Clear Cell Tumors of the Central Nervous System
A Case-Based Review
Sandra Camelo-Piragua, MD
 Clear cell tumors of the central nervous system (CNS)
encompass a variety of tumor subtypes that are challeng-
ing to diagnose given their similar morphologic features.
Here, I use a case-based approach to review the
clinicopathologic and radiologic features to help guide
the general pathologist in the diagnosis of clear cell tumors
of the CNS. First, the reader is invited to study 6 images of
different CNS tumors with clear cell morphology. Then,
each case is expanded in light of clinical and radiologic
data and includes a histopathologic description of the
C lear cell tumors (CCT) of the central nervous system
(CNS) share similar morphologic features that have led
to misdiagnosis in the past. With the advent of electron
microscopy and immunohistochemical stains, some of those
tumors have been reclassified later.1–4 The CCT case studies
that follow are taken in part (cases 1–3) from a breakout
session held at the 2011 New Frontiers in Pathology
meeting hosted by the University of Michigan in Ann
Arbor. Two complementary cases are also presented to
provide a comprehensive picture of the most common CCTs
in the CNS and to illustrate the morphologic similarities that
pose challenges to practicing pathologists.
To illustrate the similar morphologic features on light
microscopy and the challenges to accurately diagnose CCT,
Figure 1, A through F, shows representative hematoxylin-
eosin images of the cases presented in this review in the
absence of any clinical or radiologic data. Description of the
clinical, radiologic, and pathologic features associated with
the cases and their relevance to the accurate diagnosis of
these tumors is then discussed.
REPORT OF CASES
Case 1
Clinical History.—A 52-year-old, right-handed woman com-
plained of right-sided numbness and an inability to hold a cigarette
Accepted for publication April 17, 2012.
From the Department of Pathology, University of Michigan, Ann Arbor.
The author has no relevant financial interest in the products or
companies described in this article.
Presented in part at the New Frontiers in Pathology: An Update for
Practicing Pathologists meeting; University of Michigan; October 13,
2011; Ann Arbor, Michigan.
Reprints: Sandra Camelo-Piragua, MD, Department of Pathology,
University of Michigan, 1301 Catherine Rd, MSB1, Room M4213,
Ann Arbor, MI 48108 (e-mail: sandraca@umich.edu).
Arch Pathol Lab Med—Vol 136, August 2012
tumor. A brief discussion follows with up-to-date diagnos-
tic tools. Finally, I propose an immunohistochemical
algorithm to navigate through the complex features that
characterize clear cell tumors of the CNS. This review
aims to provide a comprehensive approach to diagnosing
clear cell neoplasms of the CNS based on improved
assessment of the clinicopathologic and radiologic features
of each entity.
(Arch Pathol Lab Med. 2012;136:915–926; doi: 10.5858/
arpa.2012-0216-CR)
with her right hand. Past medical history was relevant for
squamous supraglottic carcinoma (T3N2c, M0), following chemo-
therapy and radiation 4 years before the current symptoms. Her
tumor was thought to be in remission. Recent brain magnetic
resonance imaging showed high T2 and fluid-attenuated inversion
recovery signal with loss of brain parenchyma, prominence of the
sulci and encephalomalacia in the left paramedial frontal region,
consistent with a left anterior cerebral artery stroke. In addition,
another incidental lesion was found on the right frontal lobe, which
had an increased fluid-attenuated inversion recovery and a T2
signal abnormality with very minimal contrast enhancement. The
right frontal lesion had expanded some of the gyri and blurred the
grey white mater junction, changes suggestive of a primary
neoplasm (Figure 2, A). An excisional biopsy was performed on
the right side of the frontal lobe.
Brain Biopsy Findings.—At low power, marked distention of
the cortical ribbon, with loss of cortical layering and normal
cytoarchitecture, was observed (Figure 2, B). Higher magnification
showed increased cellularity, composed of cells with round nuclei.
Overall, the chromatin was open, and one or more small nucleoli
were present. Nuclear pleomorphism was minimal with no overt
nuclear atypia. The cytoplasm was clear, and discrete cytoplasmic
borders were present. Specific structures, such as rosettes or canals,
were not seen. In addition, there was a delicate, thin vasculature
running throughout the tumor (‘‘chicken-wire pattern’’). Although
occasional mitoses were present, mitotic activity was not brisk.
Entrapped, healthy neurons were evident within the tumor,
suggesting a diffusely infiltrating neoplasm (Figure 2, C). Immu-
nohistochemical stains demonstrated that the tumor was diffusely
immunoreactive for glial fibrillary acidic protein (GFAP) and for a
mutant variant of isocitrate dehydrogenase 1 (IDH1) (Figure 2, D
and E). Neurofilament highlighted entrapped axons within the
tumor, confirming the infiltrating nature of the tumor (Figure 2, F).
Synaptophysin staining was negative, and the proliferation index
(Ki-67) was low, approximately 3%.
Diagnosis.—The diagnosis was oligodendroglioma, World
Health Organization (WHO) grade II. Subsequent molecular
studies showed codeletion of 1p and 19q chromosomal material.
Clear Cell Tumors of the Central Nervous System––Camelo-Piragua 915
Figure 1. Representative cases of clear cell tumors in the central nervous system with similar morphologic features on hematoxylin-eosin staining. A,
Hemangioblastoma. B, Oligodendroglioma. C, Clear cell meningioma. D, Clear cell ependymoma. E, Central neurocytoma. F, Renal cell carcinoma
(original magnifications 3200 [A] and 3400 [B through F]).

COMMENT infiltrated the cortex, as illustrated by the presence of

Histologic features of the incidentally found lesion of the
right side of the frontal lobe demonstrated that the lesion
expanded the gyri, blurred the grey-white mater junction,
and distorted the normal cortical cytoarchitecture, indicating
that the lesion was infiltrative. At high power, the tumor
916 Arch Pathol Lab Med—Vol 136, August 2012
entrapped neurons within the tumor. These features are key
characteristics that differentiate this tumor from other CCTs.
Oligodendrogliomas are part of the infiltrating glial
neoplasms and, as such, are characterized by secondary
structures of Scherer, which are perineuronal satellitosis,
Clear Cell Tumors of the Central Nervous System––Camelo-Piragua
Figure 2. Case 1, oligodendroglioma, World Health Organization grade II. A, Axial fluid-attenuated inversion recovery: left anterior cerebral artery
stroke and a right frontal lobe lesion, with expansion of the gyrus. B, Hematoxylin-eosin results show thickening of the cerebral cortex with loss of
normal layering and cytoarchitecture. C, Hematoxylin-eosin results show tumor cells with round nuclei, clear cytoplasm, minimal nuclear
pleomorphism, and infiltration of the cortex (arrowheads: entrapped neuron), in the background of a thin capillary network. D, The GFAP stain
highlights tumor cells in a membranous pattern. E, Positive staining for mutant-specific IDH1. F, Neurofilament stain shows the thin delicate
entrapped axons, demonstrating tumor infiltration (arrowhead: neuronal satellitosis) (original magnifications 340 [B] and 3400 [C through F]).

perivascular satellitosis, subpial aggregation, and infiltration
of white matter tracts. Oligodendrogliomas often display a
delicate capillary network (chicken-wire vasculature), which
makes them prone to hemorrhage. Areas of microcalcifica-
tion are commonly observed and illustrate the slow-
Arch Pathol Lab Med—Vol 136, August 2012
growing nature of the tumor. When sufficient tissue is
available for evaluation, tumor growth in a nodular pattern
is often detected. Smear preparations often reveal regular,
round nuclei with relatively short glial processes, which can
help guide the pathologist toward the glial nature of the
Clear Cell Tumors of the Central Nervous System––Camelo-Piragua 917
tumor during frozen-section analysis. The rounded nuclei
morphology is lost once the tissue is frozen. In addition, the
clear cytoplasm becomes more evident once the specimen
has been embedded in paraffin sections.
Immunohistochemical studies are helpful in distinguish-
ing oligodendrogliomas from other CCTs of the CNS. As
glial neoplasms, they are diffusely immunoreactive for
GFAP. Oligodendrogliomas can have 3 different staining
patterns: strong cytoplasmic staining with short, stubby
processes; perinuclear staining with a clear cytoplasm; and/
or membranous staining with a clear cytoplasm. Given its
infiltrative nature, the use of additional markers is helpful to
highlight that feature. For example, neurofilament staining
will highlight entrapped axons in the middle of an
infiltrative tumor. Synaptophysin staining is negative in
oligodendrogliomas, although you may see it in the
background neuropil. Caution is needed when interpreting
synaptophysin results to ensure that the immunoreactivity is
not within the tumor cells. Finally, staining for a mutant-
specific antibody against IDH1 can be diagnostically helpful
and informative as a prognostic marker.
IDH1 is a mitochondrial protein that is mutated in most
infiltrating gliomas: astrocytomas, oligodendrogliomas, and
mixed oligoastrocytomas. In contrast, mutant IDH is rarely
detected in other primary CNS tumors: neuronal, circum-
scribed gliomas, ependymomas, meningiomas, or systemic
malignancies, with the exception of a subset of acute
myeloid leukemias.5–10 Mutations can occur in IDH1 and
IDH2; however, IDH1 mutations are more frequently
observed. Approximately 70% to 80% of all oligodendro-
gliomas harbor IDH mutations.6,11 The most common IDH1
mutation involves codon 132, where arginine is replaced by
histidine (R132H).6–8,11 A monoclonal antibody for the
most-common mutant form of IDH1 (R132H) has been
recently developed.12 This mutant-specific antibody has
proven to be very helpful in the differential diagnosis of
infiltrating gliomas from other primary CNS tumors and
from reactive conditions that can mimic low-grade glio-
mas.13,14 Similarly, the mutant-specific IDH1 antibody can
be used to distinguish various CNS tumors with clear cell
morphology.15 Recent studies have suggested that glial
tumors harboring IDH mutations have a more favorable
outcome, which may soon help stratify patient status and to
tailor therapy.16,17 In addition, a molecular marker in
oligodendrogliomas that carries a favorable prognosis is
codeletion of 1p and 19q material. An oligodendroglioma
with those molecular alterations has a better response to
PCV (procarbazine hydrochloride, lomustine [CCNU; Cee-
NU], and vincristine sulfate) chemotherapy.18,19 In our
practice, all oligodendrogliomas are studied for their 1p
19q status.
Case 2
Clinical History.—A 25-year-old woman complained of head-
aches that had been worsening in the previous 1 to 2 months. The
patient did not mention any visual symptoms, focal neurologic
deficits, nausea, or vomiting. Magnetic resonance imaging of the
brain showed a large mass on the right lateral ventricle extending
into the third ventricle, with concomitant dilation of the third
ventricle and both lateral ventricles (Figure 3, A). A tumor resection
was performed.
918 Arch Pathol Lab Med—Vol 136, August 2012
Brain Biopsy Findings.—Smear preparations performed in the
frozen-section room showed a homogenous population of small,
round cells with scant cytoplasm; round nuclei; and salt-and-
pepper chromatin. Some of the cells clustered around a central area
of eosinophilic granular material, forming so-called Homer-Wright
rosettes (Figure 3, B). Paraffin-embedded sections show a relatively
well-circumscribed tumor with monomorphous, round cells, some
of which had clear cytoplasm (Figure 3, C). A thin, delicate
vasculature network was also present. No mitotic activity was
identified (Figure 3, D). The tumor staining was diffusely
immunoreactive for synaptophysin and negative for GFAP (Figure
3, E). Some of the tumor cells showed nuclear immunoreactivity for
neuronal nuclear antigen (NeuN) stain (Figure 3, F). The
proliferation index (Ki-67) was less than 1%.
Diagnosis.—The diagnosis was a central neurocytoma, WHO
grade II.
COMMENT
Central neurocytomas are benign tumors that commonly
arise in the midline of the cerebral ventricular system. The
lateral ventricles and foramen of Monroe are the most
common locations for central neurocytomas. Attachment to
the septum pellucidum is frequently seen. Their peak
incidence is in the third decade of life. Symptoms are due
to cerebrospinal fluid obstruction and associated increased
intracranial pressure. Central neurocytomas are enhanced
by magnetic resonance imaging and computed tomography
scan.
Histologically, central neurocytomas are composed of
sheets of uniform cells with small, round nuclei; salt-and-
pepper chromatin; and fine, granular eosinophilic cytoplasm
that stains positive for synaptophysin. Homer-Wright
rosettes may be present. Occasionally, ganglionic cells with
Nissl substance can be detected. The tumor cells express
neuronal markers, such as class III-b tubulin, microtubule-
associated protein 2 (MAP2), NeuN, and neurofilament
protein. Of note, GFAP may be focally positive, which has
been interpreted as reactive astroglia. Because of their
capillary network, central neurocytomas may present with
bleeding. Microcalcifications can also be observed. Mitoses,
nuclear atypia, or hyperchromasia are usually not detected.
Tumors that show microvascular proliferation, necrosis, and
mitotic activity have been designated as atypical neurocyto-
mas.20–22 Recurrence is associated with incomplete surgical
resection and a proliferation index (Ki-67) more than 2%.21,23
Neurocytomas were misdiagnosed as oligodendrogliomas
or ependymomas until their neuronal nature was elucidated
by electron microcopy and immunohistochemistry.1,3,24–26
Extraventricular neurocytomas (EVNs) are neurocytic tu-
mors located within the brain parenchyma or in areas of the
neuroaxis other than ventricles. Given its unusual location,
EVNs pose a greater challenge in differentiating from other
CCTs.27,28 One diagnostic clue lies in the radiologic
appearance. Indeed, EVNs are usually well circumscribed
and cystic with several mural nodules, thus sharing
radiologic characteristics with other low-grade neoplasms
of the CNS. However, EVNs, like their central counterpart,
can have nuclear atypia, mitotic activity, vascular prolifer-
ation, and necrosis, making it difficult to differentiate from a
primary, high-grade, glial neoplasm in the diagnosis. The
EVN or atypical EVN is also considered a WHO grade II
tumor. The most important predictive features for recur-
rence of EVN are subtotal resection, a high proliferation
Clear Cell Tumors of the Central Nervous System––Camelo-Piragua
Figure 3. Case 2, central neurocytoma, World Health Organization grade II. A, Axial T2 fluid-attenuated inversion recovery sequence: right
intraventricular tumor with attachment to the septum pellucidum and dilation of the ventricular system. B, Hematoxylin-eosin (H&E) intraoperative
staining shows uniform, round nuclei, with minimal nuclear atypia; salt-and-pepper chromatin; and occasional, small nucleoli, with no discrete
cytoplasm, admixed in a granular, eosinophilic background, focally forming ill-defined rosettes (squares). C, The H&E results show relatively well-
circumscribed tumor, with surrounding brain parenchyma. D, The H&E paraffin sections highlight the uniform nuclei and thin, delicate vasculature. E,
Synaptophysin is diffusely positive. F, The NeuN stain shows nuclear staining in some of the tumor cells (original magnifications 3200 [B and F], 340
[C], and 3400 [D and E]).

index, atypical features, and older age of the patient; in
those cases concomitant radiation is required.28
Central neurocytomas and EVNs have not been associated
with IDH mutations. Therefore, the presence of a CCT that
Arch Pathol Lab Med—Vol 136, August 2012
harbors IDH mutations, as observed either by mutation analysis
or immunohistochemistry, favors the diagnosis of an oligo-
dendroglioma.15,29 Finally, another ancillary test to aid in
distinguishing this tumor from oligodendroglioma is immuno-
Clear Cell Tumors of the Central Nervous System––Camelo-Piragua 919
Figure 4. Case 3, clear cell meningioma, World Health Organization grade II. A, Sagittal T2: intrathecal lesion extending from the lower thoracic
cord to the conus medullaris. B, Hematoxylin-eosin (H&E) results show polygonal cells with round-to-oval nuclei, clear cytoplasm, and occasional
mitosis. C, The H&E results show dense, sclerotic collagen bundles, with intervening clear cells. D, The H&E results show focal meningothelial whorls.
E, the H&E results show tumor necrosis. F, The EMA stain highlights the membrane of the meningothelial cells (original magnifications 3400 [B, D,
and E] and 3200 [C and F]).

histochemistry for Olig-2. This transcription factor is expressed
highly in oligodendroglial tumors and to a lesser degree in other
glial neoplasms but is not expressed in neurocytomas.30
Case 3
Clinical History.—A 13-year-old girl presented with a 2-month
history of back pain, followed by right leg pain, and a few days of
leg weakness. The patient had 2 episodes of decreased urination.
920 Arch Pathol Lab Med—Vol 136, August 2012
She has normal sacral sensation and good rectal tone. Magnetic
resonance imaging of the brain and spine were performed, which
revealed a heterogeneous intrathecal lesion extending from T12 to
the most distal aspect of the conus medullaris, which caused
significant compression of the conus and the cauda equina (Figure
4, A). The lesion was resected.
Spinal Cord Biopsy Findings.—Histologic sections showed a
nodular, well circumscribed tumor with a thick, fibrous capsule.
Clear Cell Tumors of the Central Nervous System––Camelo-Piragua
Most of the tumor cells had ample, clear cytoplasm. The nuclei
were round to oval with moderate pleomorphism and occasional
prominent nucleoli (Figure 4, B). Traversing, thick, hyalinized
collagen bands were commonly present (Figure 4, C). In some
areas, cytoplasmic borders were well defined, giving the appear-
ance of polygonal cells. However, in other areas, a syncytial growth
pattern was present. Focally, meningothelial whorls were noted
(Figure 4, D). Mitotic activity reached up to 3 mitoses per 10 high-
power fields. There were multiple small areas of tumor necrosis
(Figure 4, E). Immunohistochemistry demonstrated that the tumor
was diffusely immunoreactive for epithelial membrane antigen
(EMA) and vimentin but negative for GFAP and synaptophysin
staining (Figure 4, F). The proliferation index (Ki-67) was 22%.
Diagnosis.—The diagnosis was clear cell meningioma, WHO
grade II.
COMMENT
Imaging studies suggested that the lesion was intradural
and intra-axial. The original radiologic differential diagnosis
included an ependymoma, myxopapillary ependymoma,
infiltrating glioma, or, less likely, a primary nerve sheath
tumor.
Histologic sections showed a clear cell neoplasm. The key
histologic features toward reaching the diagnosis included
the presence of meningothelial differentiation, such as
whorls, and areas with a syncytial growth pattern where
cytoplasmic borders could not be elucidated. However, the
typical meningothelial features may be focal or ill defined. In
addition, the classic psammoma bodies are not expected in
this meningioma variant. Meningiomas usually show
membranous EMA staining, which can be diffuse or focal.
Vimentin was positive but is also detected in other
neoplasms. Cytokeratin, GFAP, and synaptophysin were
negative, which can be helpful in excluding other tumors in
the differential diagnosis. If histologic and immunohisto-
chemical features are not sufficient to reach the diagnosis,
ultrastructural studies can be performed, where the tumor
cells should demonstrate intercellular junctions, interdigi-
tating cell processes, and intermediate filaments (10 nm) of
vimentin.
Clear cell meningioma is a variant of meningiomas
classified as WHO grade II for its propensity to recur.
Similar to atypical meningiomas, recurrence can be local or
distant and may have a mortality rate of up to 23%.31,32 It
commonly affects children and young adults. Clear cell
meningiomas are often rich in glycogen, which gives them
their clear cell appearance. Collagen bands are common,
and sometimes, the tumor has a sclerotic appearance with
only sparse clear cells in between the collagen bands. Clear
cell meningioma diagnoses are challenging because the
defining meningothelial features are usually focal or ill
defined. It is important to differentiate this tumor from other
CCTs, such as ependymomas, oligodendrogliomas, and
central neurocytomas.33 Clear cell meningiomas are often
found in the cerebellopontine angle and the cauda equina.
Although rare, meningiomas can occur in the ventricles, and
if the morphology has clear cells, a diagnostic challenge
arises in differentiating these tumors from central neurocy-
tomas or clear cell ependymomas.34,35
Case 4
Clinical History.—An 85-year-old woman who complained of
back pain was found to have on imaging studies an enhancing,
Arch Pathol Lab Med—Vol 136, August 2012
expansile mass in the spinal cord at T7-8 level. The tumor was
resected in an outside institution and sent for histopathologic
consultation.
Spinal Cord Biopsy Findings.—Histologic sections showed a
densely packed tumor composed of clear cells with rounded nuclei
and minimal nuclear pleomorphism. The tumor had areas devoid
of nuclei, predominately around blood vessels. Instead, eosino-
philic processes that extended from the tumor cells toward the
vessel wall, forming pseudorosettes were observed (Figure 5, A). At
high power, areas of tumor cells with eosinophilic processes
forming true rosettes were also noted (Figure 5, B). Mitoses were
not common, and microvascular proliferation or necrosis was not
identified. GFAP was diffusely immunoreactive, with increased
staining of the glial processes extending toward the vessels
(pseudorosettes) (Figure 5, C). EMA showed only focal perinuclear
dot positivity (Figure 5, D). Neurofilament was present, predom-
inately at the edge of the tumor, suggesting a relatively well-
circumscribed tumor. Synaptophysin and mutant-specific IDH1
immunostaining were negative. The proliferation index (Ki-67) was
2%.
Diagnosis.—The diagnosis was clear cell ependymoma, WHO
grade II.
COMMENT
Clear cell ependymoma is a rare variant that commonly
occurs in a supratentorial location in children and young
adults, although they can be seen at any age. Other
locations in the neuroaxis, such as the cauda equina are
also reported.36 Histologically, clear cell ependymomas can
resemble any of the CCTs discussed here. Clear cell
ependymomas have round to oval nuclei, clear cytoplasm,
and occasional microcalcifications. Identifying the presence
of perivascular pseudorosettes or true ependymal rosettes is
instrumental in the diagnosis. Ependymomas are immuno-
reactive for GFAP; however, GFAP expression may be
variable. The GFAP expression is strongest in areas forming
pseudorosettes, with cell processes radiating toward the
vessels. EMA is often focal and consists of perinuclear dot
positivity, or, less frequently, a ringlike pattern, lining the
lumens of the ependymal rosettes. In addition, ependymo-
mas are relatively well-circumscribed tumors. Absence of
infiltrative characteristics (neurofilament) is helpful in
differentiating clear cell ependymomas from oligodendro-
gliomas. Ependymomas are negative for neuronal markers
(neurofilament, synaptophysin, NeuN) and mutant IDH1.
If light microscopy and immunohistochemical stains are
inconclusive, one can resort to electron microscopy studies.
The main features of ependymal differentiation include the
presence of intermediate glial filaments (10 lm in diameter),
surface microvilli and cilia, and complex intercellular
junctions.37,38
Grading is usually done as with conventional ependymo-
mas; however, some studies have shown that clear cell
ependymomas have a more aggressive behavior.39
Case 5
Clinical History.—A 66-year-old woman complained of head-
aches, which were exacerbated when leaning forward. In addition,
the patient felt out of balance. The symptoms started 2 weeks
before her presentation to medical attention. Recent thyroid
ultrasound identified 2 nodules in the left thyroid. Family history
was significant for breast and ovarian cancer in her mother,
pancreatic cancer in her father, breast cancer in a sister, and colon
cancer in a brother. Brain magnetic resonance imaging demon-
Clear Cell Tumors of the Central Nervous System––Camelo-Piragua 921
Figure 5. Case 4, clear cell ependymoma, World Health Organization grade II. A, Hematoxylin-eosin results show a clear cell tumor with
pseudorosettes. B, Hematoxylin-eosin staining shows round nuclei, with minimal pleomorphism, surrounded by clear halos. Focal areas with true
ependymal rosettes (arrowhead) are shown. C, The GFAP staining is diffusely positive and highlights pseudorosettes. D, The EMA staining shows
focal perinuclear dot positivity (original magnifications 3200 [A and C] and 3400 [B and D]).

strated an enhancing intraparenchymal mass in the right cerebellar
hemisphere, partially cystic, with surrounding vasogenic edema
and mass effect. The cerebellar lesion was resected.
Cerebellar Biopsy Findings.—The tumor was a well-circum-
scribed lesion with displacement of the cerebellar folia at the
periphery, and no evidence of infiltration (Figure 6, A). The tumor
was composed of clear cells with round to oval nuclei in a rich
vascular network with vessels of different calibers (Figure 6, B).
Some areas of the tumor showed clear cells with a bubbly
cytoplasm and more nuclear pleomorphism (Figure 6, C). Mitoses
were not prominent. Oil red O in frozen tissue showed numerous
lipid globules of different sizes within the tumor cells (Figure 6, D).
Permanent sections showed the tumor was positive for S100 and
inhibin A, focally positive for D2-40, and negative for GFAP (Figure
6 E and F).
Diagnosis.—The diagnosis was hemangioblastoma, WHO
grade I.
COMMENT
Given the prominent family history of carcinomas, the
possibility of a metastatic lesion was high in the differential
diagnosis. The resection of the tumor showed a clear cell
tumor embedded in a rich capillary network, similar to
previously described cases in this review. Focally, however,
922 Arch Pathol Lab Med—Vol 136, August 2012
some of those clear cells showed prominent vacuolated and
bubbly cytoplasm, indicating the possibility of a hemangio-
blastoma. Oil red O staining, performed on frozen tissue,
showed the rich lipid content of the tumor, which is
characteristic of this entity. Unfortunately, fat globules
disappear on processing and embedding the tissue in
paraffin sections; therefore, if frozen tissue is not available,
one might have to use other ancillary studies to confirm the
diagnosis.
Hemangioblastomas are relatively uncommon neoplasms
that can occur sporadically or in the setting of von Hippel-
Lindau disease. Sporadic cases are usually seen in the
cerebellum as a single lesion in patients with a mean age of
45 years. Tumors associated with von Hippel-Lindau
disease present at a younger age (mean, 36 years), they
can be multiple, and they can occur in unusual locations,
such as retina, brain, and spinal cord. Patients with von
Hippel-Lindau disease may develop renal cell carcinomas
(RCCs). In such cases, assessing whether the brain lesion is
a primary hemangioblastoma, a metastatic clear cell variant
of RCC, or, in some rare instances, an RCC metastatic to a
hemangioblastoma, is challenging.40
Clear Cell Tumors of the Central Nervous System––Camelo-Piragua
Figure 6. Case 5, hemangioblastoma, World Health Organization grade I (A through F) and example of metastatic renal cell carcinoma (G through
H). A, Hematoxylin-eosin (H&E) staining shows a well-circumscribed tumor, pushing aside the cerebellar folia. B, The H&E staining shows clear cells,
with round nuclei, embedded in a rich capillary network. C, The H&E staining shows cells with bubbly cytoplasm and nuclear pleomorphism. D, Oil
red O in frozen tissue highlights the stromal cells, which are rich in lipid globules. E, Inhibin A staining is diffusely and strongly immunoreactive. F, The
D2-40 staining is focally positive in a membranous pattern. G, The H&E staining shows metastatic renal cell carcinoma with clear cell morphology. H,
The PAX2 staining shows strong nuclear immunoreactivity (original magnifications 340 [A], 3200 [B, E, and F], and 3400 [C, D, G, and H]).

Radiologically, a hemangioblastoma is frequently cystic tumor is embedded in a rich anastomosing network of

with a mural nodule. Intratumoral bleeding is not uncom-
mon and can be the presenting sign. Grossly, the tumor is
red because of the rich capillary network. Histologically, the
tumor is well circumscribed and may have a thin capsule.
The cells can range from clear cytoplasm with minimal
nuclear pleomorphism to very bubbly cytoplasm with
moderate or even marked nuclear atypia. Despite areas of
nuclear pleomorphism, mitoses are seldom found. The
Arch Pathol Lab Med—Vol 136, August 2012
capillaries. Extramedullary hematopoiesis and mast cells can
be part of the tumor, and, in some instances, patients may
have increased erythropoietin that normalizes after the
tumor is resected.41 Immunohistochemically, the tumor
cells, also called stromal cells, have variable reactivity for
neuron-specific enolase (NSE), S100, and CD56. Vimentin
and vascular endothelial growth factor (VEGF) are usually
diffusely positive. Staining with GFAP is generally negative
Clear Cell Tumors of the Central Nervous System––Camelo-Piragua 923
Figure 7. Immunohistochemical algorithm for the differential diagnosis of clear cell tumors in the central nervous system. Abbreviations: þ, positive;
þ/, positive or negative; /þ, can be focally positive; CC, clear cell; EMA, epithelial membrane antigen; GFAP, glial fibrillary acid protein; mIDH1,
mutant-specific IDH1; NeuN, neuronal nuclear antigen; NF, neurofilament; ORO, oil red O; SYN, synaptophysin.
but can be seen in some cells.42–44 Recently, inhibin A, D2-
40, and brachyury have been found to be present in
hemangioblastomas and may be helpful in differentiating
them from other CCTs.45–47
When the clear cell variant of RCC is in the differential
diagnosis or suspected to be metastatic within the heman-
gioblastoma, the use of ancillary studies is helpful. Staining
with CD10 and PAX2 is more sensitive and specific in
differentiating RCC with hemangioblastoma than are other
markers, such as RCC, D2-40, or inhibin A (Figure 6, G and
H).48
CONCLUSIONS
Accurate diagnosis of CCTs in the CNS can be difficult,
especially in the absence of comprehensive clinical and
radiologic data. Histologically, CCTs of the CNS have
similar morphologic features, and often, ancillary studies are
required to accurately diagnose these lesions.
In some instances, morphologic features may direct us
toward one diagnosis or the other. For example, the
presence of pseudorosettes and ependymal rosettes is
consistent with ependymal differentiation. In the presence
of whorls and intranuclear inclusions, clear cell meningioma
is the most likely diagnosis. A bubbly cytoplasm in a tumor
that was cystic with a mural nodule will suggest a
hemangioblastoma. However, when such features are not
924 Arch Pathol Lab Med—Vol 136, August 2012
found, ancillary studies are needed to achieve an accurate
diagnosis.
Figure 7 proposes an immunohistochemical algorithm for
differentiating CCTs in the CNS. The first step is identifying
whether the lesion is infiltrative or not. Good evidence of
infiltration is the entrapment of normal brain structures.
Other infiltrative features of gliomas, especially oligoden-
drogliomas, are the presence of secondary structures of
Scherer: perineuronal satellitosis, perivascular satellitosis,
subpial aggregation, and infiltration of white matter tracts. If
the sample is small or these features are not evident,
observation of entrapped axons with neurofilaments in the
middle of the tumor is a reliable indicator that the lesion is
infiltrative and likely oligodendroglial in nature. In addition,
if the tumor is immunoreactive for mutant-specific IDH1 (a
signature for infiltrating gliomas) and negative for synapto-
physin and other neuronal markers, the presence of an
oligodendroglioma is highly suspected.
If the tumor is well circumscribed or axons are only seen
at the periphery of the tumor, identifying the origin of the
lesion by combining GFAP, EMA, and synaptophysin is
important. If the tumor shows diffuse immunoreactivity for
GFAP or focal staining with an accentuation of the staining
in glial processes toward vessels (pseudorosettes), it is most
consistent with a clear cell ependymoma. In addition, focal
staining with EMA in a perinuclear dot or ringlike pattern
may support such a diagnosis. If GFAP is negative and EMA
Clear Cell Tumors of the Central Nervous System––Camelo-Piragua
shows a diffuse membranous pattern of staining, then a
diagnosis of clear cell meningioma is more likely. Staining
with GFAP can be focally positive in other CCTs, and
additional studies will be necessary, such as in the case
of neurocytoma and hemangioblastoma. Synaptophysin
should be diffusely positive in neurocytomas and generally
negative in hemangioblastomas. Hemangioblastoma, how-
ever, is immunoreactive for S100, VEGF, D2-40, and inhibin
A, among other markers. Also, close space between this
and previos sentence. Finally, if all of the above markers are
negative and a metastatic clear cell carcinoma, sarcoma, or
melanoma is suspected, specific stains for those entities
should be performed.
In some cases, histology and immunohistochemical
studies are not sufficient to elucidate the etiology of the
tumor. Ultrastructural studies may identify specific features;
for example, cilia or microvilli in ependymomas, interdig-
itating junctions in meningiomas, and neurosecretory
granules in central neurocytoma. Ultrastructural studies
can be done from paraffin-embedded tissue but are best
from tissue fixed in glutaraldehyde.
When performed, comprehensive assessment of the
clinical and radiologic presentation of the case is crucial
for correlation with the histologic findings and essential to
guide the pathologist to a cost-effective and finally accurate
diagnosis of CCTs in the CNS.
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