Cystic Tumor of the Cerebellum With
Megaloblastic Erythropoiesis
Annika M. Svensson, MD, PhD; Yijun Pang, MD, PhD; Nicholas J. E. Moore, MD; Barbara H. Tindle, MD
A
52-year-old man suffered an accidental 4.5-m fall from
a ladder while trimming trees; he sustained a fracture of the left femur. During the workup following the
trauma, a computed tomographic scan of the neck and
spine incidentally revealed a 3.4 3 3.6-cm solitary cystic
lesion in the right inferior cerebellar hemisphere with
some hemorrhage and an enhancing mural nodule. Magnetic resonance imaging confirmed this finding (Figure 1).
The patient had no previous medical history. He denied
symptoms from any organ system, including neurologic
problems. Physical examination was unremarkable except
for the skin, on which were found a few scattered soft,
nontender lumps on the back, forearms, and chest. The
Accepted for publication February 2, 2006.
From the Departments of Pathology and Laboratory Medicine (Drs
Svensson, Pang, and Tindle) and Radiology (Dr Moore), University of
Vermont and Fletcher Allen Health Care, Burlington, Vt.
The authors have no relevant financial interest in the products or
companies described in this article.
Corresponding author: Annika M. Svensson, MD, PhD, Department
of Pathology and Laboratory Medicine, University of Vermont and
Fletcher Allen Health Care, 111 Colchester Ave, Burlington, VT 05401
(e-mail: [email protected]).
Reprints not available from the authors.
886 Arch Pathol Lab Med—Vol 130, June 2006
patient conveyed that the lumps had been classified as lipomas in the past. There were no nevi or other discoloration. Family history was negative for phakomatoses, including von Hippel-Lindau (VHL) syndrome.
At the time of surgical removal of the lesion, several
arteries were seen entering into the mural nodule. Frozen
section showed cyst wall with increased cellularity, collagen, and hemosiderin deposition. The cyst wall and the
mural nodule were grossly removed in toto and submitted
for evaluation, along with fluid from the cyst. On gross
examination, the specimen consisted of a tan-pink to red,
hemorrhagic, 0.8 3 0.6 3 0.3 cm piece of soft tissue. Hematoxylin-eosin–stained sections revealed a hypervascular and hypercellular lesion containing epitheloid cells
with vesicular cytoplasm (Figure 2). Rosenthal fibers were
observed in the cyst wall (Figure 3). Immunohistochemical
evaluation revealed that the cells were positive for neuronspecific enolase, negative for epithelial membrane antigen,
and negative for CD10. The cystic fluid specimen was
composed of blood containing lymphocytes and megaloblastic erythropoiesis (Figure 4). There was no evidence of
myelopoiesis or megakaryopoiesis.
What is your diagnosis?
Cystic Tumor of the Cerebellum—Svensson et al
Arch Pathol Lab Med—Vol 130, June 2006
Cystic Tumor of the Cerebellum—Svensson et al 887
Pathologic Diagnosis: Hemangioblastoma With
Megaloblastic Hematopoiesis
Abstract
Cerebellar hemangioblastomas constitute 1% to 2% of
all primary nervous system tumors and are generally
considered to be benign. Hemangioblastoma is the most
common presenting manifestation of von Hippel-Lindau
disease. However, most cerebellar hemangioblastomas
are not associated with von Hippel-Lindau disease. The
main differential diagnosis is metastatic renal cell carcinoma, which may be distinguished from hemangioblastoma by staining with glucose transporter 1 or, as
recently described, by inhibin a-subunit (inhibin A).
Although extramedullary hematopoiesis is a rare finding
in tumors of the central nervous system, several cases of
hemangioblastoma with hematopoiesis in the central
nervous system have been described previously. However, to our knowledge this is the first observation of
megaloblastic erythropoiesis in a cerebellar hemangioblastoma.
Cerebellar hemangioblastomas represent 1% to 2% of all
primary tumors of the central nervous system. They are
considered to be benign neoplasms, but may cause major
morbidity. Hemangioblastoma is the most common presenting manifestation of the autosomal-dominant VHL
disease (OMIM 193300), which is associated with a germline mutation of the VHL tumor suppressor gene.1,2 This
diagnosis should be considered in patients with more than
one tumor or a tumor in an unusual location. In this case,
computed tomographic imaging of the thorax, abdomen,
and pelvis to rule out VHL lesions was unremarkable. The
majority of cerebellar hemangiomas are not associated
with VHL. Somatic inactivation of the VHL gene has been
shown in sporadic cases of hemangioblastoma.1,2 Cerebellar hemangioblastomas occur most often in adults aged 30
to 50 years; there is a slight male predominance. Symptoms depend on localization and size, and may include
signs of cerebellar dysfunction as well as hydrocephalus.
Major hemorrhages are rare.2 Although hemangioblastomas associated with VHL are often multiple, and may present significant surgical challenges, the prognosis for a
radically excised solitary, sporadic cerebellar hemangioblastoma is considered favorable.
Four types of hemangioblastoma have been described:
type 1 (6%), simple cyst form with no macroscopic evidence of mural nodule; type 2 (65%), macrocystic form,
consisting of a variably sized cyst with a mural nodule
0.502.5 cm in size; type 3 (25%), solid tumor; and type 4
(4%), predominantly solid with several small cysts.2 Histologically, hemangioblastomas typically show a mixture
of variably sized capillary vessels and epitheloid stroma
cells containing lipid vacuoles, the latter feature allowing
for differentiation from angioma. Hemangioblastomas are
slow-growing and typically display no mitotic figures.
The origin of the neoplastic stromal cells is not well defined. These cells seem to represent a heterogeneous population of mesenchymal cells of angiogenic lineage.3 Immunohistochemical studies have shown frequent expression of vimentin, S100 protein, neuron-specific enolase,
and cytokeratins; less expression of desmin, factor XIIIa
and Ricinus communis lectin receptors; occasional expression of factor VIII and ulex europaeus lectin; and negativity for other markers of endothelial, neuronal, glial, neu888 Arch Pathol Lab Med—Vol 130, June 2006
roendocrine, and smooth muscle differentiation.3 Electron
microscopy has demonstrated a clear relationship of stromal cells with endothelial cells, smooth muscle cells, and
pericytes.3 The current World Health Organization classification of brain tumors lists hemangioblastoma as a single
entity in the tumors of uncertain histogenesis.4
The main differential diagnosis is metastatic renal cell
carcinoma, which shares the clear cell features of the hemangioblastoma cells. Compared with the tumor cells of renal cell carcinoma, the hemangioblastoma cells tend to
have more uniform nuclear chromatin, smaller nucleoli,
and a more intimate arrangement of capillaries and stromal cells. The absence of necrosis is also a distinguishing
feature. Immunohistochemically, glucose transporter 1 immunoreactivity has been used to distinguish hemangioblastoma from metastatic renal cell carcinoma.5 In addition, immunohistochemical staining of inhibin A, which is
expressed in the stromal cells of hemangioblastoma but
rarely in renal clear cell carcinoma, has recently been used
for this purpose.6,7 In the present case, a panel consisting
of neuron-specific enolase, epithelial membrane antigen,
and CD10 was used for diagnosis. Hemangioblastoma, in
contrast to renal cell carcinoma, tends to stain for neuronspecific enolase but not for epithelial membrane antigen.
The tumor in this case was positive for neuron-specific
enolase but negative for epithelial membrane antigen. In
addition, the tumor was negative for CD10 (whereas it
was positive in more than 90% of renal cell carcinomas).8
Sampling of the cyst wall of hemangioblastomas may
show gliosis, and Rosenthal fibers may be prominent,
mimicking pilocytic astrocytoma. Furthermore, during
processing for frozen section, lipid contained in the vacuoles may vanish. In cases in which frozen sections show
cyst wall with fibroid cells, the surgeon should be asked
to inspect for mural nodules. In this case, the nodule had
already been observed on the neuroimaging studies and
tissue was submitted for routine processing.
Extramedullary hematopoiesis is rarely found in primary brain tumors.9 Cases described include a pilocytic
astrocytoma.10 However, hemangioblastoma is the central
nervous system tumor that is most commonly associated
with extramedullary hematopoiesis, with approximately
10 cases documented in the literature.9 For instance, a previous study revealed hematopoiesis in 4 of 26 hemangioblastoma specimens examined. One case was associated
with erythrocytosis.10 Approximately 20% of cerebellar
hemangioblastomas display polycythemia caused by local
production of erythropoietin.2,10 Disruption of VHL-mediated degradation of hypoxia-inducible factors may increase the expression of erythropoietin.1 Hypoxia-inducible factors may also act to stimulate angiogenesis by increased levels of vascular endothelial growth factor and
platelet-derived growth factor-b.1 Our patient, however,
did not display erythrocytosis (data not shown).
Megaloblastic erythropoiesis is characterized by erythroblasts larger than normal at all stages of maturation,
dissociation between nuclear and cytoplasmic maturation,
and the presence of macrocytes in the peripheral blood.
Although the erythropoietic cells found in the cyst fluid
in this case were clearly megaloblastic, the patient did not
display megaloblastosis of the peripheral blood (mean
corpuscular volume, 85 fl [reference range, 81–95 fl] with
normal red cell morphology). The megaloblastosis was
thus restricted to the tumor area. To our knowledge,
megaloblastic erythropoiesis has not previously been obCystic Tumor of the Cerebellum—Svensson et al
served in hemangioblastomas. Reporting hematopoiesis in
hemangioblastomas is important in light of frequent recurrences of the tumor. New treatments, including growth
factors, may work to expand intracranial extramedullary
hematopoiesis.9
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