonk MJ, 2145. Rodriguez EF, Scheithauer BW, Giannini (2005). Molecular classification of human glio- et al. (2005). [11 C]-Methionine PET: dysem-
Dreef EJ, Prins FA, Jansen PM, et al. (2005). C, Rynearson A, Cen L, Hoesley B, etal. (2011). mas using matrix-based comparative genomic bryoplastic neuroepithelial tumours compared
High numbers of tumour-infiltrating activated PI3K/AKT pathway alterations are associated hybridization. Int J Cancer. 117(1):95-103. with other epileptogenic brain neoplasms. J
cytotoxic T lymphocytes, and frequent loss with clinically aggressive and histologically ana- PMID:15880582 Neurol Neurosurg Psychiatry. 76(12):1686-92.
of HLA class I and II expression, are featu- plastic subsets of pilocytic astrocytoma. Acta 2161. Roessler E, Belloni E, Gaudenz K, Jay P, PMID:16291894
res of aggressive B cell lymphomas of the Neuropathol. 121(3):407-20. PMID:21113787 Berta P, Scherer SW, et al. (1996). Mutations 2178. Rosenblum MK (1998). Ependymal
brain and testis. J Pathol. 206(3):328-36. 2146. Rodriguez FJ, Folpe AL, Giannini C, in the human Sonic Hedgehog gene cause tumors: A review of their diagnostic surgical
PMID:15887291 Perry A (2012). Pathology of peripheral nerve holoprosencephaly. Nat Genet. 14(3):357-60. pathology. Pediatr Neurosurg. 28(3): 160-5.
2129. Rienstein S, Adams EF, Pilzer D, Gol- sheath tumors: diagnostic overview and update PMID:8896572 PMID:9705595
dring AA, Goldman B, Friedman E (2003). on selected diagnostic problems. Acta Neuro- 2162. Roggendorf W, Strupp S, Paulus W 2179. Rosenblum MK, Erlandson RA, Aleksic
Comparative genomic hybridization analysis of pathol. 123(3):295-319. PMID:22327363 (1996). Distribution and characterization SN, Budzilovich GN (1990). Melanotic ependy-
craniopharyngiomas. J Neurosurg. 98(1)462- 2147. Rodriguez FJ, Mota RA, Scheithauer of microglia/macrophages in human brain moma and subependymoma. Am J Surg Pathol.
4. PMID:12546365 BW, Giannini C, Blair H, New KC, et al. (2009). tumors. Acta Neuropathol. 92(3):288-93. 14(8):729-36. PMID:2378394
2130. Ringertz N (1950). Grading of gliomas. Interphase cytogenetics for 1p19q and t(1;19) PMID:8870831 2180. Rosenblum MK, Erlandson RA, Budzi-
Acta Pathol Microbiol Scand. 27(1):51-64. (q10;p10) may distinguish prognostically rele- 2163. Roldan G, Chan J, Eliasziw M, Cairn- lovich GN (1991). The lipid-rich epithelioid gli-
PMID:15406242 vant subgroups in extraventricular neurocyto- cross JG, Forsyth PA (2011). Leptomeningeal oblastoma. Am J Surg Pathol. 15(10):925-34.
2131. Ritter JH, Mills SE, Nappi O, Wick MR ma. Brain Pathol. 19(4):623-9. PMID:18710393 disease in oligodendroglial tumors: a popula- PMID4718177
(1995). Angiosarcoma-like neoplasms of 2148. Rodriguez FJ, Perry A, Gutmann DH, tion-based study. J Neurooncol. 104(3):811-5. 2181. Roser F, Nakamura M, Bellinzona M, Ro-
epithelial organs: true endothelial tumors or O’Neill BP, Leonard J, Bryant S, et al. (2008). PMID:21373968 sahl SK, Ostertag H, Samii M (2004). The pro-
variants of carcinoma? Semin Diagn Pathol. Gliomas in neurofibromatosis type 1: a clinico- 2164. Rollison DE, Utaipat U, Ryschkewitsch C, gnostic value of progesterone receptor status
12(3):270-82. PMID:8545593 pathologic study of 100 patients. J Neuropathol Hou J, Goldthwaite P, Daniel R, et al. (2005). in meningiomas. J Clin Pathol. 57(10)4033-7.
2132. Rivera AL, Takei H, Zhai J, Shen SS, Ro Exp Neurol. 67(3):240-9. PMID:18344915 Investigation of human brain tumors for the PMID45452155
JY, Powell SZ (2010). Useful immunohistoche- 2149. Rodriguez FJ, Perry A, Rosenblum MK, presence of polyomavirus genome sequences 2182. Roser F, Nakamura M, Brandis A, Hans
mical markers in differentiating hemangiob- Krawitz S, Cohen KJ, Lin D, et al. (2012). Dis- by two independent laboratories. Int J Cancer. V, Vorkapic P, Samii M (2004). Transition from
lastoma versus metastatic renal cell carcinoma. seminated oligodendroglial-like leptomeningeal 113(5):769-74. PMID:15499616 meningeal melanocytoma to primary cere-
Neuropathology. 30(6):580-5. PMID:20374497 tumor of childhood: a distinctive clinicopatho- 2165. Romani R, Niemela M, Celik O, Isarakul bral melanoma. Case report. J Neurosurg.
2133. Roach ES, Sparagana SP (2010). Diag- logic entity. Acta Neuropathol. 124(5):627-41. P, Paetau A, Hernesniemi J (2010). Ectopic re- 101 (3):528-31. PMID45352613
nostic criteria for tuberous sclerosis complex. PMID:22941225 currence of craniopharyngioma along the surgi- 2183. Rossi A, Cama A, Consales A, Gandolfo
In: Tuberous sclerosis complex. Genes, clinical 2150. Rodriguez FJ, Scheithauer BW, Burger cal route: case report and literature review. Acta C, Garre ML, Milanaccio C, et al. (2006). Neu-
features, and therapeutics, Kwiatkowski DJ, PC, Jenkins S, Giannini C (2010). Anaplasia Neurochir (Wien). 152(2):297-302, discussion roimaging of pediatric craniopharyngiomas: a
Whittemore VH, Thiele EA, eds. Wiley-Black- in pilocytic astrocytoma predicts aggressive 302. PMID:19499168 pictorial essay. J Pediatr Endocrinol Metab. 19
well: Weinheim, Germany, pp. 21-25. behavior. Am J Surg Pathol, 34(2):147-60. 2166. Romero-Rojas AE, Diaz-Perez JA, Ari- Suppl 1:299-319. PMID46700305
2134. Robbins P, Segal A, Narula S, Sto- PMID:20061938 za-Serrano LM, Amaro D, Lozano-Castillo 2184. Rossi ML, Jones NR, Candy E, Nicoll
kes B, Lee M, Thomas W, et al. (1995). 2151. Rodriguez FJ, Scheithauer BW, Giannini A (2013). Primary gliosarcoma of the brain: JA, Compton JS, Hughes JT, et al. (1989). The
References 389
mononuclear cell infiltrate compared with survi- clinicopathologic and flow cytometric study of 13(4):393-9. PMID:24506340 (2005) . Mutational analysis of the TSC1 and
val in high-grade astrocytomas. Acta Neuropa- 13 cases presenting in the central nervous sys- 2217. Sahm F, Bissel J, Koelsche C, Schweizer TSC2 genes in a diagnostic setting: genoty-
thol. 78(2):189-93. PMID:2750489 tem. Cancer. 77(9)4884-91. PMID:8646689 L, Capper D, Reuss D, et al. (2013). AKT1E17K pe-phenotype correlations and comparison of
2185. Rossi S, Rodriguez FJ, Mota RA, Dei 2201. Rushing EJ, Cooper PB, Quezado M, Be- mutations cluster with meningothelial and tran- diagnostic DNA techniques in Tuberous Sclero-
Tos AP, Di Paola F, Bendini M, et al. (2009). gnami M, Crespo A, Smirniotopoulos JG, et al. sitional meningiomas and can be detected by sis Complex. Eur J Hum Genet. 13(6)731-41.
Primary leptomeningeal oligodendroglioma (2007). Subependymoma revisited: clinicopa- SFRP1 immunohistochemistry. Acta Neuropa- PMID4 5798777
with documented progression to anaplasia and thological evaluation of 83 cases. J Neurooncol. thol. 126(5)757-62. PMID:24096618 2232. Sandberg DI, Ragheb J, Dunoyer C, Bha-
t(1;19)(q10;p10) in a child. Acta Neuropathol, 85(3):297-305. PMID47569000 2218. Sahm F, Capper D, Preusser M, Meyer J, tia S, Olavarria G, Morrison G (2005). Surgical
118(4):575-7. PMID:19562354 2202. Rushing EJ, Olsen C, Mena H, Rueda StenzingerA, Lasitschka F, et al. (2012). BRAF- outcomes and seizure control rates after resec-
2186. Rossitch E Jr, Zeidman SM, Burger PC, ME, Lee YS, Keating RF, et al. (2005). Central V600E mutant protein is expressed in cells of tion of dysembryoplastic neuroepithelial tumors.
Curnes JT, Harsh C, Anscher M, et al. (1990). nervous system meningiomas in the first two variable maturation in Langerhans cell histiocy- Neurosurg Focus. 18 6A:E5. PMID46048291
Clinical and pathological analysis of spinal decades of life: a clinicopathological analysis of tosis. Blood. 120(12):e28-34. PMID:22859608 2233. Sanford RA, Bowman R, Tomita T, De
cord astrocytomas in children. Neurosurgery. 87 patients. J Neurosurg. 103(6) Suppl:489-95. 2219. Sahm F, Koelsche C, Meyer J, Pusch S, Leon G, Palka P (1999). A 16-year-old male
27(2):193-6. PMID:2385335 PMID46383246 Lindenberg K, Mueller W, et al. (2012). CIC and with Noonan's syndrome develops progressive
2187. Rostomily RC, Bermingham-McDonogh 2203. Rushing EJ, Thompson LD, Mena H FUBP1 mutations in oligodendrogliomas, oli- scoliosis and deteriorating gait. Pediatr Neuro-
0, Berger MS, Tapscott SJ, Reh TA, Olson (2003). Malignant transformation of a dysem- goastrocytomas and astrocytomas. Acta Neuro- surg. 30(1)47-52. PMID40202309
JM (1997), Expression of neurogenic basic bryoplastic neuroepithelial tumor after radi- pathol. 123(6):853-60. PMID:22588899 2234. Sanford RA, Gajjar A (1997). Epen-
helix-loop-helix genes in primitive neuroecto- ation and chemotherapy. Ann Diagn Pathol. 2220. Sahm F, Reuss D, Koelsche C, Capper D, dymomas. Clin Neurosurg. 44:559-70.
dermal tumors. Cancer Res. 57(16):3526-31. 7(4):240-4. PMID42913847 Schittenhelm J, Heim S, et al. (2014). Farewell PMID40080027
PMID:9270024 2204. Russell DS, Rubinstein LJ (1989). Patho- to oligoastrocytoma: in situ molecular genetics 2235. Sangoi AR, Dulai MS, Beck AH, Brat
2188. Roth J, Roach ES, Bartels U, Jozwiak logy of Tumours of the Nervous System. Lon- favor classification as either oligodendroglioma DJ, Vogel H (2009). Distinguishing Chordoid
S, Koenig MK, Weiner HL, et al. (2013). Sub- don: Edward Arnold. or astrocytoma. Acta Neuropathol. 128(4):551- meningiomas from their histologic mimics: an
ependymal giant cell astrocytoma: diagnosis, 2205. Russell, DS and Rubinstein, LJ ((.Pa- 9. PMID:25143301 immunohistochemical evaluation. Am J Surg
screening, and treatment. Recommendations thology of tumours of the nervous system. 5th 2220A. Sahm F, Schrimpf D, Olar A, Koelsche Pathol. 33(5):669-81. PMID49194275
from the International Tuberous Sclerosis London: Edward Arnold. C, Reuss D, Bissel J, et al. (2015). TERT 2236. Sankhla S, Khan GM (2004). Cauda
Complex Consensus Conference 2012. Pediatr 2206. Russo C, Pellarin M, Tingby O, Bollen Promoter Mutations and Risk of Recurrence equina paraganglioma presenting with in-
Neurol. 49(6)439-44. PMID:24138953 AW, Lamborn KR, Mohapatra G, et al. (1999). in Meningioma. J Natl Cancer Inst. 108(5). tracranial hypertension: case report and review
2189. Rotman JA, Kucharczyk W, Zadeh G, Comparative genomic hybridization in patients PMID:26668184 of the literature. Neurol India. 52(2):243-4.
Kiehl TR, Al-Ahmadi H (2014). Spindle cell with supratentorial and infratentorial primitive 2221. Sainz J, Figueroa K, Baser ME, Mautner PMID4 5269482
oncocytoma of the adenohypophysis: a case neuroectodermal tumors. Cancer. 86(2):331-9. VF, Pulst SM (1995). High frequency of nonsen- 2237. Sanoudou D, Tingby O, Ferguson-Smith
report illustrating its natural history with 8-year PMID40421270 se mutations in the NF2 gene caused by C to T MA, Collins VP, Coleman N (2000). Analysis of
observation and a review of the literature. Clin 2207. Rutkowski S, Bode U, Deinlein F, Ot- transitions in five CGA codons. Hum Mol Genet. pilocytic astrocytoma by comparative genomic
Imaging. 38(4)499-504. PMID:24721021 tensmeier H, Warmuth-Metz M, Soerensen 4(1)437-9. PMID7711726 hybridization. Br J Cancer. 82(6)4218-22.
2190. Rouleau GA, Merel P, Lutchman M, San- N, et al. (2005). Treatment of early childhood 2222. Sainz J, Huynh DP, Figueroa K, Ragge PMID40735509
son M, Zucman J, Marineau C, et al. (1993). medulloblastoma by postoperative chemothe- NK, Baser ME, Pulst SM (1994). Mutations of 2238. Sanson M, Marie Y, Paris S, Idbaih A,
Alteration in a new gene encoding a putative rapy alone. N Engl J Med. 352(10):978-86. the neurofibromatosis type 2 gene and lack of Laffaire J, Ducray F, et al. (2009). Isocitrate
membrane-organizing protein causes neuro-fi- PMID45758008 the gene product in vestibular schwannomas. dehydrogenase 1 codon 132 mutation is an im-
bromatosis type 2. Nature. 363(6429):515-21. 2208. Rutkowski S, von Hoff K, Emser A, Hum Mol Genet. 3(6):885-91. PMID7951231 portant prognostic biomarker in gliomas. J Clin
PMID:8379998 Zwiener I, Pietsch T, Figarella-Branger D, et al. 2223. Sakaguchi N, Sano K, Ito M, Baba T, Oncol. 27(25)4150-4. PMID49636000
2191. Rousseau G, Noguchi T, Bourdon V, (2010). Survival and prognostic factors of early Fukuzawa M, Hotchi M (1996). A case of von 2239. Santagata S, Hornick JL, Ligon KL
Sobol H, Olschwang S (2011). SMARCB1/ childhood medulloblastoma: an international Recklinghausen's disease with bilateral pheo- (2006) . Comparative analysis of germ cell
INI1 germline mutations contribute to 10% of meta-analysis. J Clin Oncol. 28(33)4961-8. chromocytoma-malignant peripheral nerve she- transcription factors in CNS germinoma reveals
sporadic schwannomatosis. BMC Neurol. 11:9. PMID:20940197 ath tumors of the adrenal and gastrointestinal diagnostic utility of NANOG. Am J Surg Pathol.
PMID:21255467 2209. Ryken TC, Robinson RA, VanGilder autonomic nerve tumors. Am J Surg Pathol. 30(12)4613-8. PMID47122519
2192. Roussel MF, Robinson GW (2013). Role JC (1994). Familial occurrence of subepen- 20(7):889-97. PMID:8669538 2240. Santagata S, Ligon KL, Hornick JL
of MYC in Medulloblastoma. Cold Spring Harb dymoma. Report of two cases. J Neurosurg. 2224. Sakuta R, Otsubo H, Nolan MA, Weiss (2007) . Embryonic stem cell transcription fac-
Perspect Med. 3(11):3. PMID:24186490 80(6)4108-11. PMID:8189269 SK, Hawkins C, Rutka JT, et al. (2005). Recur- tor signatures in the diagnosis of primary and
2193. Roy S, Chu A, Trojanowski JQ, Zhang PJ 2210. Sabbaghian N, Hamel N, Srivastava rent intractable seizures in children with cortical metastatic germ cell tumors. Am J Surg Pathol.
(2005). D2-40, a novel monoclonal antibody A, Albrecht S, Priest JR, Foulkes WD (2012). dysplasia adjacent to dysembryoplastic neu- 31(6):836-45. PMID47527070
against the M2A antigen as a marker to distin- Germline DICER1 mutation and associated loss roepithelial tumor. J Child Neurol. 20(4):377- 2241. Santagata S, Maire CL, Idbaih A, Geffers
guish hemangioblastomas from renal cell car- of heterozygosity in a pineoblastoma. J Med 84. PMID45921242 L, Cornell M, Holton K, et al. (2009). CRX is a di-
cinomas. Acta Neuropathol. 109(5)497-502. Genet. 49(7)417-9. PMID:22717647 2225. Salgado CM, Basu D, Nikiforova M, agnostic marker of retinal and pineal lineage tu-
PMID:15864611 2211. Sachdeva MU, Vankalakunti M, Rangan Bauer BS, Johnson D, Rundell V, et al. (2015). mors. PLoS One. 4(11 ):e7932. PMID49936203
2194. Rubin JB, Gutmann DH (2005). Neurofi- A, Radotra BD, Chhabra R, Vasishta RK (2008). BRAF mutations are also associated with neu- 2242. Sarkar C, Sharma MC, Sudha K, Gaik-
bromatosis type 1 - a model for nervous system The role of immunohistochemistry in medul- rocutaneous melanocytosis and large/giant wad S, Varma A (1997). A clinico-pathological
tumour formation? Nat Rev Cancer. 5(7):557- lomyoblastoma-a case series highlighting congenital melanocytic nevi. Pediatr Dev Pa- study of 29 cases of gliosarcoma with special
64. PMID:16069817 divergent differentiation. Diagn Pathol. 3:18. thol. 18(1)4-9. PMID:25490715 reference to two unique variants. Indian J Med
2195. Rubinstein LJ (1986). The malformative PMID48439235 2226. Salunke PS, Gupta K, Srinivasa R, Sura Res. 106:229-35. PMID:9378529
central nervous system lesions in the central 2212. Sadetzki S, Bruchim R, Oberman B, S (2011). Functional? Paraganglioma of the ce- 2243. Sarkar H, K S, Ghosh S (2013). Pure int-
and peripheral forms of neurofibromatosis. A Armstrong GN, Lau CC, Claus EB, et al.; Glio- rebellum. Acta Neurochir (Wien). 153(7)4527- raventricular origin of gliosarcoma - a rare entity.
neuropathological study of 22 cases. Ann N Y gene Consortium (2013), Description of selec- 8. PMID:21491190 Turk Neurosurg. 23(3):392^t. PMID:23756982
Acad Sci. 486:14-29. PMID:3105387 ted characteristics of familial glioma patients 2227. Salvati M, Ciappetta P, Raco A (1993). 2244. Sarkaria JN, Kitange GJ, James CD,
2196. Rueda-Pedraza ME, Heifetz SA, Sester- - results from the Gliogene Consortium. Eur J Osteosarcomas of the skull. Clinical re- Plummer R, Calvert H, Weller M, et al. (2008).
henn IA, Clark GB (1987). Primary intracranial Cancer. 49(6)4335^15. PMID:23290425 marks on 19 cases. Cancer. 71(7):2210-6. Mechanisms of chemoresistance to alkylating
germ cell tumors in the first two decades of life. 2213. Sadetzki S, Chetrit A, Freedman L, PMID:8453540 agents in malignant glioma. Clin Cancer Res.
A clinical, light-microscopic, and immunohisto- Stovall M, Modan B, Novikov I (2005). Long- 2228. Salvati M, Oppido PA, Artizzu S, Fioren- 14(10):2900-8. PMID48483356
chemical analysis of 54 cases. Perspect Pediatr term follow-up for brain tumor development za F, Puzzilli F, Orlando ER (1991). Multicen- 2245. Sartoretti-Schefer S, Wichmann W,
Pathol. 10:160-207. PMID:3588245 after childhood exposure to ionizing radiation tric gliomas. Report of seven cases. Tumori. Aguzzi A, Valavanis A (1997). MR differentia-
2197. Ruggieri M, Polizzi A, Spalice A, Salpietro for tinea capitis. Radiat Res. 163(4)424-32. 77(6):518-22. PMID4666470 tion of adamantinous and squamous-papillary
V, Caltabiano R, D’Orazi V, et al. (2015). The PMID45799699 2229. Sampson JR, Maheshwar MM, Aspin- craniopharyngiomas. AJNR Am J Neuroradiol.
natural history of spinal neurofibromatosis: a 2214. Saesue P, Chankaew E, Chawalparit O, wall R, Thompson P, Cheadle JP, Ravine D, 18(1)77-87. PMID:9010523
critical review of clinical and genetic features. Na Ayudhya NS, Muangsomboon S, Sangruchi et al. (1997). Renal cystic disease in tuberous 2246. Sasaki H, Zlatescu MC, Betensky RA,
Clin Genet. 87(5)401-10 PMID:25211147 T (2004). Primary extraskeletal osteosarcoma sclerosis: role of the polycystic kidney disea- Ino Y, Cairncross JG, Louis DN (2001). PTEN is
2198. Ruland V, Hartung S, Kordes U, Wolff JE, in the pineal region. Case report. J Neurosurg. se 1 gene. Am J Hum Genet. 61(4):843-51. a target of chromosome 10q loss in anaplastic
Paulus W, Hasselblatt M (2014). Choroid ple- 101(6)4061-4. PMID45597771 PMID:9382094 oligodendrogliomas and PTEN alterations are
xus carcinomas are characterized by complex 2215. Safaee M, Oh MC, Bloch O, Sun MZ, 2229A. Sampson JR, Scahill SJ, Stephenson associated with poor prognosis. Am J Pathol.
chromosomal alterations related to patient age Kaur G, Auguste Kl, et al. (2013). Choroid ple- JB, Mann L, Connor JM (1989). Genetic aspects 159(1):359-67. PMID41438483
and prognosis. Genes Chromosomes Cancer. xus papillomas: advances in molecular biology of tuberous sclerosis in the west of Scotland. J 2247. Sato H, Ohmura K, Mizushima M, Ito J,
53(5):373-80. PMID:24478045 and understanding of tumorigenesis. Neuro On- Med Genet. 26(1):28-31. PMID:2918523 Kuyama H (1983). Myxopapillary ependymoma
2199. Rupani A, Modi C, Desai S, Rege J col. 15(3):255-67. PMID:23172371 2230. Sanai N, Alvarez-Buylla A, Berger of the lateral ventricle. A study on the mecha-
(2005). Primary anaplastic large cell lympho- 2216. Safaee M, Oh MC, Mummaneni PV, MS (2005). Neural stem cells and the origin nism of its stromal myxoid change. Acta Pathol
ma of central nervous system-a case report. Weinstein PR, Ames CP, Chou D, et al. (2014). of gliomas. N Engl J Med. 353(8):811-22. Jpn. 33(5)4017-25. PMID:6359815
J Postgrad Med. 51(4):326-7. PMID:16388180 Surgical outcomes in spinal cord ependymo- PMID46120861 2248. Sato TS, Kirby PA, Buatti JM, Moritani T
2200. Rushing EJ, Armonda RA, Ansari Q, Mena mas and the importance of extent of resection in 2231. Sancak O, Nellist M, Goedbloed M, (2009). Papillary tumor of the pineal region: re-
H (1996). Mesenchymal chondrosarcoma: a children and young adults. J Neurosurg Pediatr. Elfferich P, Wouters C, Maat-Kievit A, et al. port of a rapidly progressive tumor with possible
390 References
multicentric origin. Pediatr Radiol. 39(2):188- 40:159-98. Neuropathol. 29(5):323-9. PMID20860896 pathological features of breast disease in Cow-
90. PMID:19037636 2266. Scherer HJ (1938). Structural develop- 2284. Schittenhelm J, Roser F, Tatagiba M, Be- den's syndrome: an underrecognized syndrome
2249. Satoh T, Smith A, Sarde A, Lu HC, Mian ment in gliomas. Am J Cancer. 34:333-51. schorner R (2012). Diagnostic value of EAAT-1 with an increased risk of breast cancer. Hum
S, Trouillet C, et al. (2012). B-RAF mutant al- 2267. Scherer HJ (1940). The forms of growth and Kir7.1 for distinguishing endolymphatic sac Pathol. 29(1):47-53. PMID:9445133
leles associated with Langerhans cell histiocy- in gliomas and their practical significance. tumors from choroid plexus tumors. Am J Clin 2299. Schroers R, Baraniskin A, Heute C, Vor-
tosis, a granulomatous pediatric disease. PLoS Brain. 63:1-35. Pathol. 138(1 ):85-9. PMID22706862 gerd M, Brunn A, Kuhnhenn J, et al. (2010).
One. 7(4):e33891. PMID:22506009 2268. Scheurlen WG, Schwabe GC, Joos S, 2285. Schlamann A, von Bueren AO, Hagel C, Diagnosis of leptomeningeal disease in diffuse
2250. Sawamura Y, Hamou MF, Kuppner MC, Mollenhauer J, Sorensen N, Kuhl J (1998). Mo- Zwiener I, Seidel C, Kortmann RD, et al. (2014). large B-cell lymphomas of the central nervous
de Tribolet N (1989). Immunohistochemical and lecular analysis of childhood primitive neuroec- An individual patient data meta-analysis on system by flow cytometry and cytopathology.
in vitro functional analysis of pineal-germino- todermal tumors defines markers associated characteristics and outcome of patients with pa- Eur J Haematol. 85(6):520-8. PMID:20727005
ma infiltrating lymphocytes: report of a case. with poor outcome. J Clin Oncol. 16(7):2478- pillary glioneuronal tumor, rosette glioneuronal 2300. Schuettpelz LG, McDonald S, Whitesell
Neurosurgery. 25(3):454-7, discussion 457-8. 85. PMID:9667267 tumor with neuropil-like islands and rosette for- K, Desruisseau DM, Grange DK, Gurnett CA,
PMID:2671789 2269. Schiariti M, Goetz P, El-Maghraby H, ming glioneuronal tumor of the fourth ventricle. et al. (2009). Pilocytic astrocytoma in a child
2251. Sawamura Y, Ikeda J, Shirato H, Tada Tailor J, Kitchen N (2011). Hemangiopericyto- PLoS One. 9(7):e101211. PMID24991807 with Noonan syndrome. Pediatr Blood Cancer.
M, Abe H (1998). Germ cell tumours of the ma: long-term outcome revisited. Clinical article. 2286. Schlegel U (2009). Primary CNS lym- 53(6):1147-9. PMID:19621452
central nervous system: treatment considera- J Neurosurg. 114(3):747-55. PMID:20672899 phoma. Ther Adv Neurol Disord. 2(2):93-104. 2301. Schumacher T, Bunse L, Pusch S,
tion based on 111 cases and their long-term 2270. Schiefer Al, Vastagh I, Molnar MJ, Be- PMID:21180644 Sahm F, Wiestler B, Quandt J, et al. (2014).
clinical outcomes. Eur J Cancer. 34(1):104-10. reczki D, Varallyay G, Deak B, et al. (2012), Ex- 2287. Schmalisch K, Beschorner R, Psaras T, A vaccine targeting mutant IDH1 induces an-
PMID:9624246 tranodal marginal zone lymphoma of the CNS Honegger J (2010). Postoperative intracranial titumour immunity. Nature. 512(7514):324-7.
2252. Sawin PD, Theodore N, Rekate HL arising after a long-standing history of atypical seeding of craniopharyngiomas-report of three PMID:25043048
(1999). Spinal cord ganglioglioma in a child with white matter disease. Leuk Res. 36(7):e155-7. cases and review of the literature. Acta Neu- 2302. Schuss P, Ulrich CT, Harter PN, Tews
neurofibromatosis type 2. Case report and lite- PMID:22520340 rochir (Wien). 152(2):313-9, discussion 319. DS, Seifert V, Franz K (2011). Gliosarcoma with
rature review. J Neurosurg. 90(2) Suppl:231-3. 2271. Schiff D, O’Neill B, Wijdicks E, Antin JH, PMID:19859655 bone infiltration and extracranial growth: case
PMID:10199253 Wen PY (2001), Gliomas arising in organ trans- 2288. Schmidbauer M, Budka H, Pilz P (1989). report and review of literature. J Neurooncol.
2253. Sawyer JR, Roloson GJ, Chadduck WM, plant recipients: an unrecognized complication Neuroepithelial and ectomesenchymal diffe- 103(3)765-70. PMID:20957407
Boop FA (1991). Cytogenetic findings in a ple- of transplantation? Neurology. 57(8):1486-8. rentiation in a primitive pineal tumor (“pineal 2303. Schwartz AM, Ghatak NR (1990). Mali-
omorphic xanthoastrocytoma. Cancer Genet PMID:11673595 anlage tumor"). Clin Neuropathol. 8(1)7-10. gnant transformation of benign cerebellar ast-
Cytogenet. 55(2):225-30. PMID:1933824 2272. Schiffer D, Cavalla P, Migheli A, Chio A, PMID:2650944 rocytoma. Cancer. 65(2):333-6. PMID:2403835
2254. Sawyer JR, Thomas EL, Roloson GJ, Giordana MT, Marino S, et al. (1995). Apopto- 2289. Schmidt MC, Antweiler S, Urban N, Mu- 2304. Schwartzentruber J, Korshunov A, Liu
Chadduck WM, Boop FA (1992). Telomeric sis and cell proliferation in human neuroepit- eller W, Kuklik A, Meyer-Puttlitz B, et al. (2002). XY, Jones DT, Pfaff E, Jacob K, et al. (2012).
associations evolving to ring chromosomes helial tumors. Neurosci Lett. 195(2):81-4. Impact of genotype and morphology on the Driver mutations in histone H3.3 and chromatin
in a recurrent pleomorphic xanthoastrocyto- PMID:7478273 prognosis of glioblastoma. J Neuropathol Exp remodelling genes in paediatric glioblastoma.
ma. Cancer Genet Cytogenet. 60(2):152-7. 2273. Schiffer D, Chio A, Giordana MT, Leone Neurol. 61(4):321-8. PMID:11939587 Nature. 482(7384):226-31. PMID:22286061
PMID:1606558 M, Soffietti R (1988). Prognostic value of his- 2290. Schmidt Y, Kleinschmidt-DeMasters BK, 2305. Schwartzkroin PA, Wenzel HJ (2012).
2254A.Schaefer IM, Fletcher CD, Homick JL tologic factors in adult cerebral astrocytoma. Aisner DL, Lillehei KO, Damek D (2013). Ana- Are developmental dysplastic lesions epi-
(2016). Loss of H3K27 trimethylation distingu- Cancer. 61(7):1386-93. PMID:3345492 plastic PXA in adults: case series with clinicopa- leptogenic? Epilepsia. 53 Suppl 1:35-44.
ishes malignant peripheral nerve sheath tumors 2274. Schiffer D, Chio A, Giordana MT, Migheli thologic and molecular features. J Neurooncol. PMID:22612807
from histologic mimics. Mod Pathol.29(1 ):4-13. A, Palma L, Polio B, et al. (1991). Histologic 111(1 ):59-69. PMID:23096133 2306. Schwechheimer K, Huang S, Cavenee
PMID:26585554 prognostic factors in ependymoma. Childs Nerv 2291. Schmitz U, Mueller W, Weber M, Se- WK (1995). EGFR gene amplification-rearran-
2256. Scheie D, Meling TR, Cvancarova M, Syst. 7(4):177-82. PMID:1933913 venet N, Delattre O, von Deimling A (2001). gement in human glioblastomas. Int J Cancer.
Skullerud K, Mark S, Lote K, et al. (2011). Pro- 2275. Schiffer D, Giordana MT (1998). Pro- INI1 mutations in meningiomas at a potential 62(2):145-8. PMID7622287
gnostic variables in oligodendroglial tumors: a gnosis of ependymoma. Childs Nerv Syst. hotspot in exon 9. Br J Cancer. 84(2):199-201. 2307. Schweizer L, Capper D, Holsken A, Fahl-
single-institution study of 95 cases. Neuro On- 14(8):357-61. PMID:9753400 PMID:11161377 busch R, Flitsch J, Buchfelder M, et al. (2015).
col. 13(11):1225-33. PMID:21856683 2276. Schiffer D, Giordana MT, Mauro A, Mig- 2292. Schneider DT, Zahn S, Sievers S, Ale- BRAF V600E analysis for the differentiation
2257. Scheithauer BW (1978). Symptomatic heli A (1984). GFAP, F VIII/RAg, laminin, and fi- mazkour K, Reifenberger G, Wiestler OD, et of papillary craniopharyngiomas and Rath-
subependymoma. Report of 21 cases with re- bronectin in gliosarcomas: an immunohistoche- al. (2006). Molecular genetic analysis of central ke’s cleft cysts. Neuropathol Appl Neurobiol.
view of the literature. J Neurosurg. 49(5):689- mical study. Acta Neuropathol. 63(2):108-16. nervous system germ cell tumors with com- 41(6)733-42 PMID:25442675
96. PMID:712391 PMID:6428154 parative genomic hybridization. Mod Pathol. 2308. Schweizer L, Koelsche C, Sahm F, Piro
2258. Scheithauer BW (1999). Pathobiology of 2277. Schiffman JD, Hodgson JG, VandenBerg 19(6):864-73. PMID:16607373 RM, Capper D, Reuss DE, et al. (2013). Menin-
the pineal gland with emphasis on parenchy- SR, Flaherty P, Polley MY, Yu M, et al. (2010). 2293. Schneppenheim R, Friihwald MC, Gesk geal hemangiopericytoma and solitary fibrous
mal tumors. Brain Tumor Pathoi. 16(1):1-9. Oncogenic BRAF mutation with CDKN2A S, Hasselblatt M, Jeibmann A, Kordes U, et tumors carry the NAB2-STAT6 fusion and can
PMID:10532417 inactivation is characteristic of a subset of pe- al. (2010). Germline nonsense mutation and be diagnosed by nuclear expression of STAT6
2259. Scheithauer BW, Amrami KK, Folpe AL, diatric malignant astrocytomas. Cancer Res. somatic inactivation of SMARCA4/BRG1 in protein. Acta Neuropathol. 125(5):651-8.
Silva Al, Edgar MA, Woodruff JM, et al. (2011). 70(2):512-9. PMID:20068183 a family with rhabdoid tumor predisposition PMID:23575898
Synovial sarcoma of nerve. Hum Pathol. 2278. Schild SE, Scheithauer BW, Haddock syndrome. Am J Hum Genet. 86(2):279-84. 2309. Schwindt H, Vater I, Kreuz M, Monte-
42(4):568-77. PMID:21295819 MG, Wong WW, Lyons MK, Marks LB, et al. PMID:20137775 sinos-Rongen M, Brunn A, Richter J, et al.
2260. Scheithauer BW, Erdogan S, Rodriguez (1996). Histologically confirmed pineal tumors 2294. Schniederjan MJ, Alghamdi S, Castel- (2009). Chromosomal imbalances and partial
FJ, Burger PC, Woodruff JM, Kros JM, et al. and other germ cell tumors of the brain. Cancer. lano-Sanchez A, Mazewski C, Brahma B, uniparental disomies in primary central nervous
(2009). Malignant peripheral nerve sheath 78(12)2564-71. PMID:8952565 Brat DJ, et al. (2013). Diffuse leptomeningeal system lymphoma. Leukemia. 23(10):1875-84.
tumors of cranial nerves and intracranial cont- 2279. Schild SE, Scheithauer BW, Schomberg neuroepithelial tumor: 9 pediatric cases with PMID:19494841
ents: a clinicopathologic study of 17 cases. Am PJ, Hook CC, Kelly PJ, Frick L, et al. (1993). Pi- chromosome 1p/19q deletion status and IDH1 2310. Schuller U, Heine VM, Mao J, Kho AT,
J Surg Pathol. 33(3):325-38. PMID:19065105 neal parenchymal tumors. Clinical, pathologic, (R132H) immunohistochemistry. Am J Surg Pa- Dillon AK, Han YG, et al. (2008). Acquisition of
2261. Scheithauer BW, Horvath E, Kovacs and therapeutic aspects. Cancer. 72(3):870-80. thol. 37(5)763-71. PMID:23588371 granule neuron precursor identity is a critical
K (1992). Ultrastructure of the neurohypo- PMID:8334641 2294A. Schoemaker MJ, Swerdlow AJ, determinant of progenitor cell competence to
physis. Microsc Res Tech. 20(2):177-86. 2280. Schindler G, Capper D, Meyer J, Janzarik Hepworth SJ, van Tongeren M, Muir KR, form Shh-induced medulloblastoma. Cancer
PMID:1547358 W, Omran H, Herold-Mende C, et al. (2011). McKinney PA (2007). History of allergic disea- Cell. 14(2):123-34. PMID:18691547
2262. Scheithauer BW, Rubinstein LJ (1978). Analysis of BRAF V600E mutation in 1,320 se and risk of meningioma. Am J Epidemiol. 2311. Sciot R, Dal Cin P, Hagemeijer A, De
Meningeal mesenchymal chondrosarcoma: nervous system tumors reveals high mutation 165(5):477-85. PMID:17182979 Smet L, Van Damme B, Van den Berghe H
report of 8 cases with review of the literature. frequencies in pleomorphic xanthoastrocytoma, 2295. Schoenberg BS, Schoenberg DG, Chris- (1999). Cutaneous sclerosing perineurioma
Cancer. 42(6):2744-52. PMID:365318 ganglioglioma and extra-cerebellar pilocytic as- tine BW, Gomez MR (1976). The epidemiology with cryptic NF2 gene deletion. Am J Surg Pa-
2263. Scheithauer BW, Silva Al, Ketterling trocytoma. Acta Neuropathol. 121 (3):397-405. of primary intracranial neoplasms of childhood. thol. 23(7):849-53. PMID:10403310
RP, Pula JH, Lininger JF, Krinock MJ (2009). PMID21274720 Apopulation study. Mayo Clin Proc. 51(1):51-6. 2312. Scott RM, Ballantine HT Jr (1973). Cere-
Rosette-forming glioneuronal tumor: report 2281. Schittenhelm J, Mittelbronn M, Nguyen PMID:1249998 bellar astrocytoma: malignant recurrence after
of a chiasmal-optic nerve example in neuro- TD, Meyermann R, Beschorner R (2008). WT1 2296. Schofield D, West DC, Anthony DC, prolonged postoperative survival. Case report.
fibromatosis type 1: special pathology report. expression distinguishes astrocytic tumor cells Marshal R, Sklar J (1995). Correlation of loss J Neurosurg. 39(6)777-9. PMID:4759666
Neurosurgery. 64(4):E771-2, discussion E772. from normal and reactive astrocytes. Brain Pa- of heterozygosity at chromosome 9q with his- 2313. Seiz M, Tuettenberg J, Meyer J, Essig M,
PM ID: 193498062264 thol. 18(3):344-53. PMID:18371184 tological subtype in medulloblastomas. Am J Schmieder K, Mawrin C, et al. (2010). Detection
2264. Schenk PW, Van Es S, Kesbeke F, 2282. Schittenhelm J, Mittelbronn M, Wolff M, Pathol. 146(2):472-80. PMID7856756 of IDH1 mutations in gliomatosis cerebri, but
Snaar-Jagalska BE (1991). Involvement of Truebenbach J, Will BE, Meyermann R, et al. 2297. Schouten LJ, Rutten J, Huveneers HA, only in tumors with additional solid component:
cyclic AMP cell surface receptors and G-pro- (2007). Multifocal dysembryoplastic neuroepit- Twijnstra A (2002). Incidence of brain metasta- evidence for molecular subtypes. Acta Neuro-
teins in signal transduction during slug migra- helial tumor with signs of atypia after regrowth. ses in a cohort of patients with carcinoma of the pathol. 120(2):261-7. PMID:20514489
tion of Dictyostelium discoideum. Dev Biol. Neuropathology. 27(4):383-9. PMID:17899694 breast, colon, kidney, and lung and melanoma. 2314. Seizinger BR, Martuza RL, Gusella JF
145(1):110-8. PMID:1850366 2283. Schittenhelm J, Psaras T (2010). Gli- Cancer. 94(10):2698-705. PMID:12173339 (1986). Loss of genes on chromosome 22 in
2265. Scherer H-J (1940). Cerebral astrocyto- oblastoma with granular cell astrocytoma fea- 2298. Schrager CA, Schneider D, Gruener AC, tumorigenesis of human acoustic neuroma. Na-
mas and their derivatives. Am J Cancer. tures: a case report and literature review. Clin Tsou HC, Peacocke M (1998). Clinical and ture. 322(6080):644-7. PMID:3092103
References 391
2315. Seizinger BR, Rouleau GA, Ozelius LJ, Majounie E, Shenton A, Baser M, et al. (2011). multiforme. J Neurosurg. 101(2):219-26. (2012). Catecholamine-secreting paraganglio-
Lane AH, FaryniarzAG, Chao MV, et al. (1987). A molecular analysis of individuals with neuro- PMID:15309911 ma of the thoracic spinal column: report of an
Genetic linkage of von Recklinghausen neurofi- fibromatosis type 1 (NF1) and optic pathway 2348. Shinojima N, Ohta K, Yano S, Nakamura unusual case and review of the literature. Neu-
bromatosis to the nerve growth factor receptor gliomas (OPGs), and an assessment of ge- H, Kochi M, Ishimaru Y, et al. (2002). Myofibrob- rosurgery. 70(4):E1049-52, discussion E1052.
gene. Cell. 49(5):589-94. PMID:2884037 notype-phenotype correlations. J Med Genet. lastoma in the suprasellar region. Case report. PMID:21788916
2316. Sekine S, Shibata T, Kokubu A, Morishita 48(4):256-60. PMID:21278392 J Neurosurg. 97(5):1203-7. PMID:12450045 2364. Singh D, Chan JM, Zoppoli P, Niola F,
Y, Noguchi M, Nakanishi Y, et al. (2002). Crani- 2333. Sharma M, Ralte A, Arora R, Santosh V, 2349. Shintaku M, Yoneda H, Hirato J, Nagaishi Sullivan R, Castano A, et al. (2012). Transfor-
opharyngiomas of adamantinomatous type har- Shankar SK, Sarkar C (2004). Subependymal M, Okabe H (2013). Gliosarcoma with ependy- ming fusions of FGFR and TACC genes in hu-
bor beta-catenin gene mutations. Am J Pathol. giant cell astrocytoma: a clinicopathological mal and PNET-like differentiation. Clin Neuro- man glioblastoma. Science. 337(6099)4231-5.
161(6):1997-2001. PMID:12466115 study of 23 cases with special emphasis on pathol. 32(6):508-14. PMID:23863343 PMID:22837387
2317. Sekine S, Takata T, Shibata T, Mori M, proliferative markers and expression of p53 2350. Shishiba T, Niimura M, Ohtsuka F, Tsuru 2365. Singh SK, Hawkins C, Clarke ID, Squire
Morishita Y, Noguchi M, et al. (2004). Expres- and retinoblastoma gene proteins. Pathology. N (1984). Multiple cutaneous neurilemmomas JA, Bayani J, Hide T, et al. (2004). Identification
sion of enamel proteins and LEF1 in adaman- 36(2):139-44. PMID:15203749 as a skin manifestation of neurilemmomato- of human brain tumour initiating cells. Nature.
tinomatous craniopharyngioma: evidence for its 2334. Sharma MC, Ralte AM, Gaekwad S, sis. J Am Acad Dermatol. 10(5 Pt 1 ):744-54. 432(7015):396-401. PMID45549107
odontogenic epithelial differentiation. Histopa- Santosh V, Shankar SK, Sarkar C (2004). PMID:6427303 2366. Sinicrope FA, Sargent DJ (2012). Mo-
thology. 45(6):573-9. PMID:15569047 Subependymal giant cell astrocytoma-a clini- 2351. Shiurba RA, Buffinger NS, Spencer EM, lecular pathways: microsatellite instability in
2318. Sener RN (2002). Astroblastoma: dif- copathological study of 23 cases with special Urich H (1991). Basic fibroblast growth factor colorectal cancer: prognostic, predictive, and
fusion MRI, and proton MR spectroscopy. emphasis on histogenesis. Pathol Oncol Res. and somatomedin C in human medulloepithe- therapeutic implications. Clin Cancer Res.
Comput Med Imaging Graph. 26(3):187-91. 10(4):219-24. PMID:15619643 lioma. Cancer. 68(4):798-808. PMID:1855180 18(6)4506-12. PMID:22302899
PMID:11918982 2335. Sharma MK, Mansur DB, Reifenberger G, 2352. Shively SB, Falke EA, Li J, Tran MG, 2367. Sinson G, Gennarelli TA, Wells GB
2319. Senft C, Raabe A, Hattingen E, Sommer- Perry A, Leonard JR, Aldape KD, et al. (2007). Thompson ER, Maxwell PH, et al. (2011). De- (1998). Suprasellar osteolipoma: case report.
lad D, Seifert V, Franz K (2008). Pineal paren- Distinct genetic signatures among pilocytic as- velopmentally arrested structures preceding Surg Neurol. 50(5):457-60. PMID:9842872
chymal tumor of intermediate differentiation: trocytomas relate to their brain region origin. cerebellar tumors in von Hippel-Lindau disease. 2368. Skardelly M, Pantazis G, Bisdas S,
diagnostic pitfalls and discussion of treatment Cancer Res. 67(3):890-900. PMID:17283119 Mod Pathol. 24(8):1023-30. PMID:21499240 Feigl GC, Schuhmann MU, Tatagiba MS, et
options of a rare tumor entity. Neurosurg Rev. 2336. Sharpless NE, Bardeesy N, Lee KH, Car- 2353. Shlien A, Campbell BB, de Borja R, al. (2013). Primary cerebral low-grade B-cell
31(2):231-6. PMID:18266015 rasco D, Castrillon DH, Aguirre AJ,et al. (2001). Alexandrov LB, Merico D, Wedge D, et al.; lymphoma, monoclonal immunoglobulin depo-
2320. SenGupta SK, Webb S, Cooke RA, Loss of p16lnk4a with retention of p19Arf Biallelic Mismatch Repair Deficiency Consorti- sition disease, cerebral light chain deposition
Igo JD (1992). Breast filariasis diagnosed by predisposes mice to tumorigenesis. Nature. um (2015). Combined hereditary and somatic disease and “aggregoma”: an update on clas-
needle aspiration cytology. Diagn Cytopathol. 413(6851 ):86-91. PMID:11544531 mutations of replication error repair genes result sification and diagnosis. BMC Neurol. 13:107.
8(4):392-3. PMID:1638940 2337. Shaw EG, Scheithauer BW, O’Fallon JR, in rapid onset of ultra-hypermutated cancers. PMID:23947787
2321. Seol HJ, Hwang SK, Choi YL, Chi JG, Tazelaar HD, Davis DH (1992). Oligodendro- Nat Genet. 47(3):257-62. PMID:25642631 2369. Skullerud K, Stenwig AE, Brandtzaeg P,
Jung HW (2003). A case of recurrent sub- gliomas: the Mayo Clinic experience. J Neuro- 2354. Short MP, Richardson EP Jr, Haines JL, Nesland JM, Kerty E, Langmoen I, et al. (1995).
ependymoma with subependymal seeding: surg. 76(3):428-34. PMID:1738022 Kwiatkowski DJ (1995), Clinical, neuropatho- Intracranial primary leiomyosarcoma arising in
case report. J Neurooncol. 62(3):315-20. 2338. Shaw EG, Wang M, Coons SW, Brach- logical and genetic aspects of the tuberous a teratoma of the pineal area. Clin Neuropathol.
PMID:12777084 man DG, Buckner JC, Stelzer KJ, et al. (2012). sclerosis complex. Brain Pathol. 5(2):173-9. 14(4):245-8. PMID:8521631
2322. Seppala MT, Sainio MA, Haltia MJ, Randomized trial of radiation therapy plus pro- PMID:7670658 2370. Slowik F, Jellinger K, Gaszo L, Fischer J
Kinnunen JJ, Setala KH, Jaaskelainen JE carbazine, lomustine, and vincristine chemothe- 2355. Shou Y, Robinson DM, Amakye DD, (1985). Gliosarcomas: histological, immunohis-
(1998) . Multiple schwannomas: schwannomat- rapy for supratentorial adult low-grade glioma: Rose KL, Cho YJ, Ligon KL, et al. (2015). A tochemical, ultrastructural, and tissue culture
osis or neurofibromatosis type 2? J Neurosurg. initial results of RTOG 9802. J Clin Oncol. five-gene hedgehog signature developed as a studies. Acta Neuropathol. 67(3-4)201-10.
89(1):36-41. PMID:9647170 30(25):3065-70. PMID:22851558 patient preselection tool for hedgehog inhibitor PMID:4050334
2323. Serracino HS, Kleinschmidt-Demasters 2339. Shaw RJ, Paez JG, Curto M, Yaktine therapy in medulloblastoma. Clin Cancer Res. 2371. Smedby KE, Brandt L, Backlund ML,
BK (2013). Skull invaders: when surgical pa- A, Pruitt WM, Saotome I, et al. (2001). The 21 (3):585-93. PMID:25473003 Blomqvist P (2009). Brain metastases admis-
thology and neuropathology worlds collide. Nf2 tumor suppressor, merlin, functions in 2356. Shuangshoti S, Rushing EJ, Mena H, sions in Sweden between 1987 and 2006. Br
J Neuropathol Exp Neurol. 72(7):600-13. Rac-dependent signaling. Dev Cell. 1(1):63-72. Olsen C, Sandberg GD (2005). Supratentori- J Cancer. 101(11)4919-24. PMID19826419
PMID:23771219 PMID:11703924 al extraventricular ependymal neoplasms: a 2372. Smith AB, Rushing EJ, Smirniotopoulos
2324. Serrano M, Lin AW, McCurrach ME, 2340. Shen WH, Balajee AS, Wang J, Wu H, clinicopathologic study of 32 patients. Cancer. JG (2009). Pigmented lesions of the cen-
Beach D, Lowe SW (1997). Oncogenic ras pro- Eng C, Pandolfi PP, et al. (2007). Essential role 103(12):2598-605. PMID:15861411 tral nervous system: radiologic-pathologic
vokes premature cell senescence associated for nuclear PTEN in maintaining chromosomal 2357. Shweiki D, Itin A, Softer D, Keshet E correlation. Radiographics. 29(5)4503-24.
with accumulation of p53 and p16INK4a. Cell. integrity. Cell. 128(1 ):157-70. PMID:17218262 (1992). Vascular endothelial growth factor PMID19755608
88(5):593-602. PMID:9054499 2341. Shenkier TN, Blay JY, O’Neill BP, Poortm- induced by hypoxia may mediate hypoxia-initi- 2373. Smith AB, Rushing EJ, Smirniotopoulos
2325. Sestini R, Bacci C, Provenzano A, Ge- ans P, Thiel E, Jahnke K, et al. (2005). Primary ated angiogenesis. Nature. 359(6398):843-5. JG (2010). From the archives of the AFIP: le-
nuardi M, Papi L (2008). Evidence of a four-hit CNS lymphoma of T-cell origin: a descriptive PMID:1279431 sions of the pineal region: radiologic-pathologic
mechanism involving SMARCB1 and NF2 in analysis from the international primary CNS 2358. Siami-Namini K, Shuey-Drake R, Wilson correlation. Radiographics. 30(7)2001-20.
schwannomatosis-associated schwannomas. lymphoma collaborative group. J Clin Oncol. D, Francel P, Perry A, Fung KM (2005). A 15-ye- PMID21057132
Hum Mutat. 29(2):227-31. PMID:18072270 23(10):2233-9. PMID:15800313 ar-old female with progressive myelopathy. 2374. Smith JS, Tachibana I, Passe SM, Hunt-
2326. Setzer M, Lang J, Turowski B, Marquardt 2342. Shepherd CW, Houser OW, Gomez MR Brain Pathol. 15(3):265-7. PMID:16196395 ley BK, Borell TJ, Iturria N, et al. (2001). PTEN
G (2002). Primary meningeal osteosarco- (1995). MR findings in tuberous sclerosis com- 2359. Sievers S, Alemazkour K, Zahn S, Perl- mutation, EGFR amplification, and outcome
ma: case report and review of the literature. plex and correlation with seizure development man EJ, Gillis AJ, Looijenga LH, et al. (2005). in patients with anaplastic astrocytoma and
Neurosurgery. 51(2):488-92, discussion 492. and mental impairment. AJNR Am J Neurora- IGF2/H19 imprinting analysis of human germ glioblastoma multiforme. J Natl Cancer Inst.
PMID:12182789 diol. 16(1 ):149-55. PMID:7900584 cell tumors (GCTs) using the methylation-sen- 93(16)4246-56. PMID41504770
2327. Sevenet N, Sheridan E, Amram D, 2343. Shibahara J, Fukayama M (2005). Se- sitive single-nucleotide primer extension me- 2375. Smith MJ (2015). Germline and somatic
Schneider P, Handgretinger R, Delattre O condary glioblastoma with advanced neuronal thod reflects the origin of GCTs in different mutations in meningiomas. Cancer Genet.
(1999) . Constitutional mutations of the hSNF5/ immunophenotype. Virchows Arch. 447(3):665- stages of primordial germ cell development. 208(4)407-14. PMID25857641
INI1 gene predispose to a variety of cancers. Am 8. PMID:15968544 Genes Chromosomes Cancer. 44(3):256-64. 2376. Smith MJ, Beetz C, Williams SG, Bhas-
J Hum Genet. 65(5):1342-8. PMID:10521299 2344. Shibahara J, Todo T, Morita A, Mori H, PMID:16001432 kar SS, O'Sullivan J, Anderson B, et al. (2014).
2328. Shankar GM, Chen L, Kim AH, Ross GL, Aoki S, Fukayama M (2004). Papillary neu- 2360. Sieved AJ, Jackson EM, Gai X, Hakonar- Germline mutations in SUFU cause Gorlin syn-
Folkerth RD, Friedlander RM (2010). Composi- roepithelial tumor of the pineal region. A case son H, Judkins AR, Resnick AC, et al. (2009). drome-associated childhood medulloblastoma
te ganglioneuroma-paraganglioma of the filum report. Acta Neuropathol. 108(4):337-40. Duplication of 7q34 in pediatric low-grade and redefine the risk associated with PTCH1
terminate. J Neurosurg Spine. 12(6):709-13. PMID:15221340 astrocytomas detected by high-density sing- mutations. J Clin Oncol. 32(36):4155-61.
PMID:20515359 2345. Shih DJ, Northcott PA, Remke M, Korshu- le-nucleotide polymorphism-based genotype PMID25403219
2329. Shankar GM, Taylor-Weiner A, Lelic N, nov A, Ramaswamy V, Kool M, et al. (2014). arrays results in a novel BRAF fusion gene. 2377. Smith MJ, Isidor B, Beetz C, Williams SG,
Jones RT, Kim JC, Francis JM, et al. (2014). Cytogenetic prognostication within medullob- Brain Pathol. 19(3):449-58. PMID:19016743 Bhaskar SS, Richer W, et al. (2015). Mutations
Sporadic hemangioblastomas are characteri- lastoma subgroups. J Clin Oncol. 32(9):886-96. 2361. Simon SL, Moonis G, Judkins AR, Scobie in LZTR1 add to the complex heterogeneity of
zed by cryptic VHL inactivation. Acta Neuropa- PMID:24493713 J, Burnett MG, Riina HA, et al. (2005). Intracra- schwannomatosis. Neurology. 84(2)441-7.
thol Commun. 2:167. PMID:25589003 2346. Shimbo Y, Takahashi H, Hayano M, Ku- nial capillary hemangioma: case report and re- PMID25480913
2330. Shanklin WM (1953). The origin, histolo- magai T, Kameyama S (1997). Temporal lobe view of the literature. Surg Neurol. 64(2)154-9. 2378. Smith MJ, Kulkarni A, Rustad C, Bowers
gy and senescence of tumorettes in the human lesion demonstrating features of dysembryopla- PMID46051010 NL, Wallace AJ, Holder SE, et al. (2012). Vesti-
neurohypophysis. Acta Anat (Basel). 18(1)4- stic neuroepithelial tumor and ganglioglioma: a 2362. Simoneau-Roy J, O’Gorman C, Pencharz bular schwannomas occur in schwannomatosis
20. PMID: 13064969 transitional form? Clin Neuropathol. 16(2):65-8. P, Adeli K, Daneman D, Hamilton J (2010). In- and should not be considered an exclusion cri-
2331. Shanley S, Ratcliffe J, Hockey A, Haan PMID:9101106 sulin sensitivity and secretion in children and terion for clinical diagnosis. Am J Med Genet A.
E, Oley C, Ravine D, et al. (1994). Nevoid basal 2347. Shinojima N, Kochi M, Hamada J, Naka- adolescents with hypothalamic obesity follo- 158A(1):215-9. PMID22105938
cell carcinoma syndrome: review of 118 affec- mura H, Yano S, Makino K, et al. (2004). The wing treatment for craniopharyngioma. Clin En- 2379. Smith MJ, Wallace AJ, Bennett C, Has-
ted individuals. Am J Med Genet. 50(3):282-90. influence of sex and the presence of giant docrinol (Oxf). 72(3):364-70. PMID19486023 selblatt M, Elert-Dobkowska E, Evans LT, et
PMID:8042673 ceils on postoperative long-term survival in 2363. Simpson LN, Hughes BD, Karikari 10, al. (2014). Germline SMARCE1 mutations
2332. Sharif S, Upadhyaya M, Ferner R, adult patients with supratentorial glioblastoma Mehta Al, Hodges TR, Cummings TJ, et al. predispose to both spinal and cranial clear
392 References
cell meningiomas. J Pathol. 234(4):436-40. than primary glioblastoma. Int J Clin Exp Pathol. Neuro Oncol. 16(2):256-64. PMID:24305709 Pediatr. 9(6):646-53. PMID:22656257
PMID:25143307 4(7):651-60. PMID:22076165 2411. Stambolic V, Suzuki A, de la Pompa JL, 2427. Stem J, Jakobiec FA, Housepian EM
2380. Smith MJ, Wallace AJ, Bowers NL, Ea- 2395. Sonneland PR, Scheithauer BW, Brothers GM, Mirtsos C, Sasaki T, et al. (1998). (1980). The architecture of optic nerve gliomas
ton H, Evans DG (2014). SMARCB1 mutations LeChago J, Crawford BG, Onofrio BM (1986). Negative regulation of PKB/Akt-dependent cell with and without neurofibromatosis. Arch Opht-
in schwannomatosis and genotype correla- Paraganglioma of the cauda equina region. survival by the tumor suppressor PTEN. Cell. halmol. 98(3):505-11. PMID:6767467
tions with rhabdoid tumors. Cancer Genet. Clinicopathologic study of 31 cases with special 95(1):29-39. PMID:9778245 2428. Stockhammer F, Misch M, Helms HJ,
207(9):373-8. PMID:24933152 reference to immunocytology and ultrastruc- 2412. Stanescu Cosson R, Varlet P, Beuvon F, Lengler U, Prall F, von Deimling A, et al. (2012).
2381. Smith MJ, Wallace AJ, Bowers NL, ture. Cancer. 58(8):1720-35. PMID:2875784 Daumas Duport C, Devaux B, Chassoux F, et IDH1/2 mutations in WHO grade II astrocyto-
Rustad CF, Woods CG, Leschziner GD, et al. 2396. Sonneland PR, Scheithauer BW, Onof- al. (2001), Dysembryoplastic neuroepithelial tu- mas associated with localization and seizure
(2012). Frequency of SMARCB1 mutations in rio BM (1985). Myxopapillary ependymoma. mors: CT, MR findings and imaging follow-up: a as the initial symptom. Seizure. 21(3):194-7.
familial and sporadic schwannomatosis. Neuro- A clinicopathologic and immunocytochemical study of 53 cases. J Neuroradiol. 28(4):230-40. PMID:22217666
genetics. 13(2):141-5. PMID:22434358 study of 77 cases. Cancer. 56(4):883-93. PMID:11924137 2429. Stoffel EM, Mangu PB, Gruber SB, Ha-
2382. Smoll NR, Drummond KJ (2012). The in- PMID:4016681 2413. Stangl AP, Wellenreuther R, Lenartz D, milton SR, Kalady MF, Lau MW, et al.; American
cidence of medulloblastomas and primitive neu- 2397. Sonoda Y, Yoshimoto T, Sekiya T (1995). Kraus JA, Menon AG, Schramm J, et al. (1997). Society of Clinical Oncology; European Society
rectodermal tumours in adults and children. J Homozygous deletion of the MTS1/p16 and Clonality of multiple meningiomas. J Neurosurg. of Clinical Oncology (2015). Hereditary colo-
Clin Neurosci. 19(11):1541-4. PMID:22981874 MTS2/p15 genes and amplification of the CDK4 86(5):853-8. PMID:9126902 rectal cancer syndromes: American Society of
2383. Smolle E, Al-Qubati S, Stefanits H, Ha- gene in glioma. Oncogene. 11(10):2145-9. 2414. Starink TM, van der Veen JP, Arwert F, de Clinical Oncology Clinical Practice Guideline
berler C, Kleinert R, Haybaeck J (2012). Me- PMID:7478535 Waal LP, de Lange GG, Gille JJ, et al. (1986). endorsement of the familial risk-colorectal
dullomyoblastoma: a case report and literature 2398. Sorensen AG, Emblem KE, Polaskova The Cowden syndrome: a clinical and genetic cancer: European Society for Medical Oncolo-
review of a rare tumor entity. Anticancer Res. P, Jennings D, Kim H, Ancukiewicz M, et al. study in 21 patients. Clin Genet. 29(3):222-33. gy Clinical Practice Guidelines. J Clin Oncol.
32(11):4939-44. PMID:23155263 (2012) . Increased survival of glioblastoma pa- PMID:3698331 33(2):209-17. PMID:25452455
2384. Smyth I, Narang MA, Evans T, Hei- tients who respond to antiangiogenic therapy 2415. Starzyk J, Starzyk B, Bartnik-Mikuta 2430. Stojanova A, Penn LZ (2009). The role of
mann C, Nakamura V, Chenevix-Trench G, with elevated blood perfusion. Cancer Res. A, Urbanowicz W, Dziatkowiak H (2001). Go- INI1/hSNF5 in gene regulation and cancer. Bio-
et al. (1999). Isolation and characterization of 72(2):402-7. PMID:22127927 nadotropin releasing hormone-independent chem Cell Biol. 87(1):163-77. PMID:19234532
human patched 2 (PTCH2), a putative tumour 2399. Soylemezoglu F, Onder S, Tezel GG, precocious puberty in a 5 year-old girl with 2431. Stokland T, Liu JF, Ironside JW, Ellison
suppressor gene inbasal cell carcinoma and Berker M (2003). Neuronal nuclear antigen suprasellar germ cell tumor secreting beta-hCG DW, Taylor R, Robinson KJ, et al. (2010). A
medulloblastoma on chromosome 1p32. Hum (NeuN): a new tool in the diagnosis of central and alpha-fetoprotein. J Pediatr Endocrinol Me- multivariate analysis of factors determining
Mol Genet. 8(2) 291-7. PMID:9931336 neurocytoma. Pathol Res Pract. 199(7):463-8. tab. 14(6):789-96. PMID:11453531 tumor progression in childhood low-grade gli-
2385. Snuderl M, Fazlollahi L, Le LP, Nitta M, PMID:14521262 2416. Stavrou T, Bromley CM, Nicholson HS, oma: a population-based cohort study (CCLG
Zhelyazkova BH, Davidson CJ, et al. (2011). 2400. Soylemezoglu F, Softer D, Onol B, Byrne J, Packer RJ, Goldstein AM, et al. (2001). CNS9702). Neuro Oncol. 12(12):1257-68.
Mosaic amplification of multiple receptor tyrosi- Schwechheimer K, Kleihues P (1996). Lipo- Prognostic factors and secondary malignancies PMID:20861086
ne kinase genes in glioblastoma. Cancer Cell. matous medulloblastoma in adults. A distinct in childhood medulloblastoma. J Pediatr He- 2432. Stommel JM, Kimmelman AC, Ying H,
20(6):810-7. PMID:22137795 clinicopathological entity. Am J Surg Pathol. matol Oncoi. 23(7):431-6. PMID:11878577 Nabioullin R, Ponugoti AH, Wiedemeyer R, et
2386. Snyder LA, Wolf AB, Oppenlander ME, 20(4):413-8. PMID:8604807 2417. Stiier C, Vilz B, Majores M, Becker A, al. (2007). Coactivation of receptor tyrosine
Bina R, Wilson JR, Ashby L, et al. (2014). The 2401. Spanberger T, Berghoff AS, Dinhof C, Schramm J, Simon M (2007). Frequent recur- kinases affects the response of tumor cells to
impact of extent of resection on malignant Ilhan-Mutlu A, Magerle M, Hutterer M, et al. rence and progression in pilocytic astrocyto- targeted therapies. Science. 318(5848):287-
transformation of pure oligodendrogliomas. J (2013) . Extent of peritumoral brain edema cor- ma in adults. Cancer. 110(12):2799-808. 90. PMID:17872411
Neurosurg. 120(2):309-14. PMID:24313617 relates with prognosis, tumoral growth pattern, PMID:17973253 2433. Stone DM, Hynes M, Armanini M, Swan-
2387. Sobel RA (1993). Vestibular (acoustic) HIF1a expression and angiogenic activity in 2418. Steck PA, Pershouse MA, Jasser SA, son TA, Gu Q, Johnson RL, et al. (1996). The
schwannomas: histologic features in neurofibro- patients with single brain metastases. Clin Exp Yung WK, Lin H, Ligon AH, et al. (1997). Identi- tumour-suppressor gene patched encodes a
matosis 2 and in unilateral cases. J Neuropathol Metastasis. 30(4):357-68. PMID:23076770 fication of a candidate tumour suppressor gene, candidate receptor for Sonic hedgehog. Nature.
Exp Neurol. 52(2):106-13. PMID:8440992 2402. Specht CS, Smith TW, DeGirolami U, MMAC1, at chromosome 10q23.3 that is muta- 384(6605):129-34. PMID:8906787
2388. Sofela AA, Hettige S, Curran O, Bassi Price JM (1986). Myxopapillary ependymo- ted in multiple advanced cancers. Nat Genet. 2433A. Stone DM, Murone M, Luoh S, Ye W,
S (2014). Malignant transformation in cranio- ma of the filum terminale. A light and electron 15(4):356-62. PMID:9090379 Armanini MP, Gurney A, et al. (1999). Charac-
pharyngiomas. Neurosurgery. 75(3):306-14, microscopic study. Cancer. 58(2):310-7. 2419. Steel TR, Botterill P, Sheehy JP (1994). terization of the human suppressor of fused, a
discussion 314. PMID:24978859 PMID:3521831 Paraganglioma of the cauda equina with asso- negative regulator of the zinc-finger transcrip-
2389. Softer D, Pittaluga S, Caine Y, Feinsod 2403. Spence T, Sin-Chan P, Picard D, Barszc- ciated syringomyelia: case report. Surg Neurol. tion factor Gli. J Cell Sci. 112(Pt 23):4437-48.
M (1983). Paraganglioma of cauda equina. A zyk M, Hoss K, Lu M, etal. (2014). CNS-PNETs 42(6):489-93. PMID:7825103 PMID:10564661
report of a case and review of the literature. with C19MC amplification and/or LIN28 expres- 2420. Steinberg GK, Shuer LM, Conley FK, 2434. Storlazzi CT, Von Steyern FV, Domans-
Cancer. 51(10):1907-10. PMID:6831356 sion comprise a distinct histogenetic diagno- Hanbery JW (1985). Evolution and outcome in ki HA, Mandahl N, Mertens F (2005). Biallelic
2390. Soffietti R, Baumert BG, Bello L, von stic and therapeutic entity. Acta Neuropathol. malignant astroglial neoplasms of the cerebel- somatic inactivation of the NF1 gene through
Deimling A, Duffau H, Frenay M, et al.; Europe- 128(2):291-303. PMID:24839957 lum. J Neurosurg. 62(1):9-17. PMID:3964859 chromosomal translocations in a sporadic
an Federation of Neurological Societies (2010). 2404. Sperduto PW, Chao ST, Sneed PK, Luo 2421. Steinbok P, Poskitt K, Hendson G (2006). neurofibroma. Int J Cancer. 117(6):1055-7.
Guidelines on management of low-grade glio- X, Suh J, Roberge D, et al. (2010). Diagno- Spontaneous regression of cerebellar ast- PMID:15986446
mas: report of an EFNS-EANO Task Force. Eur sis-specific prognostic factors, indexes, and rocytoma after subtotal resection. Childs Nerv 2435. Stratakis CA (2002). Mutations of the
J Neurol. 17(9):1124-33. PMID:20718851 treatment outcomes for patients with newly di- Syst. 22(6):572-6. PMID:16552566 gene encoding the protein kinase A type l-al-
2391. Sohda T, Yun K (1996). Insulin-like agnosed brain metastases: a multi-institutional 2422. Stemmer-Rachamimov AO, Gonza- pha regulatory subunit (PRKAR1A) in patients
growth factor II expression in primary menin- analysis of 4,259 patients. Int J Radiat Oncol lez-Agosti C, Xu L, Burwick JA, Beauchamp R, with the “complex of spotty skin pigmentation,
geal hemangiopericytoma and its metastasis to Biol Phys. 77(3):655-61. PMID:19942357 Pinney D, et al. (1997). Expression of NF2-en- myxomas, endocrine overactivity, and schwan-
the liver accompanied by hypoglycemia. Hum 2405. Sperfeld AD, Hein C, Schroder JM, Lu- coded merlin and related ERM family proteins in nomas" (Carney complex). Ann N Y Acad Sci.
Pathol. 27(8):858-61. PMID:8760024 dolph AC, Hanemann CO (2002). Occurrence the human central nervous system. J Neuropa- 968:3-21. PMID:12119264
2392. Solis OE, Mehta Rl, Lai A, Mehta Rl, and characterization of peripheral nerve in- thol Exp Neurol. 56(6):735-42. PMID:9184664 2436. Stratakis CA, Carney JA (2009). The tri-
Farchoukh LO, Green RM, etal. (2011). Roset- volvement in neurofibromatosis type 2. Brain. 2423. Stemmer-Rachamimov AO, Horgan MA, ad of paragangliomas, gastric stromal tumours
te-forming glioneuronal tumor: a pineal region 125(Pt 5):996-1004. PMID:11960890 Taratuto AL, Munoz DG, Smith TW, Frosch and pulmonary chondromas (Carney triad), and
case with IDH1 and IDH2 mutation analyses 2406. Spiegel E (1920). Hyperplasie des Klein- MP, et al. (1997). Meningioangiomatosis is as- the dyad of paragangliomas and gastric stromal
and literature review of 43 cases. J Neurooncol. hirns. Beitr Pathol Anat. 67:539-48. sociated with neurofibromatosis 2 but not with sarcomas (Carney-Stratakis syndrome): mole-
102(3):477-84. PMID:20872044 2407. Squarize CH, Castilho RM, Gutkind JS somatic alterations of the NF2 gene. J Neuro- cular genetics and clinical implications. J Intern
2392A. Solomon DA, Wood MD, Tihan T, Bollen (2008). Chemoprevention and treatment of ex- pathol Exp Neurol. 56(5):485-9. PMID:9143261 Med. 266(1 ):43-52. PMID:19522824
AW, Gupta N, Phillips JJ, et al. (2015). Diffuse perimental Cowden’s disease by mTOR inhibi- 2424. Stemmer-Rachamimov AO, Ino Y, Lim 2437. Stratmann R, Krieg M, Haas R, Plate
Midline Gliomas with Histone H3-K27M Mutati- tion with rapamycin. Cancer Res. 68(17):7066- ZY, Jacoby LB, MacCollin M, Gusella JF, et al. KH (1997). Putative control of angiogenesis in
on: A Series of 47 Cases Assessing the Spec- 72. PMID:18757421 (1998). Loss of the NF2 gene and merlin occur hemangioblastomas by the von Hippel-Lindau
trum of Morphologic Variation and Associated 2408. Squire JA, Arab S, Marrano P, Bayani by the tumorlet stage of schwannoma develop- tumor suppressor gene. J Neuropathol Exp
Genetic Alterations. Brain Pathol, doi: 10.1111/ J, Karaskova J, Taylor M, et al. (2001). Mo- ment in neurofibromatosis 2. J Neuropathol Exp Neurol. 56(11):1242-52. PMID:9370235
bpa.12336. [Epub ahead of print) lecular cytogenetic analysis of glial tumors Neurol. 57(12):1164-7. PMID:9862639 2438. Strommer KN, Brandner S, Sarioglu AC,
2393. Song MK, Chung JS, Joo YD, Lee SM, using spectral karyotyping and comparative 2425. Stenzel W, Pels H, Staib P, Impekoven Sure U, Yonekawa Y (1995). Symptomatic ce-
Oh SY, Shin DH, et al, (2011). Clinical importan- genomic hybridization. Mol Diagn. 6(2):93-108. P, Bektas N, Decked M (2004). Concomitant rebellar metastasis and late local recurrence of
ce of Bcl-6-positive non-deep-site involvement PMID:11468694 manifestation of primary CNS lymphoma and a cauda equina paraganglioma. Case report. J
in non-HIV-related primary central nervous sys- 2409. Sredni ST, Tomita T (2015). Rhabdoid Toxoplasma encephalitis in a patient with AIDS. Neurosurg. 83(1):166-9. PMID:7782837
tem diffuse large B-cell lymphoma. J Neuroon- tumor predisposition syndrome. Pediatr Dev J Neurol. 251(6):764-6. PMID:15311360 2439. Stucky CC, Johnson KN, Gray RJ, Pockaj
col. 104(3):825-31. PMID:21380743 Pathol. 18(1 ):49-58. PMID:25494491 2426. Stephen JH, Sieved AJ, Madsen PJ, Ju- BA, Ocal IT, Rose PS, et al. (2012). Malignant
2394. Song X, Andrew Allen R, Terence Dunn 2410. Stache C, Holsken A, Fahlbusch R, dkins AR, Resnick AC, Storm PB, et al. (2012). peripheral nerve sheath tumors (MPNST):
S, Fung KM, Farmer P, Gandhi S, et al. (2011). Flitsch J, Schlaffer SM, Buchfelder M, et al. Spinal cord ependymomas and myxopapillary the Mayo Clinic experience. Ann Surg Oncol.
Glioblastoma with PNET-like components has a (2014) . Tight junction protein claudin-1 is dif- ependymomas in the first 2 decades of life: a 19(3):878-85. PMID:21861229
higher frequency of isocitrate dehydrogenase 1 ferentially expressed in craniopharyngioma clinicopathological and immunohistochemi- 2440. Stuivenvolt M, Mandl E, Verheul J,
(IDH1) mutation and likely a better prognosis subtypes and indicates invasive tumor growth. cal characterization of 19 cases. J Neurosurg Fleischeuer R, Tijssen CC (2012). Atypical
References 393
transformation in sacral drop metastasis from tumors: frequency and association with clinico- N Am. 26(1 ):99-104. PMID:25432188 S, Shigematsu H (1987). Mixed glioblastoma
posterior fossa choroid plexus papilloma. BMJ pathologic features. Hum Pathol. 41 (2):232-8. 2471. Swensen AR, Bushhouse SA (1998). and sarcoma with osteoid-chondral tissue. Clin
Case Rep. 2012:2012. PMID:22922909 PMID:19801160 Childhood cancer incidence and trends in Min- Neuropathol. 6(4)460-3. PMID:3115659
2441. Stupp R, Hegi ME, Gorlia T, Erridge SC, 2454. Sullivan JP, Nahed BV, Madden MW, Oli- nesota, 1988-1994. Minn Med. 81 (12):27-32. 2488. Taggard DA, Menezes AH (2000). Three
Perry J, Hong YK, et al.; European Organisa- veira SM, Springer S, Bhere D, et al. (2014). PMID:9866372 choroid plexus papillomas in a patient with Ai-
tion for Research and Treatment of Cancer Brain tumor cells in circulation are enriched for 2472. Swensen JJ, Keyser J, Coffin CM, Biegel cardi syndrome. A case report. Pediatr Neuro-
(EORTC); Canadian Brain Tumor Consortium; mesenchymal gene expression. Cancer Discov. JA, Viskochil DH, Williams MS (2009). Famili- surg. 33(4):219-23. PMID41124640
CENTRIC study team (2014). Cilengitide com- 4(11):1299-309. PMID:25139148 al occurrence of schwannomas and malignant 2489. Taillibert S, Chodkiewicz C, Laigle-Do-
bined with standard treatment for patients with 2455. Sulman EP, Guerrero M, Aldape K rhabdoid tumour associated with a duplication nadey F, Napolitano M, Cartalat-Carel S, San-
newly diagnosed glioblastoma with methyla- (2009). Beyond grade: molecular pathology in SMARCB1. J Med Genet. 46(1 ):68-72. son M (2006). Gliomatosis cerebri: a review
ted MGMT promoter (CENTRIC EORTC of malignant gliomas. Semin Radiat Oncol. PMID49124645 of 296 cases from the ANOCEF database
26071-22072 study): a multicentre, randomi- 19(3):142-9. PMID:19464628 2473. Swerdlow SH, Campo E, Harris NL, Jaffe and the literature. J Neurooncol. 76(2):201-5.
sed, open-label, phase 3 trial. Lancet Oncol. 2456. Sundgren P, Annertz M, Englund E, ES, Pileri SA, Stein H, et al., editors. (2008). PMID46200347
15(10):1100-8. PMID:25163906 Stromblad LG, Holtas S (1999). Paragang- WHO Classification of Tumours of Haemat- 2490. Taillibert S, Laigle-Donadey F, Chodkie-
2442. Stupp R, Hegi ME, Mason WP, van den liomas of the spinal canal. Neuroradiology. opoietic and Lymphoid Tissues. 4th ed. Lyon: wicz C, Sanson M, Hoang-Xuan K, Delattre JY
Bent MJ, Taphoorn MJ, Janzer RC, et al.; Eu- 41(10):788-94. PMID:10552032 International Agency for Research on Cancer. (2005). Leptomeningeal metastases from solid
ropean Organisation for Research and Treat- 2457. Sung CC, Collins R, Li J, Pearl DK, 2474. Szathmari A, Champier J, Ghersi-Egea malignancy: a review. J Neurooncol. 75(1 ):85-
ment of Cancer Brain Tumour and Radiation Coons SW, Scheithauer BW, et al. (1996). JF, Jouvet A, Watrin C, Wierinckx A, et al. 99. PMID46215819
Oncology Groups; National Cancer Institute of Glycolipids and myelin proteins in human oli- (2013). Molecular characterization of circum- 2491. Taipale J, Cooper MK, Maiti T, Beachy
Canada Clinical Trials Group (2009). Effects of godendrogliomas. Glycoconj J. 13(3):433-43. ventricular organs and third ventricle ependy- PA (2002). Patched acts catalytically to sup-
radiotherapy with concomitant and adjuvant te- PMID:8781974 ma in the rat: potential markers for periventri- press the activity of Smoothened. Nature.
mozolomide versus radiotherapy alone on sur- 2458. Surawicz TS, McCarthy BJ, Kupelian cular tumors. Neuropathology. 33(1):17-29. 418(6900):892-7. PMID42192414
vival in glioblastoma in a randomised phase III V, Jukich PJ, Bruner JM, Davis FG (1999). PMID:22537279 2492. Takahashi E, Kajimoto K, Fukatsu T,
study: 5-year analysis of the EORTC-NCIC trial. Descriptive epidemiology of primary brain and 2475. Szeifert GT, Pasztor E (1993). Could cra- Yoshida M, Eimoto T, Nakamura S (2005). Int-
Lancet Oncol. 10(5):459-66. PMID:19269895 CNS tumors: results from the Central Brain Tu- niopharyngiomas produce pituitary hormones? ravascular large T-cell lymphoma: a case report
2443. Sturm D, Bender S, Jones DT, Lichter P, mor Registry of the United States, 1990-1994. Neurol Res. 15(1):68-9. PMID:8098858 of CD30-positive and ALK-negative anaplastic
Grill J, Becher O, et al. (2014). Paediatric and Neuro Oncol. 1(1):14-25. PMID:11554386 2476. Szudek J, Birch P, Riccardi VM, Evans type with cytotoxic molecule expression. Vir-
adult glioblastoma: multiform (epi)genomic cul- 2459. Suresh TN, Santosh V, Yasha TC, An- DG, Friedman JM (2000). Associations of clini- chows Arch. 447(6)4000-6. PMID46189700
prits emerge. Nat Rev Cancer. 14(2):92-107. andh B, Mohanty A, Indiradevi B, et al. (2004). cal features in neurofibromatosis 1 (NF1). Ge- 2493. Takahashi E, Nakamura S (2013). His-
PMID:24457416 Medulloblastoma with extensive nodularity: net Epidemiol. 19(4)429-39. PMID:11108651 tiocytic sarcoma : an updated literature review
2444. Sturm D, Witt H, Hovestadt V, Khuong- a variant occurring in the very young-dinico- 2477. Szudek J, Joe H, Friedman JM (2002). based on the 2008 WHO classification. J Clin
Quang DA, Jones DT, Konermann C, et al. pathological and immunohistochemical study Analysis of intrafamilial phenotypic variation in Exp Hematop. 53(1)4-8. PMID:23801128
(2012). Hotspot mutations in H3F3A and IDH1 of four cases. Childs Nerv Syst. 20(1):55-60. neurofibromatosis 1 (NF1). Genet Epidemiol. 2494. Takahashi M, Yamamoto J, Aoyama
define distinct epigenetic and biological subg- PMID:14657995 23(2)450-64. PMID42214308 Y, Soejima Y, Akiba D, Nishizawa S (2009).
roups of glioblastoma. Cancer Cell. 22(4):425- 2460. Suster D, Plaza JA, Shen R (2005). 2478. Soylemezoglu F, Scheithauer BW, Esteve Efficacy of multi-staged surgery and adjuvant
37. PMID:23079654 Low-grade malignant perineurioma (perineurial J, Kleihues P (1997). Atypical central neurocyto- chemotherapy for successful treatment of aty-
2445. Stodberg T, Deniz Y, Esteitie N, Jacobs- sarcoma) of soft tissue: a potential diagnostic ma. J Neuropathol Exp Neurol. 56(5):551-6. pical choroid plexus papilloma in an infant: case
son B, Mousavi-Jazi M, Dahl H, et al. (2002). A pitfall on fine needle aspiration. Ann Diagn Pa- PMID:9143268 report. Neurol Med Chir (Tokyo). 49(10)484-7.
case of diffuse leptomeningeal oligodendroglio- thol. 9(4): 197-201. PMID:16084452 2479. Soylemezoglu F, Tezel GG, Koyba§oglu PMID49855149
matosis associated with HHV-6 variant A. Neu- 2461. Suva ML, Rheinbay E, Gillespie SM, Patel F, Er U, Akalan N (2001). Cranial infantile myo- 2495. Takami H, Fukushima S, Fukuoka K,
ropediatrics. 33(5):266-70. PMID:12536370 AP, Wakimoto H, Rabkin SD, et al. (2014). Re- fibromatosis: report of three cases. Childs Nerv Suzuki T, Yanagisawa T, Matsushita Y, et al.
2446. Sugawa N, Ekstrand AJ, James CD, constructing and reprogramming the tumor-pro- Syst. 17(9):524-7. PMID41585325 (2015). Human chorionic gonadotropin is
Collins VP (1990). Identical splicing of aberrant pagating potential of glioblastoma stem-like 2480. Taal W, Oosterkamp HM, Walenkamp expressed virtually in all intracranial germ
epidermal growth factor receptor transcripts cells. Cell. 157(3):580-94. PMID:24726434 AM, Dubbink HJ, Beerepoot LV, Hanse MC, cell tumors. J Neurooncol. 124(1):23-32.
from amplified rearranged genes in human 2462. Suva ML, Riggi N, Bernstein BE (2013). et al. (2014). Single-agent bevacizumab or lo- PMID:25994796
glioblastomas. Proc Natl Acad Sci U S A . Epigenetic reprogramming in cancer. Science. mustine versus a combination of bevacizumab 2496. Takami H, Yoshida A, Fukushima S, Ari-
87(21 ):8602-6. PMID:2236070 339(6127):1567-70. PMID:23539597 plus lomustine in patients with recurrent gliob- ta H, Matsushita Y, Nakamura T, et al. (2015).
2447. Sughrue ME, Choi J, Rutkowski MJ, 2463. Suzuki A, de la Pompa JL, Stambolic lastoma (BELOB trial): a randomised control- Revisiting TP53 Mutations and Immunohis-
Aranda D, Kane AJ, Barani IJ, et al. (2011). V, Elia AJ, Sasaki T, del Barco Barrantes I, et led phase 2 trial. Lancet Oncol. 15(9):943-53. tochemistry-A Comparative Study in 157
Clinical features and post-surgical outcome of al. (1998). High cancer susceptibility and em- PMID:25035291 Diffuse Gliomas. Brain Pathol, 25(3):256-65
patients with astroblastoma. J Clin Neurosci. bryonic lethality associated with mutation of 2481. Taal W, van der Rijt CC, Dinjens WN, Sil- PMID:25040820
18(6):750-4. PMID:21507653 the PTEN tumor suppressor gene in mice. Curr levis Smitt PA, Wertenbroek AA, Bromberg JE, 2497. Takei H, Adesina AM, Mehta V, Powell
2448. Sughrue ME, Sanai N, Shangari G, Parsa Biol. 8(21):1169-78. PMID:9799734 et al. (2015). Treatment of large low-grade oli- SZ, Langford LA (2010). Atypical teratoid/rhab-
AT, Berger MS, McDermott MW (2010). Outco- 2464. Suzuki H, Aoki K, Chiba K, Sato Y, Shi- godendroglial tumors with upfront procarbazine, doid tumor of the pineal region in an adult. J
me and survival following primary and repeat ozawa Y, Shiraishi Y, et al. (2015). Mutational lomustine, and vincristine chemotherapy with Neurosurg. 113(2):374-9. PMID49911885
surgery for World Health Organization Grade landscape and clonal architecture in grade long follow-up: a retrospective cohort study with 2498. Takei Y, Mirra SS, Miles ML (1976). Eo-
III meningiomas. J Neurosurg. 113(2):202-9. II and III gliomas. Nat Genet. 47(5)458-68. growth kinetics. J Neurooncol. 121 (2):365-72. sinophilic granular ceels in oligodendrogliomas.
PMID:20225922 PMID:25848751 PMID:25344884 An ultrastructural study. Cancer. 38(5)4968-
2449. Sugiarto S, Persson Al, Munoz EG, 2465. Svajdler M Jr, Rychly B, Gajdos M, Pa- 2482. Tabori U, Baskin B, Shago M, Alon N, 76. PMID:991110
Waldhuber M, Lamagna C, Andor N, et al. taky F, Frohlichova L, Perry A (2012). Gliosar- Taylor MD, Ray PN, et al. (2010). Universal 2499. Takei Y, Seyama S, Pearl GS, Tindall
(2011). Asymmetry-defective oligodendrocyte coma with alveolar rhabdomyosarcoma-like poor survival in children with medulloblastoma GT (1980). Ultrastructural study of the human
progenitors are glioma precursors. Cancer Cell. component: report of a case with a hitherto harboring somatic TP53 mutations. J Clin On- neurohypophysis. II. Cellular elements of neural
20(3):328-40. PMID:21907924 undescribed sarcomatous component. Cesk col. 28(8)4345-50. PMID:20142599 parenchyma, the pituicytes. Cell Tissue Res.
2450. Sugino T, Mikami T, Akiyama Y, Wa- Patol. 48(4):210-4. PMID:23121030 2483. Tabori U, Shlien A, Baskin B, Levitt S, 205(2):273-87. PMID:7188885
nibuchi M, Hasegawa T, Mikuni N (2013). 2466. Swaidan MY, Hussaini M, Sultan I, Man- Ray P, Alon N, et al. (2010). TP53 alterations 2500. Takeshima H, Kawahara Y, Hirano H,
Primary central nervous system anaplastic sour A (2012). Radiological findings in gliosar- determine clinical subgroups and survival of pa- Obara S, Niiro M, Kuratsu J (2003). Postope-
large-cell lymphoma mimicking lymphomato- coma. A single institution experience. Neurora- tients with choroid plexus tumors. J Clin Oncol. rative regression of desmoplastic infantile
sis cerebri. Brain Tumor Pathol. 30(1):61-5. diol J. 25(2):173-80. PMID:24028910 28(12)4995-2001. PMID:20308654 gangliogliomas: report of two cases. Neu-
PMID:22426596 2467. Swanson KR, Bridge C, Murray JD, Al- 2484. Tabouret E, Chinot O, Metellus P, Tal- rosurgery. 53(4):979-83, discussion 983-4.
2451. Sugiyama K, Arita K, Shima T, Nakao- vord EC Jr (2003). Virtual and real brain tumors: let A, Viens P, Gongalves A (2012). Recent PMID44519230
ka M, Matsuoka T, Taniguchi E, et al. (2002). using mathematical modeling to quantify glioma trends in epidemiology of brain metastases: 2501. Tamura M, Gu J, Matsumoto K, Aota
Good clinical course in infants with desmo- growth and invasion. J Neurol Sci. 216(1):1-10. an overview. Anticancer Res. 32(11)4655-62. S, Parsons R, Yamada KM (1998). Inhibition
plastic cerebral neuroepithelial tumor treated PMID44607296 PMID:23155227 of cell migration, spreading, and focal adhe-
by surgery alone. J Neurooncol. 59(1):63-9. 2468. Swartling FJ, Savov V, Persson Al, Chen 2485. Tachibana O, Nakazawa H, Lampe J, sions by tumor suppressor PTEN. Science.
PMID:12222839 J, Hacked CS, Northcott PA, et al. (2012). Dis- Watanabe K, Kleihues P, Ohgaki H (1995). Ex- 280(5369)4614-7. PMID:9616126
2452. Suh YL, Koo H, Kim TS, Chi JG, Park SH, tinct neural stem cell populations give rise to pression of Fas/APO-1 during the progression 2502. Tan C, Scotting PJ (2013). Stem cell
Khang SK, et al.; Neuropathology Study Group disparate brain tumors in response to N-MYC. of astrocytomas. Cancer Res. 55(23):5528-30. research points the way to the cell of origin
of the Korean Society of Pathologists (2002). Cancer Cell. 21(5):601-13. PMID:22624711 PMID:7585627 for intracranial germ cell tumours. J Pathol.
Tumors of the central nervous system in Korea: 2469. Sweet K, Willis J, Zhou XP, Gallione C, 2486. Tachibana O, Yamashima T, Yamashita J, 229(1)4-11. PMID:22926997
a multicenter study of 3221 cases. J Neuroon- Sawada T, Alhopuro P, et al. (2005). Molecu- Takabatake Y (1994). Immunohistochemical ex- 2503. Tan MH, Mester J, Peterson C, Yang Y,
col. 56(3):251-9. PMID:12061732 lar classification of patients with unexplained pression of human chorionic gonadotropin and Chen JL, Rybicki LA, et al. (2011). A clinical sco-
2453. Sukov WR, Cheville JC, Giannini C, hamartomatous and hyperplastic polyposis. P-glycoprotein in human pituitary glands and ring system for selection of patients for PTEN
Carlson AW, Shearer BM, Sinnwell JP, et al. JAMA. 294(19):2465-73. PMID46287957 craniopharyngiomas. J Neurosurg. 80(1 ):79- mutation testing is proposed on the basis of a
(2010). Isochromosome 12p and polysomy 12 2470. Sweiss FB, Lee M, Sherman JH (2015). 84. PMID:7903692 prospective study of 3042 probands. Am J Hum
in primary central nervous system germ cell Extraventricular neurocytomas. Neurosurg Clin 2487. Tada T, Katsuyama T, Aoki T, Kobayashi Genet. 88(1)42-56. PMID:21194675
394 References
2504. Tan MH, Mester JL, Ngeow J, Rybicki LA, Central neurocytomas of the cervical spi- J, Chow WY, et al. (2013). Implications of review of 46 cases. J Neurooncol. 115(1):53-9.
Orloff MS, Eng C (2012). Lifetime cancer risks nal cord. Report of two cases. J Neurosurg. tumor location on subtypes of medulloblasto- PMID:23824534
in individuals with germline PTEN mutations. 81(2):288-93. PMID:8027814 ma. Pediatr Blood Cancer. 60(9):1408-10. 2551. Tian Y, Wang J, Ge Jz, Ma Z, Ge M
Clin Cancer Res. 18(2):400-7. PMID:22252256 2520. Tavangar SM, Larijani B, Mahta A, PMID:23512859 (2015). Intracranial Rosai-Dorfman disease mi-
2505. Tan W, Huang W, Xiong J, Pan J, Geng Hosseini SM, Mehrazine M, Bandarian F 2535. Terada T (2015). Expression of cytoke- micking multiple meningiomas in a child: a case
D, Jun Z (2014). Neuroradiological features (2004). Craniopharyngioma: a clinicopatho- ratins in glioblastoma multiforme. Pathol Oncol report and review of the literature. Childs Nerv
of papillary glioneuronal tumor: a study of 8 logical study of 141 cases. Endocr Pathol. Res. 21 (3):817-9. PMID:25633990 Syst. 31(2):317-23. PMID:25183389
cases. J Comput Assist Tomogr. 38(5):634-8. 15(4):339-44. PMID:15681858 2536. Terashima K, Yu A, Chow WY, Hsu WC, 2552. Tibbetts KM, Emnett RJ, Gao F, Perry A,
PMID:24879457 2521. Taylor KR, Mackay A, Truffaux N, But- Chen P, Wong S, et al. (2014). Genome-wide Gutmann DH, Leonard JR (2009). Histopatho-
2506. Tanaka K, Waga S, Itho H, Shimizu DM, terfield YS, Morozova O, Philippe C, et al. analysis of DNA copy number alterations and logic predictors of pilocytic astrocytoma event-
Namiki H (1989). Superficial location of malig- (2014). Recurrent activating ACVR1 mutations loss of heterozygosity in intracranial germ cell free survival. Acta Neuropathol. 117(6):657-65.
nant glioma with heavily lipidized (foamy) tumor in diffuse intrinsic pontine glioma. Nat Genet. tumors. Pediatr Blood Cancer. 61(4):593-600. PMID:19271226
cells: a case report. J Neurooncol. 7(3):293-7. 46(5):457-61. PMID:24705252 PMID:24249158 2553. Tien RD, Barkovich AJ, Edwards MS
PMID:2795123 2522. Taylor MD, Gokgoz N, Andrulis IL, 2537. Thiel G, Losanowa T, Kintzel D, Nisch G, (1990). MR imaging of pineal tumors. AJR Am
2507. Tanaka M, Suda M, Ishikawa Y, Fujitake Mainprize TG, Drake JM, Rutka JT (2000). Martin H, Vorpahl K, et al. (1992). Karyotypes J Roentgenol. 155(1):143-51. PMID:2162137
J, Fujii H, Tatsuoka Y (1996). Idiopathic hyper- Familial posterior fossa brain tumors of in- in 90 human gliomas. Cancer Genet Cytogenet. 2554. Tien RD, Brasch RC, Jackson DE, Dil-
trophic cranial pachymeningitis associated with fancy secondary to germline mutation of the 58(2):109-20. PMID:1551072 lon WP (1989). Cerebral Erdheim-Chester
hydrocephalus and myocarditis: remarkable hSNF5 gene. Am J Hum Genet. 66(4):1403-6. 2538. Thiele EA (2010). Managing and un- disease: persistent enhancement with Gd-DT-
steriod-induced remission of hypertrophic dura PMID:10739763 derstanding epilepsy in tuberous sclero- PA on MR images. Radiology. 172(3)791-2.
mater. Neurology. 46(2):554-6. PMID:8614532 2523. Taylor MD, Liu L, Raffel C, Hui CC, Main- sis complex. Epilepsia. 51 Suppl 1:90-1. PMID:2772189
2508. Tanaka S, Nakada M, Nobusawa S, Su- prize TG, Zhang X, et al. (2002). Mutations in PMID:20331728 2555. Tihan T, Fisher PG, Kepner JL, Godfraind
zuki SO, Sabit H, Miyashita K, et al. (2014). SUFU predispose to medulloblastoma. Nat Ge- 2539. Thiessen B, Finlay J, Kulkarni R, Rosen- C, McComb RD, Goldthwaite PT, et al. (1999).
Epithelioid glioblastoma arising from pleomor- net. 31(3):306-10. PMID:12068298 blum MK (1998). Astroblastoma: does histo- Pediatric astrocytomas with monomorphous
phic xanthoastrocytoma with the BRAF V600E 2524. Taylor MD, Northcott PA, Korshunov A, logy predict biologic behavior? J Neurooncol. pilomyxoid features and a less favorable outco-
mutation. Brain Tumor Pathol. 31(3):172-6. Remke M, Cho YJ, Clifford SC, et al. (2012). 40(1 ):59-65. PMID9874187 me. J Neuropathol Exp Neurol. 58(10):1061-8.
PMID:24894018 Molecular subgroups of medulloblastoma: 2540. Thines L, Lejeune JP, Ruchoux MM, PMID:10515229
2509. Tanaka Y, Yokoo H, Komori T, Makita Y, the current consensus, Acta Neuropathol. Assaker R (2006). Management of delayed 2556. Tihan T, Vohra P, Berger MS, Keles GE
Ishizawa T, Hirose T, et al. (2005). A distinct 123(4):465-72. PMID:22134537 intracranial and intraspinal metastases of (2006). Definition and diagnostic implications
pattern of Olig2-positive cellular distribution in 2525. Taylor MD, Perry J, Zlatescu MC, intradural spinal paragangliomas. Acta Neu- of gemistocytic astrocytomas: a pathological
papillary glioneuronal tumors: a manifestation Stemmer-Rachamimov AO, Ang LC, Ino Y, et rochir (Wien). 148(1):63-6, discussion 66. perspective. J Neurooncol. 76(2):175-83.
of the oligodendroglial phenotype? Acta Neuro- al. (1999). The hPMS2 exon 5 mutation and PMID:16283104 PMID:16132490
pathol. 110(1):39-47. PMID:15906048 malignant glioma. Case report. J Neurosurg. 2541. Thom M, Bliimcke I, Aronica E (2012). 2557. Tihan T, Zhou T, Holmes E, Burger PC,
2510. Tanas MR, Sboner A, Oliveira AM, Er- 90(5)946-50. PMID:10223463 Long-term epilepsy-associated tumors. Brain Ozuysal S, Rushing EJ (2008). The progno-
ickson-Johnson MR, Hespelt J, Hanwright PJ, 2526. Taylor MD, Poppleton H, Fuller C, Su X, Pathol. 22(3):350-79. PMID:22497610 stic value of histological grading of posterior
et al. (2011). Identification of a disease-defi- Liu Y, Jensen P, et al. (2005). Radial glia cells 2542. Thom M, Gomez-Anson B, Revesz T, fossa ependymomas in children: a Children’s
ning gene fusion in epithelioid hemangioen- are candidate stem cells of ependymoma. Can- Harkness W, O'Brien CJ, Kett-White R, et al. Oncology Group study and a review of pro-
dothelioma. Sci Transl Med. 3(98):98ra82. cer Cell. 8(4):323-35. PMID:16226707 (1999). Spontaneous intralesional haemorrha- gnostic factors. Mod Pathol. 21 (2):165-77.
PMID:21885404 2526A. Taylor TE, Furnari FB, Cavenee WK ge in dysembryoplastic neuroepithelial tumours: PMID:18084249
2510A. Tanboon J, Williams EA, Louis DN (2012). Targeting EGFR for treatment of gliob- a series of five cases. J Neurol Neurosurg Psy- 2558. Timmermann B, Kortmann RD, Kuhl
(2015). The Diagnostic Use of Immunohistoche- lastoma: molecular basis to overcome resistan- chiatry. 67(1)97-101. PMID:10369831 J, Rutkowski S, Meisner C, Pietsch T, et al.
mical Surrogates for Signature Molecular Ge- ce. Curr Cancer Drug Targets. 12(3): 197-209. 2543. Thom M, Toma A, An S, Martinian L, (2006). Role of radiotherapy in supratentorial
netic Alterations in Gliomas. J Neuropathol Exp PMID:22268382 Hadjivassiliou G, Ratilal B, et al. (2011). One primitive neuroectodermal tumor in young child-
Neurol. [Epub ahead of print] PMID:26671986 2527. Tchoghandjian A, Fernandez C, Colin C, hundred and one dysembryoplastic neuroepit- ren: results of the German HIT-SKK87 and HIT-
2511. Tandon A, Schif D (2014). Therapeutic El Ayachi I, Voutsinos-Porche B, Fina F, et al, helial tumors: an adult epilepsy series with SKK92 trials. J Clin Oncol. 24(10):1554-60.
decision making in patients with newly diagno- (2009). Pilocytic astrocytoma of the optic pa- immunohistochemical, molecular genetic, and PMID:16575007
sed low grade glioma. Curr Treat Options On- thway: a tumour deriving from radial glia cells clinical correlations and a review of the litera- 2559. Tinat J, Bougeard G, Baert-Desur-
col. 15(4):529-38. PMID:25139406 with a specific gene signature. Brain. 132(Pt ture. J Neuropathol Exp Neurol. 70(10):859-78. mont S, Vasseur S, Martin C, Bouvignies E,
2512. Tanimura A, Nakamura Y, Hachisuka 6):1523-35. PMID:19336457 PMID:21937911 et al. (2009). 2009 version of the Chompret
H, Tanimura Y, Fukumura A (1984). Heman- 2528. Tee AR, Fingar DC, Manning BD, Kwi- 2544. Thomas C, Ruland V, Kordes U, Hartung criteria for Li Fraumeni syndrome. J Clin
gioblastoma of the central nervous system: atkowski DJ, Cantley LC, Blenis J (2002). S, Capper D, Pietsch T, et al. (2015). Pediatric Oncol. 27(26):e108-9, author reply e110.
nature of the stromal cells as studied by the Tuberous sclerosis complex-1 and -2 gene atypical choroid plexus papilloma reconsidered: PMID:19652052
immunoperoxidase technique. Hum Pathol. products function together to inhibit mamma- increased mitotic activity is prognostic only in 2560. Tirakotai W, Mennel HD, Celik I, Hellwig
15(9):866-9. PMID:6432675 lian target of rapamycin (mTOR)-mediated older children. Acta Neuropathol. 129(6)925-7. D, Bertalanffy H, Riegel T (2006). Secretory
2513. Taratuto AL, Molina HA, Diez B, Zucca- downstream signaling. Proc Natl Acad Sci U S PMID:25935663 meningioma: immunohistochemical findings
ro G, Monges J (1985). Primary rhabdomyo- A. 99(21):13571-6. PMID:12271141 2545. Thomas L, Spurlock G, Eudall C, Thomas and evaluation of mast cell infiltration. Neuro-
sarcoma of brain and cerebellum. Report of 2529. Tehrani M, Friedman TM, Olson JJ, Brat NS, Mort M, Hamby SE, et al. (2012). Exploring surg Rev. 29(1 ):41-8. PMID.16010579
four cases in infants: an immunohistochemi- DJ (2008). Intravascular thrombosis in central the somatic NF1 mutational spectrum associa- 2561. Toedt G, Barbus S, Wolter M, Felsberg
cal study. Acta Neuropathol. 66(2)98-104. nervous system malignancies: a potential role ted with NF1 cutaneous neurofibromas. Eur J J, Tews B, Blond F, et al, (2011). Molecular
PMID:4013672 in astrocytoma progression to glioblastoma. Hum Genet. 20(4):411-9. PMID:22108604 signatures classify astrocytic gliomas by IDH1
2514. Taratuto AL, Monges J, Lylyk P, Leiguar- Brain Pathol. 18(2):164-71. PMID:18093251 2546. Thomas PK, King RH, Chiang TR, mutation status. Int J Cancer. 128(5):1095-103.
da R (1984). Superficial cerebral astrocytoma 2530. Tekautz TM, Fuller CE, Blaney S, Foula- Scaravilli F, Sharma AK, Downie AW (1990). PMID:20473936
attached to dura. Report of six cases in infants. di M, Broniscer A, Merchant TE, et al. (2005). Neurofibromatous neuropathy. Muscle Nerve. 2562. Tohma Y, Gratas C, Biernat W, Peraud
Cancer. 54(11):2505-12. PMID:6498740 Atypical teratoid/rhabdoid tumors (ATRT): 13(2)93-101. PMID:2156160 A, Fukuda M, Yonekawa Y, et al. (1998). PTEN
2515. Taratuto AL, Pomata H, Sevlever G, Gallo improved survival in children 3 years of age 2547. Thommen F, Hewer E, Schafer SC, (MMAC1) mutations are frequent in primary
G, Monges J (1995). Dysembryoplastic neu- and older with radiation therapy and high-dose Vassella E, KappelerA, Vajtai I (2013). Roset- glioblastomas (de novo) but not in secondary
roepithelial tumor: morphological, immunocyto- alkylator-based chemotherapy. J Clin Oncol. te-forming glioneuronal tumor of the cerebellum glioblastomas. J Neuropathol Exp Neurol.
chemical, and deoxyribonucleic acid analyses 23(7):1491-9. PMID:15735125 in statu nascendi: an incidentally detected di- 57(7):684-9. PMID:9690672
in a pediatric series. Neurosurgery. 36(3):474- 2531. Telera S, Carosi M, Cerasoli V, Facciolo minutive example indicates derivation from the 2563. Tohma Y, Gratas C, Van Meir EG, Des-
81. PMID:7753346 F, Occhipinti E, Vidih A, et al. (2006). Hemotho- internal granule cell layer. Clin Neuropathol. baillets I, Tenan M, Tachibana O, et al. (1998).
2516. Tashjian VS, Khanlou N, Vinters HV, rax presenting as a primitive thoracic paragan- 32(5):370-6. PMID:23547894 Necrogenesis and Fas/APO-1 (CD95) ex-
Canalis RF, Becker DP (2009). Hemangiope- glioma. Case illustration. J Neurosurg Spine. 2548. Thompsett AR, Ellison DW, Stevenson pression in primary (de novo) and secondary
ricytoma of the cerebellopontine angle: a case 4(6):515. PMID:16776367 FK, Zhu D (1999). V(H) gene sequences from glioblastomas. J Neuropathol Exp Neurol.
report and review of the literature. Surg Neurol. 2532. Telfeian AE, Judkins A, Younkin D, Pol- primary central nervous system lymphomas in- 57(3):239-45. PMID:9600216
72(3):290-5. PMID:18786704 lock AN, Crino P (2004). Subependymal giant dicate derivation from highly mutated germinal 2564. Tomita T, Gates E (1999). Pituitary
2517. Tate M, Sughrue ME, Rutkowski MJ, cell astrocytoma with cranial and spinal me- center B cells with ongoing mutational activity. adenomas and granular cell tumors. Inci-
Kane AJ, Aranda D, McClinton L, et al. (2012). tastases in a patient with tuberous sclerosis. Blood. 94(5):1738-46. PMID:10477699 dence, cell type, and location of tumor in 100
The long-term postsurgical prognosis of pati- Case report. J Neurosurg. 100(5) Suppl Pedi- 2549. Thompson MC, Fuller C, Hogg TL, Dalton pituitary glands at autopsy. Am J Clin Pathol.
ents with pineoblastoma. Cancer. 118(1):173- atrics:498-500. PMID:15287462 J, Finkelstein D, Lau CC, et al. (2006). Geno- 111 (6):817-25. PMID:10361519
9. PMID:21717450 2533. Temme A, Geiger KD, Wiedemuth R, mics identifies medulloblastoma subgroups that 2565. Tomlinson FH, Scheithauer BW, Hayos-
2518. Tatevossian RG, Tang B, Dalton J, Fors- Conseur K, Pietsch T, Felsberg J, et al. (2010). are enriched for specific genetic alterations. J tek CJ, Parisi JE, Meyer FB, Shaw EG, et al.
hewT, Lawson AR, Ma J, etal. (2010). MYB up- Giant cell glioblastoma is associated with al- Clin Oncol. 24(12):1924-31. PMID:16567768 (1994). The significance of atypia and histo-
regulation and genetic aberrations in a subset tered aurora b expression and concomitant 2550. Tian R, Hao S, Hou Z, Bian L, Zhang logic malignancy in pilocytic astrocytoma of
of pediatric low-grade gliomas. Acta Neuropa- p53 mutation. J Neuropathol Exp Neurol. Y, Wu W, et al. (2013). Clinical characteristics the cerebellum: a clinicopathologic and flow
thol. 120(6)731-43. PMID:21046410 69(6):632-42. PMID:20467329 and prognostic analysis of recurrent hemangi- cytometric study. J Child Neurol. 9(3):301-10.
2519. Tatter SB, Borges LF, Louis DN (1994). 2534. Teo WY, Shen J, Su JM, Yu A, Wang opericytoma in the central nervous system: a PMID7930411
References 395
2566. Tomlinson FH, Scheithauer BW, Kelly of two cases. Acta Neuropathol. 91(6):573-7. B Cell Pathol Ind Mol Pathol. 53(1):52-7. and the UK Medical Research Council (2005).
PJ, Forbes GS (1991). Subependymoma with PMID:8781655 PMID:2885972 Long-term efficacy of early versus delayed
rhabdomyosarcomatous differentiation: report 2583. Tsukayama C, Arakawa Y (2002). A pa- 2598. Uluc K, Arsava EM, Ozkan B, Cila A, radiotherapy for low-grade astrocytoma and
of a case and literature review. Neurosurgery. pillary glioneuronal tumor arising in an elderly Zorlu F, Tan E (2004). Primary leptomeningeal oligodendroglioma in adults: the EORTC 22845
28(5):761-8. PMID:1876259 woman: a case report. Brain Tumor Pathol. sarcomatosis; a pathology proven case with randomised trial. Lancet. 366(9490):985-90.
2567. Tomura N, Hirano H, Watanabe 0, Wat- 19(1):35-9. PMID:12455887 challenging MRI and clinical findings. J Neu- PMID16168780
arai J, Itoh Y, Mineura K, et al. (1997). Central 2584. Tsumanuma I, Sato M, Okazaki H, rooncol. 66(3):307-12. PMID:15015662 2614. van den Bent MJ, Brandes AA, Rampling
neurocytoma with clinically malignant beha- Tanaka R, Washiyama K, Kawasaki T, et al. 2599. Uno K, Takita J, Yokomori K, Tanaka Y, R, Kouwenhoven MC, Kros JM, Carpentier
vior. AJNR Am J Neuroradiol. 18(6):1175-8. (1995). The analysis of p53 tumor suppressor Ohta S, Shimada H, et al. (2002). Aberrations AF, et al. (2009). Randomized phase II trial of
PMID:9194446 gene in pineal parenchymal tumors. Noshuyo of the hSNF5/INI1 gene are restricted to ma- erlotinib versus temozolomide or carmustine
2568. Tong J, Hannan F, Zhu Y, Bernards A, Byori. 12(1 ):39-43. PMID:7795728 lignant rhabdoid tumors or atypical teratoid/ in recurrent glioblastoma: EORTC brain tumor
Zhong Y (2002). Neurofibromin regulates G 2585. Tsumanuma I, Tanaka R, Abe S, Ka- rhabdoid tumors in pediatric solid tumors. group study 26034. J Clin Oncol. 27(8)1268-
protein-stimulated adenylyl cyclase activity. Nat wasaki T, Washiyama K, Kumanishi T (1997). Genes Chromosomes Cancer. 34(1):33-41. 74. PMID19204207
Neurosci. 5(2):95-6. PMID:11788835 Infrequent mutation of Waf1/p21 gene, a CDK PMID:11921280 2615. van den Bent MJ, Brandes AA, Taphoorn
2569. Torchia J, Picard D, Lafay-Cousin L, Ha- inhibitor gene, in brain tumors. Neurol Med 2600. Upadhyaya M, Huson SM, Davies M, MJ, Kros JM, Kouwenhoven MC, Delattre JY,
wkins CE, Kim SK, Letourneau L, et al. (2015). Chir (Tokyo). 37(2):150-6, discussion 156-7. Thomas N, Chuzhanova N, Giovannini S, et et al. (2013). Adjuvant procarbazine, lomus-
Molecular subgroups of atypical teratoid rhab- PMID:9059037 al. (2007). An absence of cutaneous neurofi- tine, and vincristine chemotherapy in newly
doid tumours in children: an Integrated genomic 2586. Tsumanuma I, Tanaka R, Washiyama bromas associated with a 3-bp inframe deleti- diagnosed anaplastic oligodendroglioma: long-
and clinicopathological analysis. Lancet Oncol. K (1999). Clinicopathological study of pineal on in exon 17 of the NF1 gene (c.2970-2972 term follow-up of EORTC brain tumor group
16(5):569-82. PMID:25882982 parenchymal tumors: correlation between his- delAAT): evidence of a clinically significant NF1 study 26951. J Clin Oncol. 31(3):344-50.
2570. Torres CF, Korones DN, Pilcher W (1997). topathological features, proliferative potential, genotype-phenotype correlation. Am J Hum Ge- PMID:23071237
Multiple ependymomas in a patient with Tur- and prognosis. Brain Tumor Pathol. 16(2):61-8. net. 80(1):140-51. PMID17160901 2616. van den Bent MJ, Bromberg JE (2012).
cot's syndrome. Med Pediatr Oncol. 28(1):59- PMID:10746962 2601. Upadhyaya M, Spurlock G, Kluwe L, Anaplastic oligodendroglial tumors. Handb Clin
61. PMID.8950338 2587. Tu PH, Giannini C, Judkins AR, Schwalb Chuzhanova N, Bennett E, Thomas N, et al, Neurol. 105:467-84. PMID:22230513
2571. Trehan G, Bruge H, Vinchon M, Khalil JM, Burack R, O'Neill BP, et al. (2005). Clini- (2009). The spectrum of somatic and germ- 2617. van den Bent MJ, Carpentier AF, Brandes
C, Ruchoux MM, Dhellemmes P, et al. (2004). copathologic and genetic profile of intracranial line NF1 mutations in NF1 patients with spinal AA, Sanson M, Taphoorn MJ, Bemsen HJ, et
MR imaging in the diagnosis of desmoplastic marginal zone lymphoma: a primary low-grade neurofibromas. Neurogenetics. 10(3):251-63. al. (2006). Adjuvant procarbazine, lomustine,
infantile tumor: retrospective study of six ca- CNS lymphoma that mimics meningioma. J Clin PMID:19221814 and vincristine improves progression-free sur-
ses. AJNR Am J Neuroradiol. 25(6):1028-33. Oncol. 23(24):5718-27. PMID:16009945 2602. Urbach H (2012). High-field magnetic vival but not overall survival in newly diagnosed
PMID:15205142 2588. Tucker T, Wolkenstein P, Revuz J, Zeller resonance imaging for epilepsy. Neuroima- anaplastic oligodendrogliomas and oligoast-
2572. Tresser N, Parveen T, Roessmann U J, Friedman JM (2005). Association between ging Clin N Am. 22(2)173-89, ix-x. [ix-x.] rocytomas: a randomized European Organi-
(1993). Intracranial lipomas with teratomatous benign and malignant peripheral nerve she- PMID:22548927 sation for Research and Treatment of Cancer
elements. Arch Pathol Lab Med. 117(9):918-20. ath tumors in NF1. Neurology. 65(2):205-11. 2603. Ushio Y, Arita N, Yoshimine T, Ikeda T, phase III trial. J Clin Oncol. 24(18):2715-22.
PMID:8368905 PMID:16043787 Mogami H (1987). Malignant recurrence of PMID16782911
2573. Trifanescu R, Ansorge O, Wass JA, 2589. Turcan S, Rohle D, Goenka A, Walsh LA, childhood cerebellar astrocytoma: case report. 2618. van den Bent MJ, Dubbink HJ, Marie Y,
Grossman AB, Karavitaki N (2012). Rathke's Fang F, Yilmaz E, et al. (2012). IDH1 mutation is Neurosurgery. 21(2):251-5. PMID:3309714 Brandes AA, Taphoorn MJ, Wesseling P, et al.
cleft cysts. Clin Endocrinol (Oxf). 76(2):151-60. sufficient to establish the glioma hypermethyla- 2604. Usui H, Kuzeyli K, Cakir E, Caylan R, (2010) . IDH1 and IDH2 mutations are progno-
PMID:21951110 tor phenotype. Nature. 483(7390):479-83. Sayin OC, Peksoylu B, et al. (2005). Giant stic but not predictive for outcome in anaplastic
2574. Trimbath JD, Petersen GM, Erdman PMID:22343889 cranial extradural primary fibroxanthoma: oligodendroglial tumors: a report of the Europe-
SH, Ferre M, Luce MC, Giardiello FM (2001). 2590. Turcot J, Despres JP, St Pierre F (1959). a case report. Surg Neurol. 63(3):281-4. an Organization for Research and Treatment of
Cafe-au-lait spots and early onset colorectal Malignant tumors of the central nervous system PMID15734528 Cancer Brain Tumor Group. Clin Cancer Res.
neoplasia: a variant of HNPCC? Fam Cancer. associated with familial polyposis of the colon: 2605. Vajtai I, Beck J, Kappeler A, Hewer E 16(5)1597-604. PMID:20160062
1(2):101-5. PMID:14574005 report of two cases. Dis Colon Rectum. 2:465- (2011). Spindle cell oncocytoma of the pituitary 2619. van den Bent MJ, Dubbink HJ, Sanson
2575. Trofatter JA, MacCollin MM, Rutter JL, 8. PMID: 13839882 gland with follicle-like component: organotypic M, van der Lee-Haarloo CR, Hegi M, Jeuken
Murrell JR, Duyao MP, Parry DM, etal. (1993). A 2591. Uchikawa H, Toyoda M, Nagao K, differentiation to support its origin from follicu- JW, et al. (2009). MGMT promoter methylation
novel moesin-, ezrin-, radixin-like gene is a can- Miyauchi H, Nishikawa R, Fujii K, et al. (2006). lo-stellate cells. Acta Neuropathol. 122(2):253- is prognostic but not predictive for outcome
didate for the neurofibromatosis 2 tumor sup- Brain- and heart-specific Patched-1 containing 8. PMID:21590491 to adjuvant PCV chemotherapy in anaplastic
pressor. Cell. 72(5):791-800. PMID:8453669 exon 12b is a dominant negative isoform 2606. Vajtai I, Kappeler A, Lukes A, Arnold M, oligodendroglial tumors: a report from EORTC
2576. Troost D, Jansen GH, Dingemans KP and is expressed in medulloblastomas. Bio- Luthy AR, Leibundgut K (2006). Papillary glio- Brain Tumor Group Study 26951. J Clin Oncol.
(1990). Cerebral medulloepithelioma-electron chem Biophys Res Commun. 349(1 ):277-83. neuronal tumor. Pathol Res Pract. 202(2)107- 27(35):5881 -6. PMID19901104
microscopy and immunohistochemistry. Acta PMID16934747 12. PMID16413693 2620. van den Bent MJ, Gravendeel LA, Gorlia
Neuropathol. 80(1):103-7. PMID:2360414 2592. Ud Din N, Memon A, Aftab K, Ahmad Z, 2607. Vajtai I, Varga Z, Aguzzi A (1996). MIB- T, Kros JM, Lapre L, Wesseling P, etal. (2011).
2577. Trost D, Ehrler M, Fimmers R, Felsberg J, Ahmed R, Hassan S (2012). Oligodendrogli- 1 immunoreactivity reveals different labelling A hypermethylated phenotype is a better predic-
Sabel MC, Kirsch L, et al. (2007). Identification oma arising in the glial component of ovarian in low-grade and in malignant epithelial neo- tor of survival than MGMT methylation in ana-
of genomic aberrations associated with shorter teratomas: a series of six cases and review plasms of the choroid plexus. Histopathology. plastic oligodendroglial brain tumors: a report
overall survival in patients with oligodendro- of literature. J Clin Pathol. 65(7):631-4. 29(2)147-51. PMID:8872148 from EORTC study 26951. Clin Cancer Res,
glial tumors. Int J Cancer. 120(11):2368-76. PMID:22496515 2608. Val-Bernal JF, Hernando M, Garijo 17(22)7148-55. PMID:21914791
PMID:17285580 2593. Ueba T, Okawa M, Abe H, Inoue T, Taka- MF, Villa P (1997). Renal perineurioma in 2621. Van den Bent MJ, Reni M, Gatta G, Vecht
2578. Tsai CJ, Wang Y, Allen PK, Mahajan A, no K, Hayashi H, et al. (2013). Central nervous childhood. Gen Diagn Pathol. 143(1)75-81. C (2008). Oligodendroglioma. Crit Rev Oncol
McCutcheon IE, Rao G, et al. (2014). Outco- system marginal zone B-cell lymphoma of mu- PMID:9269912 Hematol. 66(3):262-72. PMID18272388
mes after surgery and radiotherapy for spinal cosa-associated lymphoid tissue type involving 2609. Valdez R, McKeever P, Finn WG, Ge- 2622. van den Munckhof P, Christiaans I, Ken-
myxopapillary ependymoma: update of the the brain and spinal cord parenchyma. Neuro- barski S, Schnitzer B (2002). Composite germ ter SB, Baas F, Hulsebos TJ (2012). Germline
MD Anderson Cancer Center experience. Neu- pathology. 33(3):306-11. PMID:22994302 cell tumor and B-cell non-Hodgkin's lympho- SMARCB1 mutation predisposes to multiple
rosurgery. 75(3):205-14, discussion 213-4. 2594. Ueki K, Ono Y, Henson JW, Efird JT, von ma arising in the sella turcica. Hum Pathol. meningiomas and schwannomas with pre-
PMID:24818785 Deimling A, Louis DN (1996). CDKN2/p16 or 33(10)1044-7. PMID12395379 ferential location of cranial meningiomas at
2579. Tsikitis M, Zhang Z, Edelman W, Zagzag RB alterations occur in the majority of gliob- 2610. Valenti MP, Froelich S, Armspach JP, the falx cerebri. Neurogenetics. 13(1)1-7.
D, Kalpana GV (2005). Genetic ablation of Cy- lastomas and are inversely correlated. Cancer Chenard MP, Dietemann JL, Kerhli P, et al. PMID:22038540
clin D1 abrogates genesis of rhabdoid tumors Res. 56(1):150-3. PMID:8548755 (2002). Contribution of SISCOM imaging in the 2623. Van Gompel JJ, Koeller KK, Meyer FB,
resulting from Ini1 loss. Proc Natl Acad Sci U S 2595. Ulbright TM, Hattab EM, Zhang S, Ehr- presurgical evaluation of temporal lobe epilepsy Marsh WR, Burger PC, Roncaroli F, et al.
A. 102(34):12129-34. PMID:16099835 lich Y, Foster RS, Einhorn LH, et al. (2010). related to dysembryoplastic neuroepithelial tu- (2011) . Cortical ependymoma: an unusual epi-
2580. Tso CL, Freije WA, Day A, Chen Z, Primitive neuroectodermal tumors in patients mors. Epilepsia. 43(3):270-6. PMID11906512 leptogenic lesion. J Neurosurg. 114(4)1187-
Merriman B, Perlina A, et al, (2006). Distin- with testicular germ cell tumors usually re- 2611. van den Bent MJ (2010). Interobserver 94. PMID:21235315
ct transcription profiles of primary and se- semble pediatric-type central nervous system variation of the histopathological diagnosis 2624. Van Meir EG (1998). “Turcot’s syndro-
condary glioblastoma subgroups. Cancer Res. embryonal neoplasms and lack chromosome in clinical trials on glioma: a clinician’s per- me”: phenotype of brain tumors, survival and
66(1):159-67. PMID:16397228 22 rearrangements. Mod Pathol. 23(7):972-80. spective, Acta Neuropathol. 120(3):297-304. mode of inheritance. Int J Cancer. 75(1)162-4.
2581. Tsou HC, Teng DH, Ping XL, Brancolini V, PMID:20348883 PMID:20644945 PMID:9426707
Davis T, Hu R, et al. (1997). The role of MMAC1 2596. Ulm AJ, Yachnis AT, Brat DJ, Rhoton 2612. van den Bent MJ (2014). Practice ch- 2625. van Slegtenhorst M, de Hoogt R, Herm-
mutations in early-onset breast cancer: causa- AL Jr (2004). Pituicytoma: report of two ca- anging mature results of RTOG study 9802: ans C, Nellist M, Janssen B, Verhoef S, et al.
tive in association with Cowden syndrome and ses and clues regarding histogenesis. Neu- another positive PCV trial makes adjuvant (1997). Identification of the tuberous sclerosis
excluded in BRCA1-negative cases. Am J Hum rosurgery. 54(3)753-7, discussion 757-8. chemotherapy part of standard of care in gene TSC1 on chromosome 9q34. Science.
Genet. 61(5):1036-43. PMID:9345101 PMID:15028154 low-grade glioma. Neuro Oncol. 16(12)1570-4. 277(5327):805-8. PMID:9242607
2582. Tsuchida T, Matsumoto M, Shirayama 2597. Ulrich J, Heitz PU, Fischer T, Obrist E, PMID:25355680 2626. van Slegtenhorst M, Verhoef S, Tempel-
Y, Imahori T, Kasai H, Kawamoto K (1996). Gullotta F (1987). Granular cell tumors: eviden- 2613. van den Bent MJ, Afra D, de Witte O, Ben aars A, Bakker L, Wang Q, Wessels M, et al.
Neuronal and glial characteristics of central ce for heterogeneous tumor cell differentiation. Hassel M, Schraub S, Hoang-Xuan K, et al.; (1999). Mutational spectrum of the TSC1 gene
neurocytoma: electron microscopical analysis An immunocytochemical study. Virchows Arch EORTC Radiotherapy and Brain Tumor Groups in a cohort of 225 tuberous sclerosis complex
396 References
patients: no evidence for genotype-pheno- 2641. Vege KD, Giannini C, Scheithauer BW 2658. Vogazianou AP, Chan R, Backlund LM, Visakorpi T, Kallio M, Jaaskelainen J (1996).
type correlation. J Med Genet. 36(4):285-9. (2000). The immunophenotype of ependymo- Pearson DM, Liu L, Langford CF, et al. (2010). Outcome of 31 intracranial haemangiopericyto-
PMID:10227394 mas. Appl Immunohistochem Mol Morphol. Distinct patterns of 1p and 19q alterations iden- mas: poor predictive value of cell proliferation
2627. van Thuijl HF, Mazor T, Johnson BE, 8(1 ):25-31. PMID:10937045 tify subtypes of human gliomas that have dif- indices. Acta Neurochir (Wien). 138(12):1399-
Fouse SD, Aihara K, Hong C, et al. (2015). 2642. Venkataraman G, Rizzo KA, Chavez JJ, ferent prognoses. Neuro Oncol. 12(7):664-78. 408. PMID:9030346
Evolution of DNA repair defects during malig- Streubel B, Raffeld M, Jaffe ES, et al. (2011). PMID:20164239 2674. Wacker MR, Cogen PH, Etzell JE, Dane-
nant progression of low-grade gliomas after Marginal zone lymphomas involving meningeal 2659. Vogelgesang S, Junge MH, Pahnke J, shvar L, Davis RL, Prados MD (1992). Diffuse
temozolomide treatment. Acta Neuropathol. dura: possible link to lgG4-related diseases. Gaab MR, Warzok RW (2002). August 2001: leptomeningeal involvement by a ganglioglioma
129(4):597-607. PMID:25724300 Mod Pathol. 24(3):355-66. PMID:21102421 Sellar/suprasellar mass in a 59-year-old in a child. Case report. J Neurosurg. 77(2):302-
2628. VandenBerg SR (1993). Desmoplastic in- 2643. Venkataraman S, Pandian C, Kumar woman. Brain Pathol. 12(1):135-6, 139. 6. PMID:1625019
fantile ganglioglioma and desmoplastic cerebral SA (2013). Primary spinal primitive neuroecto- PMID:11770897 2675. Wakai S, Segawa H, Kitahara S, Asano
astrocytoma of infancy. Brain Pathol. 3(3):275- dermal tumour - a case report. Ann Neurosci. 2660. von Deimling A, Fimmers R, Schmidt T, Sano K, Ogihara R, et al. (1980). Teratoma in
81. PMID:8293187 20(2):80-2. PMID:25206019 MC, Bender B, Fassbender F, Nagel J, et al. the pineal region in two brothers. Case reports.
2629. VandenBerg SR, May EE, Rubinstein LJ, 2644. Venneti S, Santi M, Felicella MM, Yarilin (2000). Comprehensive allelotype and genetic J Neurosurg. 53(2):239-43. PMID:7431063
Herman MM, Perentes E, Vinores SA, et al. D, Phillips JJ, Sullivan LM, et al. (2014). A sen- anaysis of 466 human nervous system tumors. 2676. Wakamatsu T, Matsuo T, Kawano S,
(1987). Desmoplastic supratentorial neuroepit- sitive and specific histopathologic prognostic J Neuropathol Exp Neurol. 59(6):544-58. Teramoto S, Matsumura H (1971). Glioblasto-
helial tumors of infancy with divergent differen- marker for H3F3A K27M mutant pediatric gli- PM ID:10850867 ma with extracranial metastasis through vent-
tiation potential (“desmoplastic infantile ganglio- oblastomas. Acta Neuropathol. 128(5)743-53. 2661. von Deimling A, Janzer R, Kleihues P, riculopleural shunt. Case report. J Neurosurg.
gliomas”). Report on 11 cases of a distinctive PMID:25200322 Wiestler OD (1990). Patterns of differentiation 34(5):697-701. PMID:4326303
embryonal tumor with favorable prognosis. J 2645. Verhaak RG, Hoadley KA, Purdom E, in central neurocytoma. An immunohistochemi- 2677. Waldron JS, Tihan T (2003). Epide-
Neurosurg. 66(1):58-71. PMID:3097276 Wang V, Qi Y, Wilkerson MD, et al.; Cancer cal study of eleven biopsies. Acta Neuropathol. miology and pathology of intraventricular
2630. Vandewalle G, Brucher JM, Michotte A Genome Atlas Research Network (2010). In- 79(5):473-9. PMID:2109481 tumors. Neurosurg Clin N Am. 14(4):469-82.
(1995). Intracranial facial nerve rhabdomyo- tegrated genomic analysis identifies clinically 2662. von Deimling A, Kleihues P, Saremas- PMID:15024796
ma. Case report. J Neurosurg. 83(5):919-22. relevant subtypes of glioblastoma charac- lani P, Yasargil MG, Spoerri O, Sudhof TC, et 2678. Walker C, Baborie A, Crooks D, Wilkins
PMID:7472566 terized by abnormalities in PDGFRA, IDH1, al. (1991). Histogenesis and differentiation S, Jenkinson MD (2011). Biology, genetics
2631. Vang R, Heck K, Fuller GN, Medeiros EGFR, and NF1. Cancer Cell. 17(1):98-110. potential of central neurocytomas. Lab Invest. and imaging of glial cell tumours. Br J Radiol.
LJ (2000). Granular cell tumor of intracrani- PMID:20129251 64(4):585-91. PMID:1901927 84(Spec No 2):S90-106. PMID:22433833
al meninges. Clin Neuropathol. 19(1):41-4. 2646. Verhoef S, Bakker L, Tempelaars AM, 2663. von Deimling A, Larson J, Wellenreuther 2679. Walker C, Joyce KA, Thompson-Hehir J,
PMID:10774952 Hesseling-Janssen AL, Mazurczak T, Jozwiak R, Stangl AP, van Velthoven V, Warnick R, et al. Davies MP, Gibbs FE, Halliwell N, et al. (2001).
2632. Varga Z, Vajtai I, Aguzzi A (1996). The S, et al. (1999). High rate of mosaicism in tu- (1999). Clonal origin of recurrent meningiomas. Characterisation of molecular alterations in
standard isoform of CD44 is preferentially berous sclerosis complex. Am J Hum Genet. Brain Pathol. 9(4):645-50. PMID:10517503 microdissected archival gliomas. Acta Neuropa-
expressed in atypical papillomas and carcino- 64(6):1632-7. PMID.10330349 2664. von Hoff K, Hartmann W, von Bueren AO, thol. 101(4);321-33. PMID:11355303
mas of the choroid plexus. Pathol Res Pract. 2647. Verma A, Zhou H, Chin S, Bruggers C, Gerber NU, Grotzer MA, Pietsch T, et al. (2010). 2680. Walker L, Thompson D, Easton D, Pon-
192(12):1225-31. PMID:9182293 Kestle J, Khatua S (2012). EGFR as a predictor Large cell/anaplastic medulloblastoma: outco- der B, Ponder M, Frayling I, et al. (2006). A
2633. Varikatt W, Dexter M, Mahajan H, Mura- of relapse in myxopapillary ependymoma. Pedi- me according to myc status, histopathological, prospective study of neurofibromatosis type
li R, Ng T (2009). Usefulness of smears in atr Blood Cancer. 59(4):746-8. PMID:22190537 and clinical risk factors. Pediatr Blood Cancer. 1 cancer incidence in the UK. Br J Cancer.
intra-operative diagnosis of newly described 2648. Versteege I, Medjkane S, Rouillard D, 54(3):369-76. PMID:19908297 95(2):233-8. PMID:16786042
entities of CNS. Neuropathology. 29(6):641-8. Delattre O (2002). A key role of the hSNF5/ 2665. von Hoff K, Hinkes B, Dannenmann-Stern 2681. Walker LS, Sansom DM (2011). The
PMID:19563508 INI1 tumour suppressor in the control of the E, von Bueren AO, Warmuth-Metz M, Soeren- emerging role of CTLA4 as a cell-extrinsic re-
2634. Varley JM, McGown G, Thomcroft M, G1-S transition of the cell cycle. Oncogene. sen N, et al. (2011). Frequency, risk-factors gulator of T cell responses. Nat Rev Immunol.
Santibanez-Koref MF, Kelsey AM, Tricker KJ, 21 (42):6403-12. PMID:12226744 and survival of children with atypical teratoid 11(12):852-63. PMID:22116087
et al. (1997). Germ-line mutations of TP53 2649. Versteege I, Sevenet N, Lange J, Rous- rhabdoid tumors (AT/RT) of the CNS diagnosed 2682. Wallner KE, Gonzales MF, Edwards
in Li-Fraumeni families: an extended study seau-Merck MF, Ambros P, Handgretinger R, between 1988 and 2004, and registered to the MS, Wara WM, Sheline GE (1988). Treatment
of 39 families. Cancer Res. 57(15):3245-52. et al. (1998). Truncating mutations of hSNF5/ German HIT database, Pediatr Blood Cancer. results of juvenile pilocytic astrocytoma. J Neu-
PMID:9242456 INI1 in aggressive paediatric cancer. Nature. 57(6):978-85. PMID:21796761 rosurg. 69(2):171-6. PMID:3392563
2635. Vasen HF, Ghorbanoghli Z, Bourdeaut F, 394(6689):203-6. PMID:9671307 2666. von Koch CS, Gulati M, Aldape K, Berger 2683. Wanebo JE, Lonser RR, Glenn GM, Old-
Cabaret O, Caron O, Duval A, et al.; EU-Con- 2650. Vescovi AL, Galli R, Reynolds BA (2006). MS (2002). Familial medulloblastoma: case re- field EH (2003). The natural history of heman-
sortium Care for CMMR-D (C4CMMR-D) Brain tumour stem cells. Nat Rev Cancer. port of one family and review of the literature. gioblastomas of the central nervous system in
(2014) . Guidelines for surveillance of individu- 6(6):425-36. PMID:16723989 Neurosurgery. 51(1):227-33, discussion 233, patients with von Hippel-Lindau disease. J Neu-
als with constitutional mismatch repair-deficien- 2651. Villa S, Miller RC, Krengli M, Abusaris H, PMID:12182422 rosurg. 98(1 ):82-94. PMID: 12546356
cy proposed by the European Consortium “Care Baumert BG, Servagi-Vernat S, et al. (2012). 2667. Vorechovsky I, Tingby O, Hartman M, 2684. Wang CC, Turner J, Steel T (2013).
for CMMR-D” (C4CMMR-D). J Med Genet. Primary pineal tumors: outcome and prognostic Stromberg B, Nister M, Collins VP, et al. (1997). Spontaneous pineal apoplexy in a pineal pa-
51(5):283-93. PMID:24556086 fadors-a study from the Rare Cancer Network Somatic mutations in the human homologue renchymal tumor of intermediate differentiation.
2636. Vasen HF, Tomlinson I, Castells A (2015). (RCN). Clin Transl Oncol. 14(11):827-34. of Drosophila patched in primitive neuroec- Cancer Biol Med. 10(1)43-6. PMID:23691444
Clinical management of hereditary colorectal PMID:22914906 todermal tumours. Oncogene. 15(3):361-6. 2685. Wang F, Travins J, DeLaBarre B, Pen-
cancer syndromes. Nat Rev Gastroenterol He- 2652. Villano JL, Koshy M, Shaikh H, Dolecek PMID:9233770 ard-Lacronique V, Schalm S, Hansen E, et al.
patol. 12(2):88-97. PMID:25582351 TA, McCarthy BJ (2011). Age, gender, and racial 2668. Vorechovsky I, Unden AB, Sandstedt (2013). Targeted inhibition of mutant IDH2 in
2637. Vasiljevic A, Champier J, Figarella-Bran- differences in incidence and survival in primary B, Toftgard R, Stahle-Backdahl M (1997). Tri- leukemia cells induces cellular differentiation.
ger D, Wierinckx A, Jouvet A, Fevre-Montan- CNS lymphoma. Br J Cancer. 105(9):1414-8. choepitheliomas contain somatic mutations in Science. 340(6132):622-6. PMID:23558173
ge M (2013). Molecular characterization of PMID:21915121 the overexpressed PTCH gene: support for a 2686. Wang H, Zhang S, Rehman SK, Zhang
central neurocytomas: potential markers for 2653. Villano JL, Parker CK, Dolecek TA gatekeeper mechanism in skin tumorigenesis. Z, Li W, Makki MS, et al. (2014). Clinicopatho-
tumor typing and progression. Neuropathology. (2013). Descriptive epidemiology of ependy- Cancer Res. 57(21):4677-81. PMID:9354420 logical features of myxopapillary ependymoma,
33(2):149-61. PMID:22816789 mal tumours in the United States. Br J Cancer. 2669. Vortmeyer AO, Frank S, Jeong SY, Yuan J Clin Neurosci. 21(4):569-73. PMID:24332590
2638. Vasiljevic A, Frangois P, Loundou A, Fe- 108(11 ):2367-71. PMID:23660944 K, Ikejiri B, Lee YS, et al. (2003). Developmen- 2687. Wang H, Zhang S, Wu C, Zhang Z,
vre-Montange M, Jouvet A, Roche PH, et al. 2654. Vinchon M, Blond S, Lejeune JP, Krivosik tal arrest of angioblastic lineage initiates tumo- Qin T (2013). Melanocytomas of the central
(2012). Prognostic factors in central neurocyto- I, Fossati P, Assaker R, et al, (1994). Associa- rigenesis in von Hippel-Lindau disease. Cancer nervous system: a clinicopathological and mo-
mas: a multicenter study of 71 cases. Am J Surg tion of Lhermitte-Duclos and Cowden disease: Res. 63(21 ):7051-5. PMID:14612494 lecular study. Eur J Clin Invest. 43(8):809-15.
Pathol. 36(2):220-7. PMID:22251941 report of a new case and review of the literature. 2670. Vortmeyer AO, Gnarra JR, Emmert-Buck PMID:23683178
2639. Vater I, Montesinos-Rongen M, Schles- J Neurol Neurosurg Psychiatry. 57(6):699-704. MR, Katz D, Linehan WM, Oldfield EH, et al. 2688. Wang L, Motoi T, Khanin R, Olshen A,
ner M, Haake A, Purschke F, Sprute R, et al. PMID:8006650 (1997). von Hippel-Lindau gene deletion detec- Mertens F, Bridge J, et al. (2012). Identificati-
(2015) . The mutational pattern of primary lym- 2655. Vinters HV, Park SH, Johnson MW, Mi- ted in the stromal cell component of a cerebellar on of a novel, recurrent HEY1-NCOA2 fusion
phoma of the central nervous system deter- schel PS, Catania M, Kerfoot C (1999). Cortical hemangioblastoma associated with von Hip- in mesenchymal chondrosarcoma based on a
mined by whole-exome sequencing. Leukemia. dysplasia, genetic abnormalities and neuro- pel-Lindau disease. Hum Pathol. 28(5):540-3. genome-wide screen of exon-level expression
29(3):677-85. PMID:25189415 cutaneous syndromes. Dev Neurosci. 21(3- PMID:9158701 data. Genes Chromosomes Cancer. 51(2)427-
2639A. Vaubel RA, Chen SG, Raleigh DR, 5):248-59. PMID:10575248 2671. Vredenburgh JJ, Desjardins A, Herndon 39. PMID:22034177
Link MJ, Chicoine MR, Barani I, et al. (2016). 2656. Vital A, Vital C, Martin-Negrier ML, JE 2nd, Dowell JM, Reardon DA, Quinn JA, et 2689. Wang L, Yamaguchi S, Burstein MD, Te-
Meningiomas With Rhabdoid Features Lacking McGrogan G, Bioulac P, Trojani M, etal. (1994). al. (2007). Phase II trial of bevacizumab and rashima K, Chang K, Ng HK, et al. (2014). Novel
Other Histologic Features of Malignancy: A Lhermitte-Duclos type cerebellum hamarto- irinotecan in recurrent malignant glioma. Clin somatic and germline mutations in intracranial
Study of 44 Cases and Review of the Litera- ma and Cowden disease. Clin Neuropathol, Cancer Res. 13(4):1253-9. PMID:17317837 germ cell tumours. Nature. 511(7508):241-5.
ture. J Neuropathol Exp Neurol. 75(1 ):44-52. 13(4):229-31. PMID:7955671 2672. Vujovic S, Henderson S, Presneau N, PMID:24896186
PMID:26705409 2657. Vivekanandan S, Dickinson P, Bessell E, Odell E, Jacques TS, Tirabosco R, et al. (2006). 2690. Wang M, Jia D, Shen J, Zhang J, Li G
2640. Vecht CJ, Kerkhof M, Duran-Pena A O'Connor S (2011). An unusual case of primary Brachyury, a crucial regulator of notochordal (2013). Clinical and imaging features of central
(2014). Seizure prognosis in brain tumors: new anaplastic large cell central nervous system development, is a novel biomarker for chordo- neurocytomas. J Clin Neurosci. 20(5):679-85.
insights and evidence-based management. On- lymphoma: an 8-year success story. BMJ Case mas. J Pathol. 209(2):157-65. PMID:16538613 PMID:23522930
cologist. 19(7):751-9. PMID:24899645 Rep. 2011:2011. PMID:22707580 2673. Vuorinen V, Sallinen P, Haapasalo H, 2691. Wang M, Tihan T, Rojiani AM, Bodhireddy
References 397
SR, Prayson RA, lacuone JJ, et al. (2005). Brain Pathol. 6(3):217-23, discussion 23-4. 2721. Weiner HL, Wisoff JH, Rosenberg ME, PMID:7745429
Monomorphous angiocentric glioma: a dis- PMID:8864278 Kupersmith MJ, Cohen H, Zagzag D, et al. 2735. Wester DJ, Falcone S, Green BA, Camp
tinctive epileptogenic neoplasm with features 2706. Watanabe K, Tachibana O, Yonekawa Y, (1994). Craniopharyngiomas: a clinicopa- A, Quencer RM (1993). Paraganglioma of the fi-
of infiltrating astrocytoma and ependymoma. Kleihues P, Ohgaki H (1997). Role of gemis- thological analysis of factors predictive of lum: MR appearance. J Comput Assist Tomogr.
J Neuropathol Exp Neurol. 64(10):875-81. tocytes in astrocytoma progression. Lab Invest. recurrence and functional outcome. Neuro- 17(6):967-9. PMID:8227586
PMID:16215459 76(2):277-84. PMID:9042164 surgery. 35(6)4001-10, discussion 1010-1. 2736. Wharton SB, Chan KK, Anderson JR,
2692. Wang X, Dubuc AM, Ramaswamy 2707. Watanabe T, Makiyama Y, Nishimoto H, PMID:7885544 Stoeber K, Williams GH (2001). Replicative
V, Mack S, Gendoo DM, Remke M, et al. Matsumoto M, Kikuchi A, Tsubokawa T (1995). 2722. Weiner HL, Zagzag D, Babu R, Wein- Mcm2 protein as a novel proliferation marker in
(2015). Medulloblastoma subgroups remain Metachronous ovarian dysgerminoma after a reb HJ, Ransohoff J (1993). Schwannoma of oligodendrogliomas and its relationship to Ki67
stable across primary and metastatic com- suprasellar germ-cell tumor treated by radiation the fourth ventricle presenting with hemifacial labelling index, histological grade and progno-
partments. Acta Neuropathol. 129(3):449-57. therapy. Case report. J Neurosurg. 83(1)449- spasm. A report of two cases. J Neurooncol. sis. Neuropathol Appl Neurobiol. 27(4):305-13.
PMID:25689980 53. PMID:7782834 15(1):37-43. PMID:8455061 PMID41532161
2693. Wang XQ, Zhou Q, Li ST, Liao CL, Zhang 2708. Watanabe T, Mizowaki T, Arakawa Y, lizu- 2723. Weingart MF, Roth JJ, Hutt-Cabezas 2737. White FV, Dehner LP, Belchis DA, Conard
H, Zhang BY (2013). Solitary fibrous tumors of ka Y, Ogura K, Sakanaka K, et al. (2014). Pineal M, Busse TM, Kaur H, Price A, et al. (2015). K, Davis MM, Stocker JT, et al. (1999). Conge-
the central nervous system: clinical features parenchymal tumor of intermediate differentiati- Disrupting LIN28 in atypical teratoid rhabdoid nital disseminated malignant rhabdoid tumor: a
and imaging findings in 22 patients. J Comput on: Treatment outcomes of five cases. Mol Clin tumors reveals the importance of the mitogen distinct clinicopathologic entity demonstrating
Assist Tomogr. 37(5):658-65. PMID:24045237 Oncol. 2(2):197-202. PMID:24649332 activated protein kinase pathway as a the- abnormalities of chromosome 22q 11. Am J
2694. Wang Y, Xiong J, Chu SG, Liu Y, Cheng 2709. Watanabe T, Nobusawa S, Kleihues P, rapeutic target. Oncotarget. 6(5):3165-77. Surg Pathol. 23(3):249-56. PMID40078913
HX, Wang YF, et al. (2009). Rosette-forming Ohgaki H (2009). IDH1 mutations are early PMID:25638158 2738. White W, Shiu MH, Rosenblum MK,
glioneuronal tumor: report of an unusual case events in the development of astrocytomas and 2724. Weiss SW, Langloss JM, Enzinger FM Erlandson RA, Woodruff JM (1990). Cellular
with intraventricular dissemination. Acta Neuro- oligodendrogliomas. Am J Pathol. 174(4):1149- (1983). Value of S-100 protein in the diagnosis schwannoma. A clinicopathologic study of 57
pathol. 118(6):813-9. PMID:19585134 53. PMID:19246647 of soft tissue tumors with particular reference patients and 58 tumors. Cancer. 66(6)4266-
2695. Wanggou S, Jiang X, Li Q, Zhang L, Liu 2710. Watanabe T, Vital A, Nobusawa S, Klei- to benign and malignant Schwann cell tumors. 75. PMID:2400975
D, Li G, et al. (2012). HESRG: a novel biomar- hues P, Ohgaki H (2009). Selective acquisition Lab Invest. 49(3):299-308. PMID:6310227 2739. Whittle IR, Dow GR, Lammie GA, Ward-
ker for intracranial germinoma and embryo- of IDH1 R132C mutations in astrocytomas as- 2725. Weiss WA, Burns MJ, Hackett C, Alda- law J (1999). Dsyembryoplastic neuroepithe-
nal carcinoma. J Neurooncol. 106(2):251-9. sociated with Li-Fraumeni syndrome. Acta Neu- pe K, Hill JR, Kuriyama H, et al. (2003). Ge- lial tumour with discrete bilateral multifocality:
PMID:21861197 ropathol. 117(6):653-6. PMID:19340432 netic determinants of malignancy in a mouse further evidence for a germinal origin. Br J Neu-
2696. Wani K, Armstrong TS, Vera-Bolanos E, 2711. Weber DC, Wang Y, Miller R, Villa S, model for oligodendroglioma. Cancer Res. rosurg. 13(5):508-11. PMID40627786
Raghunathan A, Ellison D, Gilbertson R, et al.; Zaucha R, Pica A, et al. (2015). Long-term 63(7)4589-95. PMID42670909 2740. Wick W, Hartmann C, Engel C, Stoffels
Collaborative Ependymoma Research Network outcome of patients with spinal myxopapil- 2726. Welander J, Larsson C, Backdahl M, Felsberg J, Stockhammer F, et al. (2009).
(2012). A prognostic gene expression signature lary ependymoma: treatment results from the M, Hareni N, Sivler T, Brauckhoff M, et al. NOA-04 randomized phase III trial of sequen-
in infratentorial ependymoma. Acta Neuropa- MD Anderson Cancer Center and institutions (2012). Integrative genomics reveals frequent tial radiochemotherapy of anaplastic glioma
thol. 123(5):727-38. PMID:22322993 from the Rare Cancer Network. Neuro Oncol. somatic NF1 mutations in sporadic pheochro- with procarbazine, lomustine, and vincristine or
2697. Warmuth-Metz M, Bison B, Gerber NU, 17(4):588-95 PMID:25301811 mocytomas. Hum Mol Genet. 21(26):5406-16. temozolomide. J Clin Oncol. 27(35):5874-80.
Pietsch T, Hasselblatt M, Fruhwald MC (2013). 2712. Weber HC, Marsh DJ, Lubensky IA, Lin PMID:23010473 PMID49901110
Bone involvement in atypical teratoid/rhabdoid AY, Eng C (1998). Germline PTEN/MMAC1/ 2727. Wellenreuther R, Kraus JA, Lenartz D, 2741. Wick W, Meisner C, Hentschel B, Plat-
tumors of the CNS. AJNR Am J Neuroradiol. TEP1 mutations and association with gast- MenonAG, Schramm J, Louis DN, et al. (1995). ten M, Schilling A, Wiestler B, et al. (2013).
34(10):2039-42. PMID:23681355 rointestinal manifestations in Cowden disease. Analysis of the neurofibromatosis 2 gene re- Prognostic or predictive value of MGMT pro-
2698. Warnick RE, Raisanen J, Adornato Gastroenterology. 114S:G2902. veals molecular variants of meningioma. Am J moter methylation in gliomas depends on
BT, Prados MD, Davis RL, Larson DA, et al. 2713. Weber RG, Hoischen A, Ehrler M, Zip- Pathol. 146(4):827-32. PMID:7717450 IDH1 mutation. Neurology. 81(17)4515-22.
(1993). Intracranial myxopapillary ependymo- per P, Kaulich K, Blaschke B, et al. (2007). 2728. Weller M, Felsberg J, Hartmann C, Ber- PMID:24068788
ma: case report. J Neurooncol. 15(3):251-6. Frequent loss of chromosome 9, homozygous ger H, Steinbach JP, Schramm J, et al. (2009). 2742. Wick W, Platten M, Meisner C, Felsberg
PMID:8360710 CDKN2A/p14(ARF)/CDKN2B deletion and low Molecular predictors of progression-free and J, Tabatabai G, Simon M, et al.; NOA-08 Stu-
2699. Warren C, James LA, Ramsden RT, Wal- TSC1 mRNA expression in pleomorphic xan- overall survival in patients with newly diagnosed dy Group of Neuro-oncology Working Group
lace A, Baser ME, Varley JM, et al. (2003). Iden- thoastrocytomas. Oncogene. 26(7):1088-97. glioblastoma: a prospective translational study (NOA) of German Cancer Society (2012). Te-
tification of recurrent regions of chromosome PMID:16909113 of the German Glioma Network. J Clin Oncol. mozolomide chemotherapy alone versus radio-
loss and gain in vestibular schwannomas using 2714. Wechsler J, Lantieri L, Zeller J, Voisin 27(34):5743-50. PMID49805672 therapy alone for malignant astrocytoma in the
comparative genomic hybridisation. J Med Ge- MC, Martin-Garcia N, Wolkenstein P (2003). 2729. Weller M, Tabatabai G, Kastner B, Fels- elderly: the NOA-08 randomised, phase 3 trial.
net. 40(11):802-6. PMID:14627667 Aberrant axon neurofilaments in schwannomas berg J, Steinbach JP, Wick A, et al.; DIRECTOR Lancet Oncol. 13(7):707-15. PMID:22578793
2700. Warren KE (2012). Diffuse intrinsic pon- associated with phacomatoses. Virchows Arch. Study Group (2015). MGMT promoter methyla- 2743. Wick W, Weller M, van den Bent M, San-
tine glioma: poised for progress. Front Oncol. 443(6):768-73. PMID:14508685 tion is a strong prognostic biomarker for benefit son M, Weiler M, von Deimling A, et al. (2014).
2:205. PMID:23293772 2715. Wechsler-Reya RJ, Scott MP (1999). from dose-intensified temozolomide rechallen- MGMT testing-the challenges for biomar-
2701. Wasdahl DA, Scheithauer BW, Andrews Control of neuronal precursor proliferation in ge in progressive glioblastoma: the DIREC- ker-based glioma treatment. Nat Rev Neurol.
BT, Jeffrey RA Jr (1994). Cerebellar pleomor- the cerebellum by Sonic Hedgehog. Neuron. TOR trial. Clin Cancer Res. 21(9):2057-64. 10(7):372-85. PMID:24912512
phic xanthoastrocytoma: case report. Neu- 22(1):103-14. PMID:10027293 PMID:25655102 2744. Wicking C, Gillies S, Smyth I, Shanley
rosurgery. 35(5):947-50, discussion 950-1. 2716. Wefers AK, Warmuth-Metz M, Poschl 2730. Weller M, van den Bent M, Hopkins K, S, Fowles L, Ratcliffe J, et al. (1997). De novo
PMID:7838347 J, von Bueren AO, Monoranu CM, Seelos K, Tonn JC, Stupp R, Falini A, et al.; European mutations of the Patched gene in nevoid basal
2702. Watanabe K, Ogata N, von Ammon K, et al. (2014). Subgroup-specific localization of Association for Neuro-Oncology (EANO) Task cell carcinoma syndrome help to define the cli-
Yonekawa Y, Nagai M, Ohgaki H, et al. (1996). human medulloblastoma based on pre-ope- Force on Malignant Glioma (2014). EANO gui- nical phenotype. Am J Med Genet. 73(3):304-7.
Immunohistochemical assessments of p53 pro- rative MRI, Acta Neuropathol. 127(6):931-3. deline for the diagnosis and treatment of ana- PMID:9415689
tein accumulation and tumor growth fraction du- PMID:24699697 plastic gliomas and glioblastoma. Lancet Oncol. 2745. Wicking C, Shanley S, Smyth I, Gillies S,
ring the progression of astrocytomas. In: Brain 2717. Wei D, Rich P, Bridges L, Martin AJ, Chau 15(9):e395-403. PMID:25079102 Negus K, Graham S, et al. (1997). Most germ-
Tumour Research and Therapy. Nagai I, Bodi I, et al. (2013). Rare case of cerebral 2731. Weller M, Weber RG, Willscher E, Rieh- line mutations in the nevoid basal cell carcino-
2702A. Watanabe T, Nakamura M, Yonekawa MALToma presenting with stroke-like symp- mer V, Hentschel B, Kreuz M, et al. (2015). Mo- ma syndrome lead to a premature termination
Y, Kleihues P, Ohgaki H (2001). Promoter hy- toms and seizures. BMJ Case Rep. 2013:2013. lecular classification of diffuse cerebral WHO of the PATCHED protein, and no genotype-phe-
permethylation and homozygous deletion of the PMID:23608841 grade ll/lll gliomas using genome- and tran- notype correlations are evident. Am J Hum Ge-
p14ARF and p16INK4a genes in oligodendro- 2718. Wei G, Zhang W, Li Q, Kang X, Zhao H, scriptome-wide profiling improves stratification net. 60(1 ):21-6. PMID:8981943
gliomas. Acta Neuropathol. 101(3):185-9. Liu X, et al. (2014). Magnetic resonance charac- of prognostically distinct patient groups. Acta 2746. Wiemels J, Wrensch M, Claus EB (2010).
PMID:11307615 teristics of adult-onset Lhermitte-Duclos disea- Neuropathol. 129(5):679-93. PMID:25783747 Epidemiology and etiology of meningioma. J
2703. Watanabe K, Peraud A, Gratas C, Wa- se: An indicator for active cancer surveillance? 2732. Wellons JC 3rd, Reddy AT, Tubbs RS, Neurooncol. 99(3):307-14. PMID:20821343
kai S, Kleihues P, Ohgaki H (1998). p53 and Mol Clin Oncol. 2(3)415-20. PMID:24772310 Abdullatif H, Oakes WJ, Blount JP, et al. (2004). 2747. Wiemels JL, Wrensch M, Sison JD, Zhou
PTEN gene mutations in gemistocytic ast- 2719. Wei YQ, Hang ZB, Liu KF (1992). In situ Neuroendoscopic findings in patients with in- M, Bondy M, Calvocoressi L, et al. (2011). Re-
rocytomas. Acta Neuropathol. 95(6):559-64. observation of inflammatory cell-tumor cell in- tracranial germinomas correlating with diabetes duced allergy and immunoglobulin E among
PMID:9650746 teraction in human seminomas (germinomas): insipidus. J Neurosurg. 100(5) Suppl Pediat- adults with intracranial meningioma compa-
2704. Watanabe K, Sato K, Biernat W, Tachi- light, electron microscopic, and immunohis- rics:430-6. PMID45287450 red to controls. Int J Cancer. 129(8)4932-9.
bana O, von Ammon K, Ogata N, et al. (1997). tochemical study. Hum Pathol. 23(4)421-8. 2733. Wen PY, Kesari S (2008). Malignant glio- PMID:21520030
Incidence and timing of p53 mutations during PMID4563744 mas in adults. N Engl J Med. 359(5)492-507. 2748. Wiens AL, Cheng L, Bertsch EC, John-
astrocytoma progression in patients with mul- 2720. Weinbreck N, Marie B, Bressenot A, PMID48669428 son KA, Zhang S, Hattab EM (2012). Polysomy
tiple biopsies. Clin Cancer Res. 3(4):523-30. Montagne K, Joud A, Baumann C, et al. (2008). 2734. Wesseling P, Schlingemann RO, Riet- of chromosomes 1 and/or 19 is common and
PMID:9815715 Immunohistochemical markers to distinguish veld FJ, Link M, Burger PC, Ruiter DJ (1995). associated with less favorable clinical outco-
2705. Watanabe K, Tachibana O, Sata K, between hemangioblastoma and metastatic Early and extensive contribution of pericytes/ me in oligodendrogliomas: fluorescent in situ
Yonekawa Y, Kleihues P, Ohgaki H (1996). clear-cell renal cell carcinoma in the brain: vascular smooth muscle cells to microvascu- hybridization analysis of 84 consecutive ca-
Overexpression of the EGF receptor and p53 utility of aquaporinl combined with cytokeratin lar proliferation in glioblastoma multiforme: an ses. J Neuropathol Exp Neurol. 71(7):618-24.
mutations are mutually exclusive in the evolu- AE1/AE3 immunostaining. Am J Surg Pathol. immuno-light and immuno-electron microscopic PMID:22710961
tion of primary and secondary glioblastomas. 32(7)4051-9. PMID48496143 study. J Neuropathol Exp Neurol. 54(3):304-10. 2749. Wiens AL, Hattab EM (2014). The
398 References
pathological spectrum of solid CNS metastases O, Colas C, Entz-Werle N, et al.; EU-Consor- ependymoma. Am J Surg Pathol. 28(7):914-20. Witte D, Meijer D, et al. (2008). Plexiform and
in the pediatric population. J Neurosurg Pediatr. tium Care for CMMRD (C4CMMRD) (2014). PMID:15223962 dermal neurofibromas and pigmentation are
14(2):129-35. PMID:24926970 Diagnostic criteria for constitutional mismatch 2779. Wolter M, Reifenberger J, Blaschke caused by Nf1 loss in desert hedgehog-ex-
2750. Wiestler B, Capper D, Holland-Letz T, repair deficiency syndrome: suggestions of B, Ichimura K, Schmidt EE, Collins VP, et al. pressing cells. Cancer Cell. 13(2)405-16.
Korshunov A, von Deimling A, Pfister SM, et the European consortium ‘care for CMMRD' (2001). Oligodendroglial tumors frequently PMID48242511
al. (2013). ATRX loss refines the classification (C4CMMRD). J Med Genet. 51(6):355-65. demonstrate hypermethylation of the CDKN2A 2794. Wu L, Yang T, Deng X, Yang C, Zhao
of anaplastic gliomas and identifies a subgroup PMID:24737826 (MTS1, p16INK4a), p14ARF, and CDKN2B L, Fang J, et al. (2014). Surgical outcomes in
of IDH mutant astrocytic tumors with better 2764. Winek RR, Scheithauer BW, Wick MR (MTS2, p15INK4b) tumor suppressor genes. spinal cord subependymomas: an institutional
prognosis. Acta Neuropathol. 126(3):443-51. (1989). Meningioma, meningeal hemangi- J Neuropathol Exp Neurol. 60(12):1170-80. experience. J Neurooncol. 116(1):99-106.
PMID:23904111 opericytoma (angioblastic meningioma), pe- PMID:11764089 PMID:24062139
2751. Wiestler B, Capper D, Sill M, Jones DT, ripheral hemangiopericytoma, and acoustic 2780. Wong AJ, Bigner SH, Bigner DD, Kinz- 2795. Wu W, Tanrivermis Sayit A, Vinters HV,
Hovestadt V, Sturm D, et al. (2014). Integrated schwannoma. A comparative immunohistoche- ler KW, Hamilton SR, Vogelstein B (1987). Pope W, Mirsadraei L, Said J (2013). Primary
DNA methylation and copy-number profiling mical study. Am J Surg Pathol. 13(4):251-61. Increased expression of the epidermal growth central nervous system histiocytic sarcoma pre-
identify three clinically and biologically relevant PMID:2648875 factor receptor gene in malignant gliomas is senting as a postradiation sarcoma: case report
groups of anaplastic glioma. Acta Neuropathol. 2765. Wippold FJ 2nd, Smirniotopoulos JG, invariably associated with gene amplification. and literature review. Hum Pathol. 44(6)4177-
128(4):561-71. PMID:25008768 Pilgram TK (1997). Lesions of the cauda equi- Proc Natl Acad Sci USA. 84(19):6899-903. 83. PMID:23356953
2752. Wiestler OD, von Siebenthal K, Schmitt na: a clinical and pathology review from the Ar- PMID:3477813 2796. Wu YT, Ho JT, Lin YJ, Lin JW (2011).
HP, Feiden W, Kleihues P (1989). Distribution med Forces Institute of Pathology. Clin Neurol 2781. Wong K, Gyure KA, Prayson RA, Mor- Rhabdoid papillary meningioma: a clinicopa-
and immunoreactivity of cerebral micro-ha- Neurosurg. 99(4):229-34. PMID:9491294 rison AL, Le TQ, Armstrong RC (1999). Dysem- thologic case series study. Neuropathology.
martomas in bilateral acoustic neurofibromat- 2766. Witkowski L, Lalonde E, Zhang J, Alb- bryoplastic neuroepithelial tumor: in situ hybri- 31 (6):599-605. PMID:21382093
osis (neurofibromatosis 2). Acta Neuropathol. recht S, Hamel N, Cavallone L, et al. (2013). Fa- dization of proteolipid protein (PLP) messenger 2797. Wohrer A, Waldhor T,Heinzl H, Hackl
79(2):137-43. PMID:2596263 milial rhabdoid tumour ‘avant la lettre’-from pa- ribonucleic acid (mRNA). J Neuropathol Exp M, Feichtinger J, Gruber-Mosenbacher U, et
2752A. Wigertz A, Lonn S, Hall P, Auvinen A, thology review to exome sequencing and back Neurol. 58:542-542. al. (2009). The Austrian Brain Tumour Regis-
Christensen HC, Johansen C, et al. (2008). Re- again. J Pathol. 231(1):35-43. PMID:23775540 2782. Wong KK, Tsang YT, Chang YM, Su J, try: a cooperative way to establish a populati-
productive factors and risk of meningioma and 2767. Witt H, Mack SC, Ryzhova M, Bender S, Di Francesco AM, Meco D, et al. (2006). Ge- on-based brain tumour registry. J Neurooncol.
glioma. Cancer Epidemiol Biomarkers Prev. Sill M, Isserlin R, et al. (2011). Delineation of nome-wide allelic imbalance analysis of pedi- 95(3)401-11. PMID49562257
17(10):2663-70. PMID:18843008 two clinically and molecularly distinct subgroups atric gliomas by single nucleotide polymorphic 2798. Xekouki P, Stratakis CA (2012). Suc-
2752B. Wigertz A, Lonn S, Schwartzbaum J, of posterior fossa ependymoma. Cancer Cell. allele array. Cancer Res. 66(23):11172-8. cinate dehydrogenase (SDHx) mutations in
Hall P, Auvinen A, Christensen HC, et al. (2007). 20(2):143-57. PMID:21840481 PMID:17145861 pituitary tumors: could this be a new role for
Allergic conditions and brain tumor risk. Am J 2768. Wizigmann-Voos S, Breier G, Risau W, 2783. Wong TT, Ho DM, Chang KP, Yen SH, mitochondrial complex II and/or Krebs cycle
Epidemiol. 166(8):941-50. PMID:17646205 Plate KH (1995). Up-regulation of vascular en- Guo WY, Chang FC, et al. (2005). Primary pe- defects? Endocr Relat Cancer. 19(6):C33-40.
2753. Wikstrand CJ, Reist CJ, Archer GE, dothelial growth factor and its receptors in von diatric brain tumors: statistics of Taipei VGH, PMID:22889736
Zalutsky MR, Bigner DD (1998). The class III Hippel-Lindau disease-associated and sporadic Taiwan (1975-2004). Cancer. 104(10):2156- 2799. Xiao GH, Jin F, Yeung RS (1995). Identi-
variant of the epidermal growth factor recep- hemangioblastomas. Cancer Res. 55(6):1358- 67. PMID:16220552 fication of tuberous sclerosis 2 messenger RNA
tor (EGFRvlll): characterization and utilization 64. PMID7533661 2784. Wong TT, Ho DM, Chang TK, Yang DD, splice variants that are conserved and differen-
as an immunotherapeutic target. J Neurovirol. 2769. Wizigmann-Voos S, Plate KH (1996). Pa- Lee LS (1995). Familial neurofibromatosis 1 tially expressed in rat and human tissues. Cell
4(2):148-58. PMID:9584952 thology, genetics and cell biology of hemangi- with germinoma involving the basal ganglion Growth Differ. 6(9)4185-91. PMID:8519695
2754. Wilcox P, Li CC, Lee M, Shivalingam B, oblastomas. Histol Histopathol. 11(4):1049-61. and thalamus. Childs Nerv Syst. 11(8)456-8. 2800. Xiong J, Liu Y, Chu SG, Chen H, Chen
Brennan J, Suter CM, et al. (2015). Oligoast- PMID:8930647 PMID:7585682 HX, Mao Y, et al. (2012). Dysembryoplastic neu-
rocytomas: throwing the baby out with the 2770. WoehrerA, Hackl M, WaldhorT, Weis S, 2785. Woodruff JM, Christensen WN (1993). roepithelial tumor-like neoplasm of the septum
bathwater? Acta Neuropathol. 129(1):147-9. Pichler J, Olschowski A, et al.; Austrian Brain Glandular peripheral nerve sheath tumors. Can- pellucidum: review of 2 cases with chromosome
PMID:25304041 Tumour Registry (2014). Relative survival of cer. 72(12):3618-28. PMID:8252477 1p/19q and IDH1 analysis. Clin Neuropathol.
2755. Willard N, Kleinschmidt-DeMasters BK patients with non-malignant central nervous 2786. Woodruff JM, Godwin TA, Erlandson RA, 31(1):31-8. PMID:22192702
(2015). Massive dissemination of adult gliob- system tumours: a descriptive study by the Susin M, Martini N (1981). Cellular schwanno- 2801. Xiong J, Liu Y, Chu SG, Chen H, Chen
lastomas. Clin Neuropathol. 34(6):330-42. Austrian Brain Tumour Registry. Br J Cancer. ma: a variety of schwannoma sometimes mis- HX, Mao Y, et al. (2012). Rosette-forming gli-
PMID:26308254 110(2):286-96. PMID:24253501 taken for a malignant tumor. Am J Surg Pathol. oneuronal tumor of the septum pellucidum with
2756. Williams D, Mori T, Reiter A, Woessman 2771. WoehrerA, Slave I, Peyrl A, Czech T, Dor- 5(8):733-44. PMID:7337161 extension to the supratentorial ventricles: rare
W, Rosolen A, Wrobel G, et al.; European Inter- fer C, Prayer D, et al. (2011). Embryonal tumor 2787. Woodruff JM, Marshall ML, Godwin TA, case with genetic analysis. Neuropathology.
group for Childhood Non-Hodgkin Lymphoma, with abundant neuropil and true rosettes (ET- Funkhouser JW, Thompson NJ, Erlandson RA 32(3):301-5. PMID:22017246
the Japanese Pediatric Leukemia/Lymphoma ANTR) with loss of morphological but retained (1983). Plexiform (multinodular) schwannoma. 2802. Xu HM, Gutmann DH (1998). Merlin diffe-
Study Group (2013). Central nervous system genetic key features during progression. Acta A tumor simulating the plexiform neurofibroma. rentially associates with the microtubule and ac-
involvement in anaplastic large cell lymphoma Neuropathol. 122(6)787-90. PMID:22057788 Am J Surg Pathol. 7(7):691-7. PMID:6638259 tin cytoskeleton. J Neurosci Res. 51(3)403-15.
in childhood: results from a multicentre Europe- 2772. Wolf HK, Buslei R, Bliimcke I, Wiest- 2788. Woodruff JM, Scheithauer BW, Kurt- PMID:9486775
an and Japanese study. Pediatr Blood Cancer. ler OD, Pietsch T (1997). Neural antigens in kaya-Yapicier O, Raffel C, Amr SS, LaQuaglia 2803. Xu J, Yang Y, Liu Y, Wei M, Ren J, Chang
60(10):E118-21. PMID:23720354 oligodendrogliomas and dysembryoplastic MP, et al. (2003). Congenital and childhood Y, et al. (2012). Rosette-forming glioneuronal
2757. Williams SR, Joos BW, Parker JC, Parker neuroepithelial tumors. Acta Neuropathol. plexiform (multinodular) cellular schwannoma: tumor in the pineal gland and the third ventricle:
JR (2008). Papillary glioneuronal tumor: a case 94(5):436-43. PMID:9386775 a troublesome mimic of malignant periphe- a case with radiological and clinical implica-
report and review of the literature. Ann Clin Lab 2773. Wolf HK, Buslei R, Schmidt-Kastner R, ral nerve sheath tumor. Am J Surg Pathol. tions. Quant Imaging Med Surg. 2(3):227-31.
Sci. 38(3):287-92. PMID:18715860 Schmidt-Kastner PK, Pietsch T, Wiestler OD, et 27(10)4321-9. PMID44508393 PMID:23256084
2758. Willis B, Ablin A, Weinberg V, Zoger S, al. (1996). NeuN: a useful neuronal marker for 2789. Woodruff JM, Selig AM, Crowley K, Al- 2804. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim
Wara WM, Matthay KK (1996). Disease course diagnostic Histopathology. J Histochem Cyto- len PW (1994). Schwannoma (neurilemoma) SH, et al. (2011). Oncometabolite 2-hydroxyg-
and late sequelae of Langerhans’ cell histio- chem. 44(10):1167-71. PMID:8813082 with malignant transformation. A rare, distincti- lutarate is a competitive inhibitor of a-ketog-
cytosis: 25-year experience at the University 2774. Wolf HK, Muller MB, Spanle M, Zentner ve peripheral nerve tumor. Am J Surg Pathol. lutarate-dependent dioxygenases. Cancer Cell.
of California, San Francisco. J Clin Oncol. J, Schramm J, Wiestler OD (1994). Ganglio- 18(9):882-95. PMID:8067509 19(1)47-30. PMID:21251613
14(7):2073-82. PMID:8683239 glioma: a detailed Histopathological and im- 2790. Wrede B, Hasselblatt M, Peters O, Thall 2805. Xu X, Zhao J, Xu Z, Peng B, Huang Q, Ar-
2759. Willis SN, Mallozzi SS, Rodig SJ, Crank munohistochemical analysis of 61 cases. Acta PF, Kutluk T, Moghrabi A, et al. (2009). Atypical nold E, et al. (2004). Structures of human cyto-
KM, McArdel SL, Caron T, et al. (2009). The Neuropathol. 88(2):166-73. PMID7985497 choroid plexus papilloma: clinical experience solic NADP-dependent isocitrate dehydrogena-
microenvironment of germ cell tumors harbors 2775. Wolf HK, Normann S, Green AJ, von Ba- in the CPT-SIOP-2000 study. J Neurooncol. se reveal a novel self-regulatory mechanism
a prominent antigen-driven humoral response. kel I, Bliimcke I, Pietsch T, et al. (1997). Tube- 95(3):383-92. PMID49543851 of activity. J Biol Chem. 279(32):33946-57.
J Immunol. 182(5):3310-7. PMID:19234230 rous sclerosis-like lesions in epileptogenic hu- 2791. Wu G, BroniscerA, McEachron TA, Lu C, PMID45173171
2760. Wilson BG, Roberts CW (2011). SWI/ man neocortex lack allelic loss at the TSC1 and Paugh BS, Becksfort J, et al.; St. Jude Child- 2806. Ya$argil MG, Curcic M, Kis M, Siegent-
SNF nudeosome remodellers and cancer. Nat TSC2 regions. Acta Neuropathol. 93(1):93-6. ren’s Research Hospital-Washington Univer- haler G, Teddy PJ, Roth P (1990). Total remo-
Rev Cancer. 11(7):481-92. PMID:21654818 PMID:9006662 sity Pediatric Cancer Genome Project (2012). val of craniopharyngiomas. Approaches and
2761. Wilson BG, Wang X, Shen X, McKenna 2776. Wolff B, Ng A, Roth D, Parthey K, War- Somatic histone H3 alterations in pediatric dif- long-term results in 144 patients. J Neurosurg.
ES, Lemieux ME, Cho YJ, et al. (2010). Epige- muth-Metz M, Eyrich M, et al. (2012). Pediatric fuse intrinsic pontine gliomas and non-brains- 73(1 ):3-11. PMID:2352020
netic antagonism between polycomb and SWI/ high grade glioma of the spinal cord: results tem glioblastomas. Nat Genet. 44(3):251-3. 2807. Yamada H, Haratake J, Narasaki T, Oda
SNF complexes during oncogenic transformati- of the HIT-GBM database. J Neurooncol. PMID:22286216 T (1995). Embryonal craniopharyngioma. Case
on. Cancer Cell. 18(4):316-28. PMID:20951942 107(1):139-46. PMID:21964697 2792. Wu G, Diaz AK, Paugh BS, Rankin SL, report of the morphogenesis of a craniopharyn-
2762. Wilson C, Bonnet C, Guy C, Idziaszczyk 2777. Wolff JE, Sajedi M, Brant R, Coppes MJ, Ju B, Li Y, et al.; St. Jude Children’s Rese- gioma. Cancer. 75(12):2971-7. PMID:7773950
S. Colley J, Humphreys V, et al. (2006). Tsc1 Egeler RM (2002). Choroid plexus tumours. Br arch Hospital-Washington University Pediatric 2808. Yamamoto K, Yamada K, Nakahara T,
haploinsufficiency without mammalian target J Cancer. 87(10):1086-91. PMID:12402146 Cancer Genome Project (2014). The genomic Ishihara A, Takaki S, Kochi M, et al. (2002).
of rapamycin activation is sufficient for renal 2778. Wolfsberger S, Fischer I, Hoftberger R, landscape of diffuse intrinsic pontine glioma Rapid regrowth of solitary subependymal giant
cyst formation in Tsc1+/- mice. Cancer Res. Birner P, Slave I, Dieckmann K, et al. (2004). and pediatric non-brainstem high-grade glioma. cell astrocytoma-case report. Neurol Med Chir
66(16)7934-8. PMID:16912167 Ki-67 immunolabeling index is an accurate pre- Nat Genet. 46(5)444-50. PMID:24705251 (Tokyo). 42(5):224-7. PMID42064158
2763. Wimmer K, Kratz CP, Vasen HF, Caron dictor of outcome in patients with intracranial 2793. Wu J, Williams JP, Rizvi TA, Kordich JJ, 2809. Yamane Y, Mena H, Nakazato Y (2002).
References 399
Immunohistochemical characterization of pine- 1p/19q loss distinguish oligodendrogliomas PMID16024619 Research Hospital-Washington University
al parenchymal tumors using novel monoclonal from other cancers. J Pathol. 226(1)7-16. 2840. Zagzag D, Lukyanov Y, Lan L, Ali MA, Pediatric Cancer Genome Project (2013).
antibodies to the pineal body. Neuropathology. PMID:22072542 Esencay M, Mendez O, et al. (2006). Hypo- Whole-genome sequencing identifies genetic
22(2):66-76. PMID:12075938 2826. Yip S, Miao J, Cahill DP, lafrate AJ, Aldape xia-inducible factor 1 and VEGF upregulate alterations in pediatric low-grade gliomas. Nat
2810. Yan H, Parsons DW, Jin G, McLendon K, Nutt CL, et al. (2009). MSH6 mutations arise CXCR4 in glioblastoma: implications for angio- Genet. 45(6):602-12. PMID23583981
R, Rasheed BA, Yuan W, et al. (2009). IDH1 in glioblastomas during temozolomide therapy genesis and glioma cell invasion. Lab Invest. 2856. Zhang K, Lin JW, Wang J, Wu X, Gao H,
and IDH2 mutations in gliomas. N Engl J Med. and mediate temozolomide resistance. Clin 86(12)1221-32. PMID17075581 Hsieh YC, et al. (2014). A germline missense
360(8):765-73. PMID:19228619 Cancer Res. 15(14)4622-9. PMID19584161 2841. Zagzag D, Zhong H, Scalzitti JM, Laug- mutation in COQ6 is associated with suscepti-
2811. Yang C, Li G, Fang J, Wu L, Yang T, 2827. Yokota T, Tachizawa T, Fukino K, Tera- hner E, Simons JW, Semenza GL (2000). Ex- bility to familial schwannomatosis. Genet Med.
Deng X, et al. (2015). Clinical characteristics moto A, Kouno J, Matsumoto K, et al. (2003). pression of hypoxia-inducible factor 1 alpha in 16(10)787-92. PMID24763291
and surgical outcomes of primary spinal pa- A family with spinal anaplastic ependymoma: brain tumors: association with angiogenesis, in- 2857. Zhang M, Wang Y, Jones S, Sausen M,
ragangliomas. J Neurooncol. 122(3):539-47. evidence of loss of chromosome 22q in tumor. J vasion, and progression. Cancer. 88(11):2606- McMahon K, Sharma R, et al. (2014). Somatic
PMID:25720695 Hum Genet. 48(11):598-602. PMID:14566482 18. PMID10861440 mutations of SUZ12 in malignant peripheral
2812. Yang HJ, Kim JE, Paek SH, Chi JG, 2828. Yoo JH, Rivera A, Naeini RM, Yedururi 2842. Zajac V, Kirchhoff T, Levy ER, Horsley nerve sheath tumors. Nat Genet. 46(11)1170-
Jung HW, Kim DG (2003). The significance of S, Bayindir P, Megahead H, et al, (2008). Me- SW, Miller A, Steichen-Gersdorf E, et al. (1997). 2. PMID25305755
gemistocytes in astrocytoma. Acta Neurochir lanotic paraganglioma arising in the temporal Characterisation of X;17(q12;p13) translocation 2858. Zhang ZK, Davies KP, Allen J, Zhu L,
(Wien). 145(12): 1097-103, discussion 1103. horn following Langerhans cell histiocytosis. breakpoints in a female patient with hypomela- Pestell RG, Zagzag D, et al. (2002). Cell cycle
PMID:14663567 Pediatr Radiol. 38(5):571-4. PMID:18196230 nosis of Ito and choroid plexus papilloma. Eur J arrest and repression of cyclin D1 transcription
2813. Yang I, Tihan T, Han SJ, Wrensch MR, 2829. Yoshimoto M, de Toledo SR, da Silva NS, Hum Genet. 5(2):61-8. PMID:9195154 by INI1/hSNF5. Mol Cell Biol. 22(16):5975-88.
Wiencke J, Sughrue ME, et al. (2010). CD8+ Bayani J, Bertozzi AP, Stavale JN, et al. (2004). 2843. Zakrzewska M, Wojcik I, Zakrzewski K, PMID12138206
T-cell infiltrate in newly diagnosed glioblasto- Comparative genomic hybridization analysis of Polis L, Grajkowska W, Roszkowski M, et al. 2859. Zheng H, Chang L, Patel N, Yang J, Lowe
ma is associated with long-term survival. J Clin pediatric adamantinomatous craniopharyngio- (2005). Mutational analysis of hSNF5/INI1 and L, Burns DK, et al. (2008). Induction of abnor-
Neurosci. 17(11):1381-5. PMID:20727764 mas and a review of the literature. J Neurosurg. TP53 genes in choroid plexus carcinomas. mal proliferation by nonmyelinating schwann
2814. Yang P, Kollmeyer TM, Buckner K, 101(1) Suppl:85-90. PMID:16206977 Cancer Genet Cytogenet. 156(2)179-82. cells triggers neurofibroma formation. Cancer
Bamlet W, Ballman KV, Jenkins RB (2005). 2830. Yoshimoto T, Takahashi-Fujigasaki J, In- PMID15642401 Cell. 13(2)117-28. PMID18242512
Polymorphisms in GLTSCR1 and ERCC2 oshita N, Fukuhara N, Nishioka H, Yamada S 2844. Zaky W, Dhall G, Khatua S, Brown RJ, 2860. Zheng PP, Pang JC, Hui AB, Ng HK
are associated with the development of oli- (2015). TTF-1-positive oncocytic sellar tumor Ginn KF, Gardner SL, et al. (2015). Choroid (2000). Comparative genomic hybridization
godendrogliomas. Cancer. 103(11):2363-72. with follicle formation/ependymal differentia- plexus carcinoma in children: the Head Start detects losses of chromosomes 22 and 16 as
PMID:15834925 tion: non-adenomatous tumor capable of two experience. Pediatr Blood Cancer. 62(5)784-9. the most common recurrent genetic alterations
2815. Yang SY, Jin YJ, Park SH, Jahng TA, Kim different interpretations as a pituicytoma or a PMID:25662896 in primary ependymomas. Cancer Genet Cyto-
HJ, Chung CK (2005). Paragangliomas in the spindle cell oncocytoma. Brain Tumor Pathol. 2845. Zamecnik M, Michal M (2001). Perineuri- genet. 122(1)18-25. PMID11104027
cauda equina region: clinicopathoradiologic fin- 32(3):221-7. PMID:25893822 al cell differentiation in neurofibromas. Report of 2861. Zhong H, DeMarzoAM, LaughnerE, Lim
dings in four cases. J Neurooncol. 72(1):49-55. 2831. Yoshimura J, Onda K, Tanaka R, Ta- eight cases including a case with composite pe- M, Hilton DA, Zagzag D, et al. (1999). Overex-
PMID:15803375 kahashi H (2003). Clinicopathological study rineurioma-neurofibroma features. Pathol Res pression of hypoxia-inducible factor lalpha in
2816. Yang X, Zeng Y, Wang J (2013). Hybrid of diffuse type brainstem gliomas: analysis of Pract. 197(8):537-44. PMID11518046 common human cancers and their metastases.
schwannoma/perineurioma: report of 10 Chi- 40 autopsy cases. Neurol Med Chir (Tokyo). 2846. Zang KD (2001). Meningioma: a cyto- Cancer Res. 59(22):5830-5. PMID:10582706
nese cases supporting a distinctive entity. Int J 43(8):375-82, discussion 382. PMID:12968803 genetic model of a complex benign human 2862. Zhou H, Coffin CM, Perkins SL, Tripp
Surg Pathol. 21(1):22-8. PMID:22832113 2832. You H, Kim YI, Im SY, Suh-Kim H, Paek tumor, including data on 394 karyotyped ca- SR, Liew M, Viskochil DH (2003). Malignant
2817. Yang ZJ, Ellis T, Markant SL, Read SH, Park SH, et al. (2005). Immunohistochemi- ses. Cytogenet Cell Genet. 93(3-4):207-20. peripheral nerve sheath tumor: a comparison
TA, Kessler JD, Bourboulas M, et al. (2008). cal study of central neurocytoma, subependy- PMID11528114 of grade, immunophenotype, and cell cycle/
Medulloblastoma can be initiated by deletion moma, and subependymal giant cell astrocyto- 2847. Zarate JO, Sampaolesi R (1999). Pleo- growth activation marker expression in sporadic
of Patched in lineage-restricted progenitors ma. J Neurooncol. 74(1):1-8. PMID:16078101 morphic xanthoastrocytoma of the retina. Am J and neurofibromatosis 1-related lesions. Am J
or stem cells. Cancer Cell, 14(2):135-45. 2833. Young RJ, Sills AK, Brem S, Knopp EA Surg Pathol. 23(1)79-81. PMID:9888706 Surg Pathol. 27(10)1337-45. PMID14508395
PMID:18691548 (2005). Neuroimaging of metastatic brain disea- 2848. Zaveri J, La Q, Yarmish G, Neuman J 2862A. Zhou J, Shrikhande G, Xu J, McKay
2818. Yasargil MG, von Ammon K, von Deim- se. Neurosurgery. 57(5) Suppl:S10-23, S1-4. (2014). More than just Langerhans cell his- RM, Bums DK, Johnson JE, Parada LF (2011).
ling A, Valavanis A, Wichmann W, Wiestler OD PMID:16237282 tiocytosis: a radiologic review of histiocytic Tsc1 mutant neural stem/progenitor cells exhibit
(1992). Central neurocytoma: histopathological 2834. Yu J, Deshmukh H, Payton JE, Dunham disorders. Radiographics. 34(7):2008-24. migration deficits and give rise to subependy-
variants and therapeutic approaches. J Neuro- C, Scheithauer BW, Tihan T, et al. (2011). Ar- PMID.25384298 mal lesions in the lateral ventricle. Genes Dev.
surg. 76(1):32-7. PMID:1727166 ray-based comparative genomic hybridization 2848A. Zawlik I, Kita D, Vaccarella S, Mittel- 25(15)1595-600. PMID:21828270
2819. Yasha TC, Mohanty A, Radhesh S, identifies CDK4 and FOXM1 alterations as bronn M, Franceschi S, Ohgaki H (2009). Com- 2863. Zhou X, Hampel H, Thiele H, Gorlin
Santosh V, Das S, Shankar SK (1998). In- independent predictors of survival in malignant mon polymorphisms in the MDM2 and TP53 RJ, Hennekam RC, Parisi M, et al. (2001).
fratentorial dysembryoplastic neuroepithelial peripheral nerve sheath tumor. Clin Cancer genes and the relationship between TP53 muta- Association of germline mutation in the PTEN
tumor (DNT) associated with Arnold-Chiari Res. 17(7)1924-34. PMID:21325289 tions and patient outcomes in glioblastomas. tumour suppressor gene and Proteus and Pro-
malformation. Clin Neuropathol. 17(6):305-10. 2835. Yu T, Sun X, Wang J, Ren X, Lin N, Lin Brain Pathol. 19(2)188-94. PMID18462472 teus-like syndromes. Lancet. 358(9277):210-1.
PMID:9832257 S (2015). Twenty-seven cases of pineal paren- 2849. Zbuk KM, Eng C (2007). Cancer pheno- PMID11476841
2820. Yassa M, Bahary JP, Bourguoin P, Belair chymal tumours of intermediate differentiation: mics: RET and PTEN as illustrative models. Nat 2864. Zhou XP, Marsh DJ, Morrison CD, Chau-
M, Berthelet F, Bouthillier A (2005). Intra-pa- mitotic count, Ki-67 labelling index and extent of Rev Cancer. 7(1):35-45. PMID17167516 dhury AR, Maxwell M, Reifenberger G, et al.
renchymal mesenchymal chondrosarcoma resection predict prognosis. J Neurol Neurosurg 2850. Zbuk KM, Eng C (2007). Hamartomatous (2003). Germline inactivation of PTEN and dys-
of the cerebellum: case report and review of Psychiatry. PMID:25911570 polyposis syndromes. Nat Clin Pract Gastroen- regulation of the phosphoinositol-3-kinase/Akt
the literature. J Neurooncol. 74(3):329-31. 2836. Zacharia BE, Bruce SS, Goldstein H, terol Hepatol. 4(9):492-502. PMID:17768394 pathway cause human Lhermitte-Duclos disea-
PMID:16187026 Malone HR, Neugut Al, Bruce JN (2012). Inci- 2851. Zevallos-Giampietri EA, Yafies HH, se in adults. Am J Hum Genet. 73(5)1191-8.
2821. Yeh-Nayre LA, Malicki DM, Vinocur DN, dence, treatment and survival of patients with Orrego Puelles J, Barrionuevo C (2004). Pri- PMID14566704
Crawford JR (2012). Medulloblastoma with craniopharyngioma in the surveillance, epide- mary meningeal Epstein-Barr virus-related 2865. Zhou XP, Waite KA, Pilarski R, Hampel
excessive nodularity: radiographic features miology and end results program. Neuro Oncol. leiomyosarcoma in a man infected with human H, Fernandez MJ, Bos C, et al. (2003). Germ-
and pathologic correlate. Case Rep Radiol. 14(8)1070-8. PMID:22735773 immunodeficiency virus: review of literature, line PTEN promoter mutations and deletions
2012:310359. PMID:23133782 2837. Zada G, Lin N, Ojerholm E, Ramkisso- emphasizing the differential diagnosis and pa- in Cowden/Bannayan-Riley-Ruvalcaba syn-
2822. Yi KS, Sohn CH, Yun TJ, Choi SH, Kim on S, Laws ER (2010). Craniopharyngioma thogenesis. Appl Immunohistochem Mol Mor- drome result in aberrant PTEN protein and
JH, Han MH, et al. (2012). MR imaging findings and other cystic epithelial lesions of the sellar phol. 12(4):387-91. PMID15536343 dysregulation of the phosphoinositol-3-kinase/
of extraventricular neurocytoma: a series of region: a review of clinical, imaging, and his- 2852. Zhang CZ, Leibowitz ML, Pellman D Akt pathway. Am J Hum Genet. 73(2)404-11.
ten patients confirmed by immunohistoche- topathological relationships. Neurosurg Focus. (2013). Chromothripsis and beyond: rapid ge- PMID12844284
mistry of IDH1 gene mutation. Acta Neurochir 28(4):E4. PMID:20367361 nome evolution from complex chromosomal 2866. Zhu HD, Xie Q, Gong Y, Mao Y, Zhong P,
(Wien). 154(11):1973-9, discussion 1980, 2838. Zagzag D, Esencay M, Mendez O, Yee rearrangements. Genes Dev. 27(23)2513-30. Hang FP, et al. (2013). Lymphoplasmacyte-rich
PMID:22945896 H, Smirnova I, Huang Y, et al. (2008), Hypoxia- PMID24298051 meningioma: our experience with 19 cases and
2823. Yildiz H, Hakyemez B, Koroglu M, Ye- and vascular endothelial growth factor-induced 2853. Zhang F, Tan L, Wainwright LM, Barto- a systematic literature review. Int J Clin Exp
sildag A, Baykal B (2006). Intracranial lipomas: stromal cell-derived factor-1 alpha/CXCR4 lomei MS, Biegel JA (2002). No evidence for Med. 6(7):504-15. PMID:23936588
importance of localization. Neuroradiology. expression in glioblastomas: one plausible ex- hypermethylation of the hSNF5/INI1 promoter 2867. Zhu J, Frosch MP, Busque L, BeggsAH,
48(1 ):1-7. PMID:16237548 planation of Scherer’s structures. Am J Pathol. in pediatric rhabdoid tumors. Genes Chromoso- Dashner K, Gilliland DG, et al. (1995). Analy-
2824. Yin XL, Hui AB, Pang JC, Poon WS, Ng 173(2):545-60. PMID18599607 mes Cancer. 34(4):398-405. PMID12112529 sis of meningiomas by methylation- and tran-
HK (2002). Genome-wide survey for chromo- 2839. Zagzag D, Krishnamachary B, Yee H, 2854. Zhang J, Cheng H, Qiao Q, Zhang JS, scription-based Clonality assays. Cancer Res.
somal imbalances in ganglioglioma using com- Okuyama H, Chiriboga L, Ali MA, et al. (2005). Wang YM, Fu X, et al. (2010). Malignant solitary 55(17):3865-72. PMID7641206
parative genomic hybridization. Cancer Genet Stromal cell-derived factor-1 alpha and CXCR4 fibrous tumor arising from the pineal region: 2868. Zhu L, Ren G, Li K, Liang ZH, Tang WJ,
Cytogenet. 134(1)71-6. PMID:11996800 expression in hemangioblastoma and clear case study and literature review. Neuropatho- Ji YM, et al. (2011). Pineal parenchymal tu-
2825. Yip S, Butterfield YS, Morozova O, Chit- cell-renal cell carcinoma: von Hippel-Lindau logy. 30(3)294-8. PMID19845865 mours: minimum apparent diffusion coefficient
taranjan S, Blough MD, An J, et al. (2012). loss-of-function induces expression of a ligand 2855. Zhang J, Wu G, Miller CP, Tatevossian in prediction of tumour grading. J Int Med Res.
Concurrent CIC mutations, IDH mutations, and and its receptor. Cancer Res. 65(14):6178-88. RG, Dalton JD, Tang B, et al.; St. Jude Children's 39(4)1456-63. PMID:21986148
400 References
2869. Zhu Y, Ghosh P, Charnay P, Bums
DK, Parada LF (2002). Neurofibromas in
NF1: Schwann cell origin and role of tumor
environment. Science. 296(5569):920-2.
PMID:11988578
2870. Zhukova N, Ramaswamy V, Remke M,
Pfaff E, Shih DJ, Martin DC, et al. (2013). Sub-
group-specific prognostic implications of TP53
mutation in medulloblastoma. J Clin Oncol.
31(23):2927-35. PMID:23835706
2871. Zlatescu MC, TehraniYazdi A, Sasaki
H, Megyesi JF, Betensky RA, Louis DN, et
al. (2001). Tumor location and growth pattern
correlate with genetic signature in oligodendro-
glial neoplasms. Cancer Res. 61(18):6713-5.
PMID:11559541
2872. Zong H, Parada LF, Baker SJ (2015). Cell
of origin for malignant gliomas and its implica-
tion in therapeutic development. Cold Spring
Harb Perspect Biol. 7(5) PMID:25635044
2873. Zorludemir S, Scheithauer BW, Hirose
T, Van Houten C, Miller G, Meyer FB (1995).
Clear cell meningioma. A clinicopathologic
study of a potentially aggressive variant of
meningioma. Am J Surg Pathol. 19(5):493-505.
PMID:7726360
2874. Zou C, Smith KD, Liu J, Lahat G, Myers
S, Wang WL, et al. (2009). Clinical, pathologi-
cal, and molecular variables predictive of mali-
gnant peripheral nerve sheath tumor outcome.
Ann Surg. 249(6):1014-22. PMID:19474676
2875. Zuccaro G, Taratuto AL, Monges J (1986).
Intracranial neoplasms during the first year of
life. Surg Neurol. 26(1):29-36. PMID:3715697
2876. Zulch KJ (1957). Brain Tumours.
Their Biology and Pathology. New York:
Springer-Verlag.
2877. Zygourakis CC, Rolston JD, Lee HS, Par-
tow C, Kunwar S, Aghi MK (2015). Pituicytomas
and spindle cell oncocytomas: modern case se-
ries from the University of California, San Fran-
cisco. Pituitary. 18(1):150-8. PMID:24823438
2878. Zulch KJ, editor (1979). Histological ty-
ping of tumours of the central nervous system.
1st Edition Geneva: World Health Organization.
2879. Zoller ME, Rembeck B, Oden A, Samu-
elsson M, Angervall L (1997). Malignant and be-
nign tumors in patients with neurofibromatosis
type 1 in a defined Swedish population. Cancer.
79(11):2125-31. PMID:9179058
.
Subject index
1p34 319-321 Alpha-1-antitrypsin 38, 84, 330 Basal cell naevus syndrome 319
1 p35-36 143 Alpha-B-crystallin 83 B-cell receptor 274, 275
2-hydroxyglutarate 21, 22, 26, 62, 67 Alpha-fetoprotein 289, 290 BCL2 273, 274, 333, 336
2p16 43, 317 Alpha-internexin 65, 69, 74, 157, 308 BCL6 273-275
2q32 317 Alpha-ketoglutarate-dependent Bcl-xL 45
3p21.3 43, 317 dioxygenases 67 BCOR-CCNB3 intrachromosomal inversion
3p25 86,304 Anaplastic astrocytoma, IDH-mutant 18, 21, 260
4E-BP1 309 24-27, 54, 55, 76, 77 BCORL1 287
4q12 146 Anaplastic astrocytoma, IDH-wildtype 8, 10, Benign fibrous histiocytoma 261
5-HT 166, 171, 172 23, 25, 27, 30 Beta-catenin 37, 188, 189, 193, 300, 318,
5-methylcytosine hydroxylase 67 Anaplastic astrocytoma, NOS 27 324-328
5q11-q13 317 Anaplastic ependymoma 106, 108, 113, 202 Beta-hCG 288-290
5q13.3 146 Anaplastic ganglioglioma 138, 141 BIRC5 229
6p21 274 Anaplastic large cell lymphoma 276, 277 BK virus 61, 272
6q21 274 Anaplastic (malignant) meningioma 244 BLNK 274
7p22 43, 317 Anaplastic oligoastrocytoma, dual-genotype BMPR1A 315, 316
7q31 146 77 BNIP 37
7q34 80, 86, 96 Anaplastic oligoastrocytoma, NOS 76 Brachyury 256
8p22-pter 146 Anaplastic oligodendroglioma 33, 34, 61, 67, BRAF mutations 16, 86, 96, 140, 341
8q12.1-q12.2 274 68, 70-74, 76 Brain tumour-polyposis syndrome 1 /
9p21.3 96 Anaplastic oligodendroglioma, IDH-mutant Mismatch repair cancer syndrome 317
9q22 191,319,320 and 1p/19q-codeleted 34, 61, 70, 72-74, Brain tumour-polyposis syndrome 2 / Familial
10q21.3 146 76 adenomatous polyposis 318
10q23.21 274 Anaplastic oligodendroglioma lacking IDH BRCA1 67, 236
10q24 319, 320 mutation and 1p/19q codeletion 74 BRG1 206,208,209,211,212
11q23 143 Anaplastic oligodendroglioma, NOS 72, 74 BRIP1 236
12q14.3 146 Anaplastic pleomorphic xanthoastrocytoma BTP1 See Brain tumour-polyposis
13q21 146 98, 99 syndrome 1 / Mismatch repair cancer
16p13.3 309 Ancient neurofibroma 220 syndrome
17q11.2 294, 295 Angiocentric glioma 119,120 BTP2 See Brain tumour-polyposis
18q21.33-q23 274 Angiocentric neuroepithelial tumour 119 syndrome 2 / Familial adenomatous
19p13.2 322 Angiolipoma 260 polyposis
21 q22.11 146 Angiomatous meningioma 233, 238, 239
22q11,23 218, 302, 322 Angiopoietin 37 Butterfly glioma 30
34betaE12 105 Angiosarcoma 259
Annexin A1 336
C
A C11orf95 108, 109, 112, 206
Antoni A pattern 215
Abrikossoff tumour 329
Antoni B pattern 215 C19 286
ACKR3 37 C228T TERT mutation 235
Actin 38, 299, 300 AP1B1 235
APC 109, 163, 185, 189, 318 C250T TERT mutation 235
ACVR1 59
Aquaporin-1 256 CADM1 235
Adamantinomatous craniopharyngioma 324, Cafe-au-lait spots/macules 294-296, 299,
327 ARHGAP35 66
ASMT 172, 174, 175, 178 317
Adenoid glioblastoma 35
Astroblastoma 121, 122 CALCA 181
AE1/AE3 38, 51, 64, 105, 181, 256, 289 CAM5.2 105, 122, 181, 256, 289
AIDS-related diffuse large B-cell lymphoma Ataxia-telangiectasia 275
ATM 59 CAMP 218, 295
275
ATOH1 163,191,199 CAMTA1 66, 258
AKT 31, 39, 43, 143, 221, 287, 295, 300, 309, Carbonic anhydrase 37, 64, 256
316 AT/RT See Atypical teratoid/rhabdoid tumour
Atypical choroid plexus papilloma 126, 127 CARD11 274
AKT1 151,235,315
Atypical meningioma 241 CBL 87, 274, 287
AKT1 E17K mutation 235 CBTRUS See Central Brain Tumor Registry of
AKT2 151 Atypical neurofibroma 220, 221
Atypical teratoid/rhabdoid tumour 206, the United States
AKT3 151
209-212, 321, 322 CCDC26 42
AKT/mTOR pathway 43, 221, 287, 295, 316 CCND1 59, 211,302, 322
ALCL See Primary CNS anaplastic large cell AURKA 211
AURKB 46, 47 CCND2 21, 287
lymphoma, ALK-positive
CCNE2 229
ALDH1 253 B CD 1a 280-283
ALDH1A1 253 Bannayan-Riley-Ruvalcaba syndrome 314,
CD2 276
ALK 261, 277, 283, 341 316
CD3 240, 275, 276
Alpha-1-antichymotrypsin 38, 84, 330 BAP1 270 CD4 38, 276, 289
CD5 276, 277
WHO Classification of Tumours of the Central Nervous System is the Revised 4th Edition of the WHO series on
histological and genetic typing of human tumours. This authoritative, concise reference book provides an
international standard for oncologists and pathologists and will serve as an indispensable guide for use in the design
of studies monitoring response to therapy and clinical outcome.
Diagnostic criteria, pathological features, and associated genetic alterations are described in a strictly disease-
oriented manner. Sections on all recognized neoplasms and their variants include new ICD-0 codes, epidemiology,
clinical features, macroscopy, pathology, genetics, and prognosis and predictive factors.
The book, prepared by 122 authors from 19 countries, contains more than 800 colour images and tables, and more
than 2800 references.
ISBN 978-92-832-4492-9