-
INTRAVENTRICULAR TUMORS
CONTENTS
Preface ixAndrew T. Parsa and Mitchel S. Berger
Epidemiology and Pathology of Intraventricular TumorsJames S.
Waldron and Tarik Tihan 469
Intraventricular tumors present a diagnostic challenge to the
clinician because of a broaddifferential diagnosis with significant
variability in tumor type between adult andpediatric populations.
This expansive differential diagnosis includes choroid
plexuspapillomas and carcinomas, ependymomas, subependymomas,
subependymal giant cellastrocytomas, central neurocytomas,
meningiomas, and metastases as well as a numberof cysts,
inflammatory lesions, and other rare neoplasms. Posterior fossa
ependymomas,subependymal giant cell astrocytomas, and choroid
plexus tumors are more likely toappear in childhood, whereas
subependymomas, central neurocytomas, intraventricularmeningiomas,
and metastases are more frequent in adults. This article reviews
theepidemiology, the pathologic characteristics, and the primary
diagnostic considerationsof each tumor type.
Intraventricular Neurocytomas 483Janet Lee, Susan M. Chang,
Michael W. McDermott, and Andrew T. Parsa
Central neurocytomas (CNCs) are World Health Organization II
benign central nervoussystem (CNS) neoplasms first described in
1982 by Hassoun and his colleagues. Hall-mark features of CNC
include (1) occurrence in the lateral ventricle of young adults,(2)
a well-circumscribed isodense to hyperdense mass with contrast
enhancement onCT and isointense to hyperintense compared with
normal brain parenchyma on T1-and T2-weighted MRI, (3) resemblance
to oligodendroglioma on light microscopy, (4)neuronal origin seen
in electron microscopy and immunohistochemistry, and (5) favor-able
prognosis with benign biologic behavior. CNCs comprise 0.1% to 0.5%
of all CNSneoplasms based on pathologic review at several
neurosurgery centers. A population-based incidence has not been
established, in part because of the paucity of cases. Givenits
recent distinction as a unique tumor and its low incidence, most
reports of CNC arefrom the pathologic literature with little data
regarding its management. Furthermore,many early cases of CNC were
misdiagnosed, and treatment was based on the presumeddiagnosis of
oligodendroglioma or ependymoma. Accordingly, this article presents
acomprehensive review of the literature and proposes a management
paradigm for thetreatment of CNC.
VOLUME 14 NUMBER 4 OCTOBER 2003 v
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Surgical Approaches to Tumors of the Lateral Ventricle
509Richard C.E. Anderson, Saadi Ghatan, and Neil A. Feldstein
Tumors of the lateral ventricles comprise a relatively rare
heterogeneous group of lesionsin children and adults. They arise
from the ependyma and subependyma that line theventricles, from the
choroid plexus arachnoid and epithelium, or from ectopic
tissuerests that have become trapped within the ventricle or its
lining. Although the lateralventricles are among the most
surgically inaccessible areas of the brain, numerous op-erative
approaches to the ventricles have been developed. This article
first discusses theclinical manifestations and differential
diagnosis of lateral ventricular tumors. Relevantregional anatomy
and general operative strategies for these lesions are then
discussed,with particular focus on the following approaches:
frontal, temporal, and parietal trans-cortical approaches and
anterior and posterior interhemispheric approaches.
Surgical Approaches to Posterior Third Ventricular Tumors
527Alan P. Lozier and Jeffrey N. Bruce
Advanced microsurgical techniques combined with improved
neuroanesthetic and post-operative critical care have made
aggressive surgical resection a mainstay in the manage-ment of
posterior third ventricular and pineal region tumors. Although a
variety ofapproaches to the posterior third ventricle have been
designed, three are in commonuse. The
infratentorial-supracerebellar approach takes advantage of a
natural corridorbetween the cerebellum and the tentorium.
Supratentorial approaches include theinterhemispheric-transcallosal
and occipital-transtentorial approaches. Refinements insurgical
technique have led to a more favorable outlook for patients with
these un-common tumors.
Endoscopic Adjuncts to Intraventricular Surgery 547Sandeep
Kunwar
Recently, endoscopic intraventricular surgery has been performed
successfully in severalclinical series. Although the therapeutic
results must be compared with conventionalsurgery, neuroendoscopy
seems to be a safe surgical technique when performed by sur-geons
with appropriate experience and refined endoscopic tools. Rigid or
flexible endo-scopes equipped with various-sized working channels
should be selected depending onthe nature of the pathologic
findings. The well-proven tenets of microsurgery must notbe
sacrificed for the sake of more rapid surgical time and
noninvasiveness; thus, endo-scopic surgery must adhere to the
principles of microsurgery. The improved visualiza-tion and lower
morbidity have established neuroendoscopy in the management
ofspecific disease processes, such as obstructive hydrocephalus.
Its further use in the man-agement of intraventricular cysts and
tumors is dependent on long-term follow-up andthe development of
even better instrumentation.
Intraventricular Meningiomas 559Michael W. McDermott
Meningiomas arising in the ventricular system are rare; yet,
when they do presentclinically, they are often large, most often
within the atrium, and most frequently onthe left. For all these
reasons, they are tumors for which it is difficult to achieve
theperfect surgical result: complete removal of a benign tumor
without complicationsor new neurologic morbidity. With a thorough
understanding of the anatomy of struc-tures around the ventricle,
selection of the proper surgical approach, and use of mod-ern
neurosurgical techniques, however, modern-day surgical results
should be superiorto those of the past.
vi CONTENTS
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Intraventricular Gliomas 571Aaron S. Dumont, Elana Farace, David
Schiff, and Mark E. Shaffrey
Significant progress has been realized in the contemporary
understanding and treatmentof intraventricular gliomas. However,
there remains a substantial need for continued ad-vancement in the
clinical management of patients harboring these lesions,
particularlyependymomas. This article addresses the specific types
of intraventricular gliomas withemphasis on each tumors defining
characteristics and the specific nuances of manage-ment in each
variant.
Surgical Resection of Metastatic Intraventricular Tumors
593Giacomo G. Vecil and Frederick F. Lang
Intraventricular metastases are a unique challenge for
neurosurgical oncologists. Thispaper describes the clinical
features and surgical management strategies of intraventric-ular
metastases based on a review of the literature and an analysis of
35 patients treatedin the Department of Neurosurgery at The
University of Texas M.D. Anderson CancerCenter over the last 10
years. Intraventricular metastases comprise 0.95% of
intrapar-enchymal metastases. Renal cell carcinoma has the highest
propensity of all primary tu-mors to metastasize to the ventricle.
The trigone of the lateral ventricular is the mostcommon location
with the ventricle for metastases to occur, presumably due to the
highconcentration of choroid plexus in the region. Despite the deep
location, surgical resec-tion can be achieved safely in most cases.
The survival of surgically treated patients iscomparable to that of
patients with intraparenchymal metastases.
Intraventricular Congenital Lesions and Colloid Cysts 607Aurelia
Peraud, Anna Illner, and James T. Rutka
Intraventricular congenital lesions and colloid cysts comprise a
rather large spectrum ofdifferent pathologic conditions. In most
cases, treatment in not warranted unless there isprogressive
ventricular obstruction with hydrocephalus or growth of the lesion
itself,making tissue biopsy and histopathologic diagnosis
necessary. Accordingly, a preciseneuroradiologic evaluation is of
the utmost importance, because most lesions, if notsymptomatic,
only require clinical and radiologic follow-up.
Choroid Plexus Tumors in Children 621Nalin Gupta
Choroid plexus tumors represent a well-defined subset of brain
tumors that occurmainly in young children. Surgical resection for
papilloma is usually curative, althoughcareful surgical planning is
required to minimize the potential risks. Although
adjunctivetherapy for carcinoma includes chemotherapy or radiation,
the long-term survival forcarcinoma remains poor.
Cumulative Index 2003 633
CONTENTS vii
-
FORTHCOMING ISSUES
January 2004
Endoscopy
Rick Abbott, MD, Guest Editor
April 2004
Traumatic Neurovascular Surgery
J. Paul Elliot, MD, Guest Editor
July 2004
Pain Treatment
Gary Heit, MD, Guest Editor
RECENT ISSUES
July 2003
Neuroaugmentation forChronic Pain
Jaimie M. Henderson, MD, Guest Editor
April 2003
Surgery for Psychiatric Disorders
Ali R. Rezai, MD, Steven A. Rasmussen, MD,Benjamin D. Greenberg,
MD, PhDGuest Editors
January 2003
Pituitary Surgery
Martin H. Weiss, MD, andWilliam T. Couldwell, MD, PhD, Guest
Editors
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Neurosurg Clin N Am 14 (2003) ix
Preface
Intraventricular tumors
Guest Editors
Mitchel S. Berger, MDAndrew T. Parsa, MD, PhD
Neurosurgical oncology is an evolving disci-
pline that continually benefits from the translationof
scientific advances into clinical treatment para-digms. For the
past 30 years at the University
of CaliforniaSan Francisco, basic scientists andclinicians have
been working together to rapidlyimplement new discoveries for the
benefit of ourpatients. Several examples of these
collaborations
can be found here and at other premier neurosur-gery departments
around the world. A refinedunderstanding of the molecular pathways
that
contribute to tumor development has yieldednew targets for
chemotherapy, while our increas-ing experience with radiosurgery
has broadened
treatment options for patients. The advent of sur-gical adjuncts
such as functional mapping tech-niques, computerized frameless
stereotaxy, and
endoscopy has significantly decreased surgicalmorbidity. In
addition, surgical procedures arenow in place to facilitate local
delivery of che-motherapeutic agents with unprecedented tumor
specificity.Intraventricular tumors epitomize the chal-
lenges faced by neurosurgical oncologists in the
1042-3680/03/$ - see front matter 2003 Elsevier Inc. All
rigdoi:10.1016/S1042-3680(03)00059-7
twenty-first century. These lesions have a complex
biology and require significant skill to excisewithout attendant
morbidity. A comprehensiveunderstanding of ventricular anatomy,
surgical
approaches, and nonsurgical treatment optionsis requisite for
the neurosurgeon. Successful treat-ment of patients with these
lesions requires adedicated team of pathologists, oncologists,
and
neurosurgeons. In this issue of the NeurosurgeryClinics of North
America, we draw upon theexperience of several colleagues to
facilitate a
better understanding of intraventricular tumorsin children and
adults.
Andrew T. Parsa, MD, PhD
Mitchel S. Berger, MDDepartment of Neurological Surgery
University of CaliforniaSan Francisco505 Parnassus Avenue
M-779
San Francisco, CA 94143, USA
E-mail address: [email protected](A.T. Parsa)
hts reserved.
mailto:[email protected]
-
Neurosurg Clin N Am 14 (2003) 469482
Epidemiology and pathology of intraventricular tumorsJames S.
Waldron, MDa, Tarik Tihan, MD, PhDb,*
aDepartment of Neurological Surgery, University of California at
San Francisco, 513 Parnassus, HSW 511,
San Francisco, CA 941430511, USAbNeuropathology Unit, Department
of Pathology, University of California at San Francisco, 513
Parnassus,
HSW 408, San Francisco, CA 941430511, USA
Intraventricular tumors present a diagnosticchallenge to the
clinician because of a broad
differential diagnosis with significant variability intumor type
between adult and pediatric popula-tions. This expansive
differential includes choroidplexus papillomas (CPCs) and choroid
plexus
carcinomas (CPCs), ependymomas, subependy-momas, subependymal
giant cell astrocytomas(SEGAs), central neurocytomas,
meningiomas,
and metastases as well as a number of cysts,inflammatory
lesions, and other rare neoplasms.Posterior fossa ependymomas,
SEGAs, and cho-
roid plexus tumors are more likely to appear inchildhood,
whereas subependymomas, centralneurocytomas, intraventricular
meningiomas,
and metastases are more frequent in adults. Eachof these tumor
types involves the ependymallining and subependymal plate of the
ventricularwall, the septum pellucidum, or the highly
vascular choroid plexus. This article reviews theepidemiology,
the pathologic characteristics, andthe primary diagnostic
considerations of each
tumor type.
Choroid plexus papilloma and carcinoma
Epidemiology
Choroid plexus tumors are epithelial neo-plasms with a
prevalence of 0.3 cases per million[1]. In two large series,
choroid plexus tumors
accounted for 0.4% [2] and 0.6% [3] of allreported intracranial
tumors. The tumor pre-
* Corresponding author.
E-mail address: [email protected] (T. Tihan).
1042-3680/03/$ - see front matter 2003 Elsevier Inc. All
rigdoi:10.1016/S1042-3680(03)00060-3
dominantly occurs in childhood, although it canbe seen at any
age. The median age of onset is 3.5
years [4], with 20% of patients presenting in thefirst year of
life and almost 50% in the first decade[5]. The most common
locations for choroidplexus tumors are the lateral and fourth
ventricles,
followed by the third ventricle. Cerebellopontineangle examples
are less common and are causedby extension of tumor through the
foramen of
Luschka [6]. In addition, rare suprasellar caseshave been
reported [7]. Tumor location is closelycorrelated with patient age.
The most common
location in children is the lateral ventricle,whereas the fourth
ventricle is the most frequentsite in adults. Choroid plexus tumors
are divided
into the CPP (World Health Organization [WHO]grade I) and the
more aggressive CPC (WHOgrade III). CPCs make up a small proportion
ofchoroid plexus tumors, primarily present in
children less than 3 years of age, and are mostcommonly found in
the lateral ventricles [8]. CPPsand CPCs have been shown to spread
through the
cerebrospinal fluid, and rare metastatic cases havebeen
documented outside the CNS [4].
Macroscopic and microscopic features
Choroid plexus tumors are often soft to
rubbery and may have a gritty texture becauseof calcification.
The tumors are frequently shadesof orange-brown. During surgery, an
anchoring
pedicle can be seen attached to the normalchoroid plexus or the
ventricular wall. Somepapillomas have a cauliflower-like
appearance.
CPPs and CPCs exhibit features akin tomany papillary neoplasms
in other organs. CPPshave well-developed fibrovascular cords
within
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papillary structures and do not exhibit architec-tural or
cytologic atypia (Fig. 1A). Epithelial andstromal cells contain
many characteristics of the
normal choroid plexus, such as calcifications andxanthomatous
change [9,10]. In some cases, thereis a striking nuclear
monomorphism withoutother aggressive features, such as mitoses
or
vascular proliferation. Rarely, geographic necro-sis without the
pseudopalisading that is suggestiveof an infarct can be seen in an
otherwise typical
CPP. Osseous or cartilaginous metaplasia andacinar or tubular
differentiation are reported inchoroid plexus neoplasms [1113]. In
addition,
a number of studies report a pigmented variantthat contains
neuromelanin and lipofuscin [14].CPPs with marked oncocytic
transformation aswell as glial differentiation are rare [12].
Transi-
tional zones between the normal and neoplasticchoroid plexus can
be found in CPPs and CPCs.
Carcinomas of the choroid plexus are tumors
that exhibit all the histologic hallmarks ofaggressiveness (see
Fig. 1B). A typical CPC isa neoplasm with increased architectural
complex-
ity demonstrating partially solid and partiallynonpapillary
growth. Most tumors have markedcytologic atypia, atypical mitotic
figures, and
frank necrosis. Some high-grade tumors havecytologic and
architectural features that resembleanaplastic oligodendrogliomas.
Invasion intoneuropil is characteristic of CPCs, although some
CPPs can occasionally exhibit invasion intosurrounding
parenchyma. Rare CPCs resembleundifferentiated carcinomas without
any distin-
guishing features [15].
Immunohistochemical features
Cytokeratins and vimentin are expressed byvirtually all CPPs and
most CPCs. Glial fibrillary
acidic protein (GFAP) can be found focally inabout 25% to 55% of
CPPs and in 20% of CPCs[16]. Most of the GFAP-positive cells are
simul-
taneously positive for cytokeratin [17]. S-100protein is present
in almost all cases of CPP and,less frequently, in CPCs. The
staining for S-100 is
often stronger and more diffuse than GFAPstaining. Synaptophysin
has been suggested asa possible marker for choroid plexus
epithelium,but staining of tumors with this marker produces
variable results. Epithelial membrane antigen(EMA) is positive
in tumor cells only focally, ifat all. A recent study suggested
that immunohis-
tochemical staining for prealbumin and carci-noembryonic acid
(CEA) is of significant value forthe differentiation of CPPs and
CPCs [18].
Staining for insulin-like growth factor-II (IGF-II) is also a
potentially useful marker to distin-guish normal choroid plexus and
CPP from CPC[19]. Additionally, indirect indices of
proliferation,
such as the Ki-67/MIB-1 antibody, have been usedto distinguish
CPP from CPC [20,21]. The meanKi-67/MIB-1 labeling index is often
less than 2%
in CPPs and greater than 10% in CPCs. Immu-nohistochemical
staining for p53 protein is foundmore often in carcinomas than in
CPPs [22].
Ultrastructural features
Most CPPs exhibit apical microvilli withscattered cilia,
junctional complexes, interdigitat-ing lateral cell borders,
basement membrane, and
fenestrated capillaries. Cilia contain the 9 + 0microtubule
configuration characteristic of neuro-epithelial cells. Some tumors
have irregularly
shaped structures containing lipid droplets, fila-mentous
material, and structures that resemblethe silver bodies of Biondi
seen in normal
choroid plexus [23]. CPCs are often more varied intheir
ultrastructural appearance and can showepithelial features as well
as cilia and microvilli,although such findings are focal in many
cases.
CPCs can also display immature cellular features,such as
polyribosomes, glycogen granules, andhypertrophied rough
endoplasmic reticulum [24].
Fig. 1. (a) Choroid plexus papilloma: low magnification showing
well-formed papillae composed of uniform small
epithelial type cells. Mitotic figures and necrosis are rare.
(b) Choroid plexus carcinoma: a tumor with irregular
architecture, the presence of marked pleomorphic cells with a
less prominent papillary pattern, and frequent mitoses and
necrosis. (c) Ependymoma: medium magnification showing uniform
cells arranged in a perivascular fashion. (d )
Ependymoma: high magnification of an ependymal pseudorosette, an
angiocentric arrangement of cells with fibrillary
processes perpendicular to the luminal axis. (e) Subependymoma:
a paucicellular tumor showing a multinodular compact
architecture without mitotic figures. ( f ) Subependymal giant
cell astrocytoma: a tumor composed of gemistocytic
astrocytes, scattered inflammatory cells, and dystrophic
calcifications. (g) Central neurocytoma: a tumor typically
described as oligodendroglioma-like with clear cells (fried-egg
cells) and a delicate vasculature (chicken-wire
vasculature). (h) Meningioma: a typical meningioma in the
lateral ventricle. The tumor shows multiple whorl formation as
well as calcifications known as psammoma bodies.
c
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Molecular and genetic features
In CPP, recurrent abnormalities, includingpartial gains of
chromosome 7, have beenreported [25]. A comparative genomic
hybridiza-
tion study of a large number of choroid plexustumors showed that
+5q, +6q, +7q, +9q,+15q, +18q, and 21q were significantly
morecommon in CPPs, whereas CPCs were character-
ized by +1, +4q, +10, +14q, +20q, +21q,5q, 9p, 11, 15q, and 18q
[26].
Choroid plexus neoplasms have been associ-
ated with the Li-Fraumeni syndrome as well asthe Aicardi
syndrome [2729]. Several reportshave identified SV-40 virus genetic
material within
tumor cells; however, the contribution of thisvirus to the
formation of choroid plexus tumors isunknown [3032].
Pathologic differential diagnosis
The most frequent challenge during pathologicevaluation is the
distinction of CPP from normalchoroid plexus. The normal choroid
plexus has
regular single-layered cells with hobnail luminalsurfaces,
whereas CPP displays a more crowdedepithelium with significant
nuclear variability. The
diagnosis of CPP by the pathologist is unreason-able in the
absence of clinical and radiologicfindings, especially without a
distinct contrast-enhancing intraventricular mass.
The second diagnostic challenge is the exclu-sion of a rare
papillary ependymoma [33].Papillary ependymomas can form epithelial
sur-
faces but retain a fibrillary background. Ependy-momas with
focal papillary change can bedistinguished by their predominantly
glial appear-
ance. In cases where the distinction cannot bemade in routine
stains, immunohistochemistryand ultrastructural studies are
helpful. Largepartially intraventricular tumors in young
patients
with poorly differentiated morphology should alsoraise the
possibility of an atypical teratoid/rhabdoid tumor (AT-RT). Some
AT-RTs have
been misdiagnosed as CPC in the past. Distinctionof AT-RT can be
made by using a panel ofimmunohistochemical markers as well as
genetic
studies to confirm the presence of
characteristicabnormalities.
CPCs are extremely rare in adults, and
metastatic carcinoma should be viewed as a morelikely cause for
an intraventricular papillarycarcinoma. Metastases from the
pulmonary andgenitourinary systems have been shown to mimic
CPC [3436]. Distinction may be difficult because
of overlapping histologic, ultrastructural,
andimmunohistochemical features. Typical CPC im-munohistochemistry
reveals positivity for cyto-
keratin cocktail and absent or only faint EMAand CEA
immunoreactivity. If positive, synapto-physin can also be used to
distinguish CPC. Inaddition, BerEp4 staining is considered a
reliable
marker for most metastatic carcinomas, and itspresence may
exclude a CPC (Marc K. Rose-nblum, MD, personal communication,
1999).
Ependymomas
Epidemiology
Ependymomas are neoplasms derived from the
ependymal layer lining the ventricular system andcan occur
intracranially and in the spine. In-tracranial ependymomas account
for 2% to 8% of
all primary CNS neoplasms [37], with more thanhalf presenting in
the first two decades of life. Ina series of 467 pediatric
intracranial neoplasms
reviewed by Farwell et al [38], ependymomasmade up 9% of all
intracranial tumors, making itthe third most common pediatric
intracranial
tumor. Within the pediatric population, ependy-momas favor young
patients, with more than 50%occurring within the first 3 years of
life. Noconsistent gender predilection has been identified.
Intracranial ependymomas can be divided bylocation into those
appearing infratentoriallyand those appearing supratentorially.
Infratento-
rial ependymomas make up approximately twothirds of all cases
[39], comprise most pediatriccases, and most frequently occur in
the fourth
ventricle [40]. Supratentorial ependymomas occurmore frequently
in older children and adults. Inaddition to the lateral ventricles,
approximately50% of supratentorial ependymomas involve the
parenchyma [41].
Macroscopic and microscopic features
Ependymomas are often sharply demarcated,
fleshy, hemorrhagic, soft, and sometimes rubberymasses. Rare
examples are heavily calcified, givingthe tumor a gritty texture.
Intraventricular exam-
ples of ependymomas are often lobulated anddisplay a discrete
interface with surroundingbrain. Some tumors may exhibit a delicate
over-
lying ependymal layer that gives them a shinytexture.
Ependymomas are glial neoplasms composedof a monomorphous
proliferation of neoplastic
cells with typical perivascular pseudorosettes
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469482
(see Fig. 1C, D). Some ependymomas are pre-dominantly glial in
appearance and may not havedistinct perivascular pseudorosettes,
whereasothers may be predominantly epithelial. The latter
may present as a tumor with oval to round nuclei,discrete
cytoplasmic borders, frank papillarystructures, and well-formed
fibrovascular cores.
Other tumors may show true ependymal ro-settes distinguished by
their well-defined luminaand cells forming pseudoglandular
structures.
Most ependymomas show a substantial numberof nuclear grooves
that can be identified inintraoperative smears and help with the
rapid
interpretation of frozen sections [42]. This feature,however,
needs to be interpreted in the context ofother histologic findings,
because many othertumors, such as meningiomas and other
gliomas,
can exhibit nuclear grooves. The tumor nuclei areuniform, round
to oval, and often featurea distinct nucleolus.
Clear cell change in ependymoma is a rare butsignificant finding
[43]. Intraventricular ependy-momas may exhibit focal or
predominant clear
cell change. When clear cell change is predomi-nant, the
hematoxylin-eosin appearance of anoligodendroglioma is
recapitulated. It is likely
that many tumors previously reported as in-traventricular
oligodendroglioma are examplesof clear cell ependymoma [21]. Clear
cell ependy-momas are usually higher grade and exhibit
increased mitotic activity and vascular prolifera-tion. The
so-called tanycytic ependymoma isremarkably similar to a pilocytic
astrocytoma.
This highly fibrillary tumor has moderate celldensity, spindled
cells, and a fascicular architec-ture. It has also been described
as a piloid tumor
with ependymal nuclei [44]. The tanycyticependymoma often lacks
nuclear pleomorphismor aggressive features, such as mitoses or
vascularproliferation. Perivascular pseudorosettes are ru-
dimentary and sometimes absent.Ependymomas are commonly
calcified and
rarely exhibit cartilaginous and osseous meta-
plasia. Rare ependymomas contain cytoplasmiceosinophilic
granules, clear vacuoles, lipid, ormelanin [45,46].
The current WHO classification defines gradeII ependymomas as
tumors with mild cellularpleomorphism, pseudorosettes, or true
ependymal
rosettes. The tumors can have occasional mitoticfigures and
necrosis without pseudopalisading.Occasional foci of
hypercellularity and increasedmitoses are allowed. Anaplastic,
high-grade,
or grade III ependymomas have moderate to high
cellularity, increased mitotic figures, and
vascularproliferation. Necrosis is often present, either inthe form
of geographic necrosis or, rarely, in thepseudopalisading form.
Perivascular pseudoro-
settes or occasional true ependymal rosettes canbe found in most
high-grade ependymomas. Thereis controversy around whether focal
atypia or
anaplasia should elevate a lesion to grade IIIanaplastic
ependymoma. Some require atypiaand anaplasia to predominate in the
tumor tissue,
whereas others report a less favorable prognosiseven for tumors
with focal anaplastic features.
Immunohistochemical features
Ependymomas are variably positive for
GFAP, which highlights the fibrillary processesaround vessels.
Tumors are diffusely positive forvimentin and stain less avidly
with S-100 protein
and neurospecific enolase (NSE). Positive stainingfor epithelial
markers, such as EMA and cytoker-atins, has been reported in most
posterior fossa
and spinal cord ependymomas [47]. Rare tumorcells, true
rosettes, and occasional papillarystructures are EMA-positive.
Studies suggest that high Ki-67/MIB-1 and p53protein positivity
might be reliable indicators ofhigh-grade ependymomas [48]. Even
though thereseems to be a positive correlation between high-
grade features and the Ki-67/MIB-1 index [49],none of the
immunohistochemical variables sig-nificantly correlate with tumor
grade. Conversely,
Ki-67/MIB-1 and p53 were reported to correlatewith patient
survival [50]. Currently, there is noclear evidence for the utility
of these markers in
determination of tumor grade or behavior.
Ultrastructural features
The acellular zones around pseudorosettes arecomposed of large
numbers of closely packed,
filament-rich, cytoplasmic processes. Microluminaare often
present, even though they may not beobserved by light microscopy
[51]. These micro-
lumina contain slender curving microvilli anda variable number
of cilia. Bordering cells areconnected by unusually long tight
junctions. This
triad (cilia, intracytoplasmic intermediate fila-ments, and cell
junctions) makes up the typicalultrastructural components. The
epithelioid cellsfound in ependymomas and true rosettes are
characterized by intracellular lumina, cilia, andmicrovilli.
Clear cell ependymomas reveal denselypacked polyhedral cells with
clear cytoplasm and
well-developed intercellular junctions. Abundant
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474 J.S. Waldron, T. Tihan /Neurosurg Clin N Am 14 (2003)
469482
hyaloplasmic lipid vacuoles can also contribute tothe clear
appearance of the tumor cells [46].
Molecular and genetic features
There is a body of evidence suggesting the
presence of a tumor suppressor gene on the longarm of chromosome
22 that plays a role in thepathogenesis of ependymomas [52]. In one
study,
the most frequent copy number abnormality inependymomas was 22q
loss, followed by gain ofchromosome 9 and occasional loss of 6q,
3p, 10q,
and 15q [25]. A heterozygous mutation in theMEN1 gene has also
been reported in ependymo-mas [53].
Pathologic differential diagnosis
Formulation of the differential diagnosis forependymoma is
dependent on the location of thelesion. In the posterior fossa,
medulloblastoma
needs to be considered first in the differentialdiagnosis,
although its architecture is morereminiscent of a small blue round
cell tumor thanthat of a glioma. Pilocytic astrocytoma of the
cerebellum or brain stem is a second possibilitybut can be
easily excluded when classic features ofpilocytic astrocytomas,
such as Rosenthal fibers,
eosinophilic granular bodies, and a fairly pauci-cellular
appearance, are present. Infiltratingastrocytomas or the so-called
brain stem glio-
mas may have an exophytic quality and mayresemble ependymoma.
They are easily distin-guished by their invasive quality, lack of
epithelial
features or pseudorosettes, and marked nuclearpleomorphism.
Supratentorial intraventricular ependymomasneed to be
distinguished from subependymomas.
Such distinction is often subjective and may notalways translate
into a significant change inclinical outcome. Nevertheless, based
on the
overall clinical behavior of ependymomas andthe likelihood of
supratentorial examples beinghigher grade, one is compelled to make
the
distinction. The distinction is usually not difficult,and the
differential diagnosis is confounded bylimited tissue sample size.
A second yet more
important differential diagnosis is oligodendro-glioma, which
can easily be confused with clearcell ependymoma. Clear cell
ependymomas arenoninfiltrating, solid, and distinct from the
surrounding brain. Purely intraventricular neo-plasms are not
likely to be oligodendrogliomas,but when a question exists,
immunohistochemis-
try and electron microscopy readily settle the
issue. Another diagnostic consideration is thecentral
neurocytoma. The central neurocytoma isa highly cellular neoplasm
that may show
perivascular pseudorosettes. The cells appearmore neurocytic,
and the fibrillar areas resembleneuropil. The tumor strongly reacts
with synap-tophysin and only weakly (if at all) with GFAP.
Electron microscopy can distinguish the twoentities. Papillary
ependymomas may resembleCPP. The overall immunohistochemical
profile
and ultrastructural features can be used toseparate the two
entities.
Subependymoma
Epidemiology
Subependymomas are slow-growing, benignintraventricular lesions
first identified as a separate
entity in 1945 by Scheinker [54]. They originate inthe
subependymal glial matrix and typically pro-ject into the
ventricular lumen. Intracranial
subependymomas frequently remain asymptom-atic and are
documented on autopsy or as anincidental finding on imaging. A
prevalence of
0.4% has been reported in a series of 1000necropsies of
asymptomatic patients reviewed byMatsumura and colleagues [55].
Subependymo-mas have been reported over a wide age range, but
generally occur in middle-aged to older adults.The fourth
ventricle, followed by the lateralventricles, is the most common
site of presenta-
tion. Less common locations include the thirdventricle, the
septum pellucidum, and the cerebralaqueduct.
Macroscopic and microscopic features
Subependymomas are solid nodular tumorsfirmly attached to the
ventricular surface. Tumors
are typically soft but can be rubbery and, rarely,cystic and
occasionally have a gritty texture.
Subependymomas are typically paucicellular,
fibrillar, and markedly nodular neoplasms (seeFig. 1E). Tumor
nuclei cluster within the nodularregions. Supratentorial tumors,
especially those
near the foramen of Monro, are predominantlymicrocystic and
focally myxoid. The cells areoften spindled with oval nuclei and
fibrillaryprocesses. The tumor exhibits an extensive fibril-
lary background on intraoperative smear prepa-rations. Nuclear
pleomorphism is rare, andmitoses are typically absent. Tumor
vessels show
focal hyalinization with occasional hemosiderindeposition. There
is some evidence that the
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475J.S. Waldron, T. Tihan /Neurosurg Clin N Am 14 (2003)
469482
histologic features in larger and symptomaticsubependymomas may
be different. Larger symp-tomatic tumors more frequently
demonstrate cystformation, microcalcification, and vessel
degener-
ation accompanied by hemorrhage [56]. Subepen-dymomas in the
posterior fossa are usually smallerwithout significant microcystic
change. The tu-
mors are prominently nodular and show nuclearclustering and
calcifications. Mitoses are rare, andvascular proliferation and
necrosis are absent.
Immunohistochemical features
Subependymomas are strongly GFAP-positivein accord with their
high content of intermediate
glial filaments. Vimentin staining is often strong,and S-100
protein stains the cytoplasm and thenuclei. Compared with other
ependymal tumors,
subependymomas have the lowest rate of cellproliferation, as
evidenced by a Ki-67/MIB-1index of less than 1% [57]. In contrast
to
ependymomas, staining with epithelial markers,such as EMA, is
usually not observed.
Ultrastructural features
Subependymomas display an abundance ofclosely packed cell
processes filled with interme-diate filaments. This meshwork of
processes
widely separates small clusters of tumor cells.Larger cells
lacking specialized features andresembling ependymal precursor
cells are oftenfound. Other cells with transitional forms
between
these two types can be identified [58]. Pockets ofmicrovilli are
present, but they differ fromependymal type rosettes because of the
lack of
tight junctions.
Molecular and genetic features
There is limited information on the cytogenet-
ics and molecular genetics of subependymomas. Afew case reports
have demonstrated a normalkaryotype in subependymomas investigated
with
conventional cytogenetic techniques [59].
Pathologic differential diagnosis
The main component of the differential di-
agnosis for intraventricular subependymoma isthe classic
ependymoma. It may not be possible todistinguish all cases,
especially if the amount of
tissue available for pathologic analysis is limited.Both
neoplasms appear remarkably similar, andfoci identical to
subependymoma are commonly
seen in ventricular ependymomas. In general,ependymomas can be
distinguished by occurrenceprimarily in children, hypercellularity,
perivascu-lar pseudorosettes, and true ependymal rosettes.
Most supratentorial ependymomas have a solidcystic appearance
and are symptomatic. Subepen-dymomas may also be confused with the
tanycytic
variant of ependymomas. Often, tanycytic epen-dymomas are more
cellular and resemble pilocyticastrocytomas. Ultrastructural
examination of
tanycytic ependymoma reveals characteristicependymal features,
including intracytoplasmicintermediate filaments, prominent
intercellular
junctions, numerous slender surface microvilli,and
microvilli-lined lumina.
Subependymal giant cell astrocytoma
Epidemiology
SEGAs are intimately associated with thetuberous sclerosis
complex, an autosomal domi-
nant dysgenetic syndrome that is associated withthe classic
triad of seizures, mental retardation,and papular facial lesions.
In the CNS, the
complex is characterized by cortical tubers,subependymal
nodules, and SEGAs. The inci-dence of tuberous sclerosis is
approximately1:10,000 [60] in the general population. Approx-
imately 6% [61] of these patients develop SEGAs.Almost all SEGAs
arise near the foramen ofMonro and typically present with
hydrocephalus
or increased seizure frequency, most commonlywithin the first
two decades of life [61].
Macroscopic and microscopic features
SEGAs are well-defined typically pedunculated
intraventricular masses that can be soft to rubberyand often
have a broad base on the ventricularsurface. The tumor can be
easily removed from its
base. Tumors may be friable, pink as a result ofvascularization,
and occasionally gritty fromcalcification.
SEGAs are characteristically solid and havea typical swirling
architecture. They exhibitcompact growth with spindled and
gemistocytic
cells and are sharply demarcated from theadjacent normal
parenchyma (see Fig. 1F).Spindled cells are responsible for the
swirlingappearance of the tumor on low magnification.
The gemistocyte-like cells have round vesicularnuclei with
distinct nucleoli and an eosinophiliccytoplasm. In addition, they
display thick hairlike
processes and have a tendency to form cohesive
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476 J.S. Waldron, T. Tihan /Neurosurg Clin N Am 14 (2003)
469482
clusters and occasional pseudorosettes [62]. Thetumor maintains
a compact and uniform appear-ance despite varying tumor cell types.
SEGAs
often contain inflammatory cells, including occa-sional mast
cells. Even though rare mitotic figuresare occasionally seen, brisk
mitotic activity, nec-rosis, or vascular proliferation is typically
absent.
Some tumors undergo focal infarction, which canappear ominous
and be confused with the necrosischaracteristic of a high-grade
astrocytic neoplasm.
Calcification is sometimes present.
Immunohistochemical features
The gemistocytic and spindle cells are oftenstrongly positive
for GFAP; however, the abso-
lute number of positive cells in each tumor ishighly variable.
SEGAs also show strong positiv-ity for S-100 protein. Neurofilament
epitopes,
class III b-tubulin, and calbindin 28-kDa areexpressed in some
cases [63]. Cytoplasmic stainingfor somatostatin, met-enkephalin,
5-hydroxytryp-
tamine, b-endorphin, and neuropeptide Y has alsobeen noted in
more than half of cases of SEGA[63,64]. The divergent glial and
neuronal staining
has been shown to colocalize within the same cell.SEGAs are
negative for HMB-45 antibody, andthe Ki-67/MIB-1 labeling index is
usually lessthan 2% [65].
Ultrastructural features
SEGAs contain numerous intermediate fila-ments, frequent
lysosomes, and occasional rectan-
gular or rhomboid membrane-bound crystalloidsthat exhibit
lamellar periodicity and structuraltransition to lysosomes.
Microtubules and stacksof rough endoplasmic reticulum are common,
but
true neuronal differentiation, such as neurosecre-tory granules
or synaptic formations, is oftenabsent [63]. Rare tumor cells have
features
suggestive of neuronal differentiation, includingstacks of rough
endoplasmic reticulum, occasionalmicrotubules, and a few poorly
defined dense core
granules. Gemistocytic cells are characterized byabundant
intermediate filaments within the cellbody and the processes.
Lysosomes are common
and, rarely, may contain distinctive membrane-bound
crystalloids.
Molecular and genetic features
Cytogenetic analysis of SEGAs within thetuberous sclerosis
complex (TSC) reveals clonalchromosomal changes, resulting in the
partial loss
of chromosome 22q in some tumors [66]. TSC-associated tumors
also demonstrate loss ofheterozygosity in chromosomes 9 and 16,
which
are known to harbor TSC genes [67]. One of twosuspected genes,
TSC2, was found in chromosome16 by positional cloning. The gene
product fromTSC2 has been named tuberin. TSC1 was
discovered earlier in chromosome 9 but has notyet been
characterized. Genetic analysis on TSCfamilies reveals mutations in
chromosome 9q34
(TSC1) and chromosome 16p13 (TSC2) as theonly common genetic
anomalies [68].
The Eker rat, a naturally occurring animal
model of TSC, provides a powerful tool forinvestigations of TSC.
In this model, a conservedlinkage group on rat 10q corresponds to
human16p13.3 (TSC2 gene) [69]. Currently, it is believed
that the products of TSC1 and TSC2 genesinteract with each other
in the cell.
Pathologic differential diagnosis
SEGAs are fairly distinct intraventricular neo-plasms that may
be confused with gemistocyticastrocytoma or high-grade glioma if
the typical
pathologic and radiologic features are overlooked.Small biopsies
can also potentially be interpretedas tanycytic ependymoma or
subependymoma,
but this is less likely, because SEGAs are in-variably more
cellular, less fibrillary, and far moregemistocytic.
Central neurocytoma
Epidemiology
The term central neurocytoma was first used byHassoun et al [70]
in 1982 to describe differenti-ated intraventricular neuronal
lesions observed in
2 cases. Central neurocytomas are rare neoplasms,with 127
reported cases through 1993 [71].Reported rates in series of
pathologically con-firmed primary CNS neoplasms range from 0.1%
to 0.5% [7274]. Central neurocytomas areprimarily tumors of
young adults, with 45%occurring in the third decade of life and
almost
75% between the ages of 20 and 40 years [71].Gender distribution
is equal. Central neuro-cytomas arise predominantly from the
septum
pellucidum or, less frequently, from the lateral ven-tricular
wall. The anterior lateral ventricle is themost frequent site
(77%), followed by lateral andthird ventricle involvement (21%)
[71]. Bilateral
lateral ventricular involvement is uncommon.
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477J.S. Waldron, T. Tihan /Neurosurg Clin N Am 14 (2003)
469482
Rare cases have been reported in the third andfourth
ventricles.
Macroscopic and microscopic features
The tumor forms a soft to gritty, tan, discrete
mass that may be solid or partly cystic.Central neurocytomas are
histologically and
cytologically uniform neoplasms. The cells arestrikingly
monomorphous with finely distributed
chromatin and a fine fibrillary matrix. The tumoris one of
several neuroepithelial neoplasms withsalt and pepper chromatin.
Central neuro-
cytoma joins the list of oligodendroglioma-liketumors because of
a striking preponderance ofcells with perinuclear halos that
resemble classic
oligodendroglioma (see Fig. 1G). In some cases,there are
perivascular fibrillary zones reminiscentof ependymal
pseudorosettes. In addition, someexamples resemble nodular
medulloblastomas by
exhibiting neurocytic differentiation with cellstreaming and
nodular growth.
Intraoperative frozen sections can sometimes
obscure the histologic and cytologic uniformitytypical of
central neurocytomas. The processingof frozen tissue also adds a
degree of nuclear
pleomorphism that can raise the possibility ofa small blue round
cell tumor. This is furtherconfounded in permanent sections of
frozen tissue
because of the obscured neuronal/neurocyticbackground. Most
central neurocytomas aregrade II lesions with minimal nuclear
pleomor-phism and rare mitotic figures. Tumors with
atypical features and transitional characteristicsbetween
neurocytoma and neuroblastoma havebeen reported [75].
Central neurocytomas may show ganglioniccell differentiation and
have a preponderance ofneuropil with variable numbers of
ganglion-like
cells. Such cases have been designated as gan-glioneurocytoma or
differentiated neurocy-toma. An intraventricular lesion that
combinesthe features of a neurocytoma with ganglion cells
and a malignant small cell component has beenreported but is
extremely rare. It has also beensuggested that some central
neurocytomas can
express photoreceptor differentiation, potentiallyrelating them
to pineocytomas [76]. Rare centralneurocytomas exhibit lipofuscin
or neuromelanin
pigment [77].
Immunohistochemical features
Central neurocytomas consistently exhibitimmunoreactivity for
NSE and synaptophysin,
indicating neuronal differentiation [78]. Synapto-physin
antibody stains the fibrillar zones and, toa lesser extent, the
perinuclear cytoplasm of tumorcells. Anti-Hu autoantibodies stain
neurocyte
nuclei. Tumor cells are also positive for Leu-7 andS-100
protein, whereas staining for GFAP is pre-dominantly negative
andvimentin is confined to the
nonneoplastic mesenchymal elements of bloodvessels [79].
Staining for myelin basic protein,chromogranin, andneurofilament is
often negative.
Some studies have shown a small subpopulation ofGFAP-positive
neoplastic cells, and glial differen-tiation has been suggested in
tissue culture. This
mixed phenotype of glial and neuronal markerpositivity in
central neurocytoma can be interpre-ted as a glioneuronal neoplasm,
with an overwhel-mingly neurocytic component. In rare examples,
a tumormayhave an increasedKi-67/MIB-1 index.Such neoplasms are
described as atypical neuro-cytomas and have a significantly
elevated in-
cidence of local recurrence [80]. Even though noclear cutoff
point exists between classic and atypicalneurocytomas, most authors
suggest that tumors
with an MIB-1 index of greater than 2% be placedin the atypical
category. Nevertheless, some studiesshow no difference in MIB-1
labeling between
tumors with atypical features and typical centralneurocytomas
[81]. CurrentlyMIB-1 labeling is notused to modify grading of
central neurocytomas.
Ultrastructural features
Central neurocytoma is readily recognizable asneuronal, with
microtubules, terminations, clearvesicles, and dense core granules
[79,82,83]. Some
examples may display round cells with abundantcell processes
containing microtubules, cellularjunctions, and lysosome-like
structures. Otherscontain numerous synaptic vesicles, neuritic
pro-
cesses, and neurosecretory granules. In addition,rare tumors
contain ganglionic cells with well-developed processes.
Molecular and genetic features
Reported recurrent genetic changes in centralneurocytomas
include alterations on chromo-
somes 2p, 10q, and 18q. The candidate genes inthese loci are
currently unknown [84]. Otherstudies have suggested gain of
chromosome 7 asa nonrandom genetic alteration in central neuro-
cytomas [85]. Recent studies have demonstratedthat central
neurocytomas are genetically distinctfrom oligodendrogliomas and
that chromosomes
1p and 19q probably do not play an important
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478 J.S. Waldron, T. Tihan /Neurosurg Clin N Am 14 (2003)
469482
role in their pathogenesis. In addition, N-myc andepidermal
growth factor receptor amplificationsare rare or absent in these
tumors [86].
Pathologic differential diagnosis
The critical differentiation for central neuro-cytoma is from
oligodendroglioma. Some cases ofcentral neurocytoma perfectly
recapitulate oligo-
dendroglioma in routine microscopic examina-tion. In such cases,
it is important to use a panelof immunohistochemical stains and to
perform an
ultrastructural examination to establish the cor-rect diagnosis.
Furthermore, radiologic informa-tion should be critically
interpreted and thediagnosis of oligodendroglioma challenged in
purely intraventricular tumors. A second entityin the
differential diagnosis is the clear cellependymoma, which also
exhibits a remarkable
resemblance to oligodendroglioma. The presenceof ependymal
features as well as immunohisto-chemical analysis should
distinguish a clear cell
ependymoma from central neurocytoma. Smallbiopsies from a
dysembryoplastic neuroepithelialtumor may also mimic central
neurocytoma, butexclusive intraventricular location, the absence
of
floating neurons, and the immunohistochemicalprofile should
distinguish between the two. Lastly,the presence of an
intraventricular clear cell
neoplasm in older patients should raise thepossibility of a
metastatic lesion, especially a renalcell carcinoma. Often, the
highly anaplastic
histologic features are sufficient to distinguisha renal
carcinoma metastasis from a classic centralneurocytoma. Additional
immunohistochemical
studies can be used to provide further support.
Other tumors and tumor-like lesions within the
ventricular system
Other purely intraventricular tumors and tu-mor-like lesions are
rare. One example includes theintraventricular meningioma [8789].
The intra-
ventricular location is uncommon, with an ap-proximate incidence
of 0.5% to 4.5% among allintracranial meningiomas [89].
Intraventricular
meningiomas are more common in adults becauseof the higher
overall frequency of meningiomas butmake up a larger percentage of
meningiomas in
the pediatric population [9092]. Meningiomascan arise anywhere
in the ventricular system andexhibit the histologic features common
to allmeningiomas (see Fig. 1H). Rare cases of intraven-
tricular clear cell meningioma [93] and malignantmeningioma [94]
have been reported.
Intraventricular metastases from epithelial
malignancies are extremely rare but can mimica choroid plexus
tumor clinically and pathologi-cally. Intraventricular metastases
originate froma number of cancers, including renal cell carci-
noma [35,95,96], pulmonary adenocarcinoma [34],gastric carcinoma
[97], adrenocortical carcinoma[98], and bladder carcinoma [36]. In
such cases,
immunohistochemical analysis, including a cyto-keratin panel,
can help to identify the nature ofthe neoplasm and differentiate
such tumors from
CPCs [99].Rare cases of perineurioma from the choroid
plexus of the third ventricle, malignant schwan-noma, solitary
fibrous tumors, and hemangio-
pericytoma have been reported as purelyintraventricular tumors
[100102].
A diverse list of cystic tumor-like lesions can
exist within the ventricular system and can beconfused with a
neoplasm [103]. Colloid cysts ofthe third ventricle [104],
ependymal or glioepen-
dymal cysts [105], choroid plexus cysts [106],arachnoid cysts
[107], and cavernous angioma[108] have been reported as
intraventricular
masses. Choroid plexus cysts are more commonin fetuses with
chromosomal aneuploidies, partic-ularly trisomy 18.
Inflammatory or infectious processes can also
present as purely intraventricular masses thatresemble tumors.
Such a presentation is muchless common than the usual parenchymal
or
leptomeningeal forms. Reports of infectious orinflammatory
processes that present as masseswithin the ventricular system
include cysticercosis
[109], cryptococci [110], and nocardiosis [111]among others.
Summary
Tumors that primarily or exclusively involvethe ventricular
system constitute a rare and
heterogeneous group. Certain histologic tumortypes predominantly
occur in children, whereasothers are more common in adults.
Tumor
location provides additional clues to correctdiagnosis. When
used in conjunction with clinicaland radiologic data,
histopathologic features can
distinguish among this wide range of possibilitiesto provide the
correct diagnosis for optimalpatient management.
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469482
Acknowledgement
J.S. Waldron was supported in part by a grantfrom the Khatib
Research Foundation as a Khatib
Fellow 20022003.
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-
Neurosurg Clin N Am 14 (2003) 483508
Intraventricular neurocytomasJanet Lee, MS, Susan M. Chang, MD,
Michael W. McDermott, MD,
Andrew T. Parsa, MD, PhD*Department of Neurological Surgery,
University of California at San Francisco, 505 Parnassus
Avenue,
M-779, San Francisco, CA 94143, USA
Background
Epidemiology and clinical presentation
A review of 385 reported neurocytoma cases[196] shows that, in
general, central neuro-
cytomas (CNCs) are well-differentiated intraven-tricular tumors
that affect young adult men andwomen equally. Most commonly, CNCs
occur in
the anterior portion of the lateral ventricle aroundthe foramen
of Monro and can attach to either theseptum pellucidum or the
lateral wall of the
ventricle [19,58,71,97]. Whereas 75% of casesoccur in patients
between the ages of 20 and40 years [15,28,98], CNC occurring in
patients18 years of age or younger [3,5,14,19,32,36,42,
44,58,68,69,71,74,76,78,88,94] and in patients 50years of age or
older [3,4,7,19,40,44,45,53,69,76,78,93,99] have been reported. The
term
extraventricular neurocytoma is used to describehistologically
similar tumors not found in in-traventricular locations [43].
Extraventricular
locations include the occipital lobe [8,22,54,72],parietal lobe
[3,22,54], frontal lobe [8,22,24,58,96],temporal lobe [8,9,22,58],
thalamus [8,72,100],
hypothalamus [8,22,69], cerebellum [7,17], pons[77], spinal cord
[3,12,18,44,47,79,82,83], caudaequina [81], retina [52], and pelvis
[101] as well asmature cystic teratoma of the ovary [102].
Cases
J. Lee was supported in part by a grant from the
Khatib Research Foundation as a Khatib Scholar
(20032004).
* Corresponding author.
E-mail address: [email protected]
(A.T. Parsa).
1042-3680/03/$ - see front matter 2003 Elsevier Inc. All
rigdoi:10.1016/S1042-3680(03)00064-0
of neurocytoma have previously been reported asintraventricular
oligodendroglioma, differentiatedcerebral neuroblastoma [34,95],
primary cerebral
neuroblastoma [64,103,104], and intraventricularneuroblastoma
[105].
A review of the available data from clinical
reports has provided some insight into commonsigns and symptoms
associated with CNC. Theclinical presentation usually involves
signs
and symptoms of increased intracranial pressure(ICP) of a few
weeks to several months as aresult of noncommunicating
hydrocephalus. Asshown in Table 1, reported symptoms include
headache, visual disturbance, motor disturbance,altered mental
status, sensory disturbance, sei-zure, dizziness, and nausea or
vomiting without
associated headache. Not all reported cases ofCNC include a
detailed clinical history, however.Table 1 also reports signs
elicited on physical
examination; however, this analysis is limited bythe lack of
detailed information in some reports.Other authors have reported
headache, nausea
and vomiting, and visual disturbance as the mostcommon symptoms,
with papilledema present inmost patients [46,69]. Signs like ataxia
[32,42,46,58,69,94], altered level of consciousness [16,
46,62,69,87,91], hemiparesis [16,32,40,46,63], andseizures
[3,8,22,42,46,58,63,89] were less com-mon. Patients presenting with
intraventricular
hemorrhage (IVH) [12,23,37,62,76,84,91] andsudden death [4] have
also been reported. Inaddition, many cases have been discovered
in-
cidentally in patients undergoing neuroimagingfor unrelated
reasons [15,22,32,58,87,91]. Neuro-logic examination often yields
no focal neurologicfindings other than those caused by
increased
ICP [46].
hts reserved.
mailto:[email protected]
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484 J. Lee et al /Neurosurg Clin N Am 14 (2003) 483508
Neuroimaging
CT/MRI/angiographyAppropriate diagnostic imaging studies for
patients with CNC may include CT, MRI, orangiography. Relative
to the brain parenchyma,CNC appears as a well-circumscribed,
isodense,
hyperdense, or mixed isodense/hyperdense masswith slight to
moderate contrast enhancement onCT examination. Noncommunicating
(obstruc-
tive) hydrocephalus is often present. Calcificationsand
cyst-like areas may also be seen on CTimages. Compared with the
surrounding whitematter, T1-weighted and proton-weighted images
typically appear isodense. T2-weighted imagesappear
heterogeneous with areas of calcificationand cysts appearing
hyperintense and the tumor
appearing isointense to hyperintense. Variableenhancement with
gadolinium is common, reflect-ing the heterogeneous vascularity of
CNC (Fig. 1).
For tumor localization and visualization of the
Table 1
Signs and symptoms
Signs and Symptoms No. %
HA 178/202 88.1
N/V without HA 2/202 1.0
Dizziness 4/202 2.0
Visual disturbance 51/202 25.2
Altered mental status 22/202 10.9
Seizure 9/202 4.5
Motor disturbance 40/202 19.8
Sensory disturbance 14/202 6.9
Papilledema 46/51 90.2
Abbreviations:HA, headache or reported as signs and
symptoms of increased intracranial pressure; N/V,
nausea and/or vomiting without headache. Dizziness
includes dizziness or vertigo; visual disturbance includes
blurring, diplopia, decreased acuity, intermittent vision
loss, photophobia, blindness, or abducens nerve palsy;
altered mental status includes altered level of conscious-
ness, loss of memory, apathy, disorientation to mild
dementia, loss of concentration, mood swings, syncope,
personality change, depression, psychosis, irritability, or
mental change; motor disturbance includes spasticity of
extremities, hemiparesis, hemiplegia, atrophy, clonus,
hypotonia, increased DTR, imbalance, left hemisyn-
drome, gait disturbance, ataxia, loss of balance, weak-
ness, pyramidal signs unsteady gait, or gait dysfunction;
sensory disturbance includes pain, paresthesia, left
hemisyndrome, hemihypaesthesia; seizure includes all
types of seizures and papilledema includes unilateral and
bilateral types. Data from references [18,10,11,14,15,18,
23,26,27,29,31,33,34,39,41,42,45,5658,6266,68,70,71,
7476,82,85,87,89,91,93,95,96,99,104,108,114, and 118].
attachment site, MRI is preferred [15,46,97,106].Angiography has
also been used to assessvascularity; however, the results are
nonspecific,
ranging from avascular [3,36,40,71] to highlyvascular
[40,46,53,85]. Feeding arteries are re-ported to include anterior
choroidal [1,15,40,53,71,76], posterior choroidal
[1,31,40,53,57,87],
lenticulostriate [40,53], and branches of perical-losal arteries
[40,53].
Magnetic resonance spectroscopy/single photonemission computed
tomography/positronemission tomography
Magnetic resonance spectroscopy (MRS)[33,35,38,54,94], single
photon emission comput-erized tomography (SPECT) [35], and
positron
emission tomography (PET) [35,53,85] have allbeen used in
preoperative evaluation. The experi-ence using these modalities is
limited, however,and there is no consensus on the characteristics
of
CNC. Many investigators suggest that prominentglycine and
choline with low N-acetyl aspartate(NAA) peaks are characteristic
markers of CNC
on MRS [33,38,94]. Others have found an in-creased choline peak
and decreased NAA signalbut failed to consistently find the
3.55-ppm peak
characteristic of glycine [35,54]. SPECT analysisshows increased
uptake of 201T on delayed images,indicating a high activity of
sodium potassiumtriphosphate on cell membranes. PET analysis
has
demonstrated decreased O2 extraction fraction,cerebral metabolic
rate of O2, and cerebralmetabolic rate of glucose in CNC. Cerebral
blood
flow and blood volume were increased in three offour cases,
correlating with the angiographicfindings in these patients [53].
The authors suggest
that CNC metabolism is more oxidative than thatof other brain
tumors and that a decreased rate ofglucose metabolism may predict a
favorable
prognosis [52]. Further study is necessary todetermine whether
these combined findings aretruly characteristic of CNC.
Pathologic examination
After reviewing such factors as presentingsymptoms, patient age,
and location of the tumor,
a focused differential diagnosis for CNC includessubependymoma,
astrocytoma, ependymoma, in-traventricular meningioma,
intraventricular oligo-dendroglioma, and subependymal giant
cell
astrocytoma [43,46,58,79,97]. Adding informationfrom imaging
studies usually narrows the differ-ential diagnosis to
intraventricular meningioma,
-
485J. Lee et al / Neurosurg Clin N Am 14 (2003) 483508
Fig. 1. (A) Axial CT image with contrast. (B) Contrast-enhanced
coronal T1-weighted MRI. (C) Axial T1-weighted
MRI. (D) Sagittal T1-weighted MRI.
ependymoma, and CNC. A definitive diagnosisrequires tissue
analysis with light microscopy,immunohistochemistry, and, in some
cases, ultra-structural examination.
Light microscopyOn light microscopy, CNC appears similar to
oligodendroglioma (Fig. 2). Clinically, they can be
distinguished based on their location. CNCs aretypically
intraventricular and centrally located,whereas oligodendrogliomas
arise more peripher-
ally. Light microscopy shows a honeycomb archi-tecture with
uniform small round cells with centralnuclei and clear cytoplasm
dispersed within a
fibrillary stroma. The chromatin typically has asalt and pepper
appearance. Microcalcificationsor microcysts may be present, and
mitoses, endo-thelial proliferation, and necrosis are rare [15,
43,46,98,106]. The presence of neuroblastic ro-settes and nuclei
with a ganglionic appearance issuggestive of neurocytoma; however,
immunohis-
tochemistry or electron microscopy is required toconfirm the
diagnosis [46].
Immunohistochemistry
The hallmark characteristic of CNC is positiv-ity for
synaptophysin, a calcium-binding mem-brane protein of presynaptic
vessels. In addition,CNC is usually positive for neuronal
specific
enolase (NSE) and negative for glial fibrillaryacidic protein
(GFAP) and neurofilament protein(NFP) (Fig. 3A)
[15,43,46,51,98,106]. These char-
acteristics differentiate CNC from oligodendro-glioma and
ependymoma.
Ultrastructural featuresUltrastructural examination is only
required in
the diagnosis of CNC if synaptophysin is lackingor equivocal or
if extraventricular neurocytoma issuspected. CNC shows neuronal
differentiation,
microtubules, dense core and clear vesicles, andabortive or
typical synapses (see Fig. 3B)[15,27,28,46,51,98,106]. Occasional
mitochondria,
-
486 J. Lee et al /Neurosurg Clin N Am 14 (2003) 483508
Fig. 1 (continued )
moderate free ribosomes, and variable endoplasticreticulum may
also be present [15,43,46,98].
Histogenesis/geneticsCNC is thought to be derived from
bipotential
progenitor cells from the subependymal plate thatare capable of
neuronal and glial differentiation[30,89,93,97,107]. Indeed, on
cell culture, CNC
differentiates into neuronal and glial cells [30,89].In
addition, CNC is capable of ependymal dif-ferentiation [75]. CNCs
are genetically distinct
from oligodendrogliomas and neuroblastomas, asevidenced by a
lack of association with specific 1pand 19q loss of heterozygosity
and rarity of N-myc amplification [75].
Atypical neurocytomaAtypical neurocytomas are a rare variant
of
CNC, with cellular pleomorphism, mitotic activ-
ity, necrosis, or vascular proliferation (Fig.
4)[3,19,54,62,71,73,77,92,108111]. Although mostCNCs appear as
uniform small round cells on
light microscopy, atypical CNCs may show peri-
Fig. 2. Histological stain of a central neurocytoma
demonstrating sheets of monomorphic pale cells with
small delicate capillaries in the background. The tumor
cells have round uniform nuclei with fine chromatin and
inconspicuous nucleoli. There is no evidence of necrosis
or mitotic activity. (From Anderson RC, Elder JB,
Parsa AT, Issacson SR, Sisti MB. Radiosurgery for the
treatment of recurrent central neurocytomas. Neurosur-
gery 2001;48(6):12318; with permission.)
-
487J. Lee et al / Neurosurg Clin N Am 14 (2003) 483508
vascular pseudorosettes, neuropil islands, multi-nucleate cells,
or ganglion cells. Mitotic activitycan be as high as 30 mitoses per
high-power field,and evidence of necrosis may range from focal
to
extensive. Although the correlation betweenhistologic atypia and
proliferation potential inatypical CNC was poor [110], vascular
prolifera-
tion showed a significant correlation with theMIB-1 labeling
index (LI) (P = 0.0006) [77]. It isunclear how the histology of
atypical CNC relates
to biologic behavior. Although elevated prolifer-
Fig. 3. (A) Central neurocytoma showing immunoreac-
tivity for synaptophysin (synaptophysin immunohisto-
chemistry, original magnification 20). (B) Electronmicroscopy of
central neurocytoma. The tumor cells
have round nuclei and clear cytoplasm. The cytoplasm
contains microtubules, dense core vesicles, and synapses
(*) (original magnification 10,500). (From Hara M,Aoyagi M,
Yamamoto M, Maehara T, Takada Y, Nojiri
T, et al. Rapid shrinkage of remnant central neuro-
cytoma after gamma knife radiosurgery: a case report.
J Neurooncol 2003;62(3):26973; with permission.)
ation potential correlates with poor outcome,histologic grade
does not seem to have prognosticvalue [77,110].
Treatment
Overview
Treatment strategies for CNC are based onretrospective case
series (Table 2), case reports, andanalysis of pooled data. There
are no randomized
clinical trials and few prospective studies. In manyearlier
reported cases, initial management mayhave been based on a
diagnosis that was revised on
retrospective review [40,42,46,65,67,68,70,71,89].Most authors
agree that, when possible, com-
plete tumor resection for symptomatic CNC is the
treatment of choice [19,40,44,46,60,70,96]. Theaddition of
adjuvant radiation therapy (RT) inthe immediate postoperative
period is controver-
sial. Some authors routinely use RT after subtotaltumor
resection (STR) [1,5,19,39,46,59,89]. Al-though some have used RT
after gross totalresection (GTR) as well
[3,7,15,19,27,32,40,45,53,
58,70,96], several authors state that RT after GTRis not
indicated [3,5,27,41,46,56,57,64,70,71,90].Given the potential for
long-term radiation side
effects, some advocate for adjuvant RT only forrecurrent or
progressive CNC [24,46,57], becausethe subependymal and
subventricular zone is
sensitive to radiation. More recent reports ofstereotactic
radiosurgery address the concerns of
Fig. 4. Central neurocytoma with atypical histologic
features, including necrosis, vascular endothelial pro-
liferation, and cellular pleomorphism (hematoxylin-
eosin, original magnification 10). (From MackenzieIR. Central
neurocytoma: histologic atypia, prolifera-
tion potential, and clinical outcome. Cancer 1999;85(7):
160610; with permission.)
-
cal
ntrol
Survival
rate Outcome
Refer-
ence
p initial
rgery,
0% p GKS
100.0% Returned to work with
full fxn, 3/4 neurologically
nl, 1/4 on dilatin for
postoperative seizure
[2]
.30% 91.7% 7 KPS 100, 1 KPS 50, 1
died secondary to
hemorrhage
[3]
0% 100.0% 3 asymptomatic, 1
neurologically intact
[11]
.40% 83.0% 2 dead, tumor recurrence;
7 alive, no tumor
recurrence; 6 alive, tumor
recurrence; dead no
tumor recurrence; 1 dead
4 days after surgery; 1
dead, 2 years after surgery
[19]
0% 100.0% 10/10 no evidence or
recurrence
[20]
100.0% 2 asymptomatic, returned
to work; 1 mild residual
hemiplegia; 1 behavioral,
cognitive, and dexterity
problems; 1 short-term
memory deficit; 1 re-
covering well after surgery
[23]
488
J.Lee
etal/Neurosurg
Clin
NAm
14(2003)483508
Table 2
Larger case series
n
MIBY
labeling
index Location
Primary
treatment
Recur-
rence
Average
months to
recurrence
(range) Radiation
Timing
of RT
Average
FU in
months
(range)
Lo
co
4 Not
reported
3 LLV, 1
LLV/3rd
4 CTR 4/4 17.25
(925)
GKS, 1620
Gy to tumor margin
4 salvage 20.25 p
GKS, 54.5
p CTR
0%
su
10
9 3.6375 9 intraven-
tricular
6 ITR, 3
CTR, 3 RT
2/9 618 55 Gy (2 adjuvant, 1
salvage for
asymptomatic
progression)
2 adjuvant,
1 salvage
45.33
(689)
83
4 Not
reported
3 LLV,
1 BLV
1 CTR with
GKS for
recurrence, 3
ITR/GKS
1/4 53 GKS, 913 Gy (3
adjuvant, 1 salvage)
3 adjuvant,
1 salvage
44
(1299)
10
18 Not
reported
2 3rd, 3 3rd/
LV, 2 CC,