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					                        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 frac-
ture of the left femur. During the workup following the
                                                                       patient conveyed that the lumps had been classified as li-
                                                                       pomas in the past. There were no nevi or other discolor-
                                                                       ation. Family history was negative for phakomatoses, in-
trauma, a computed tomographic scan of the neck and                    cluding von Hippel-Lindau (VHL) syndrome.
spine incidentally revealed a 3.4   3.6-cm solitary cystic                At the time of surgical removal of the lesion, several
lesion in the right inferior cerebellar hemisphere with                arteries were seen entering into the mural nodule. Frozen
some hemorrhage and an enhancing mural nodule. Mag-                    section showed cyst wall with increased cellularity, colla-
netic resonance imaging confirmed this finding (Figure 1).               gen, and hemosiderin deposition. The cyst wall and the
The patient had no previous medical history. He denied                 mural nodule were grossly removed in toto and submitted
symptoms from any organ system, including neurologic                   for evaluation, along with fluid from the cyst. On gross
problems. Physical examination was unremarkable except                 examination, the specimen consisted of a tan-pink to red,
for the skin, on which were found a few scattered soft,
                                                                       hemorrhagic, 0.8     0.6    0.3 cm piece of soft tissue. He-
nontender lumps on the back, forearms, and chest. The
                                                                       matoxylin-eosin–stained sections revealed a hypervascu-
                                                                       lar and hypercellular lesion containing epitheloid cells
   Accepted for publication February 2, 2006.                          with vesicular cytoplasm (Figure 2). Rosenthal fibers were
   From the Departments of Pathology and Laboratory Medicine (Drs
                                                                       observed in the cyst wall (Figure 3). Immunohistochemical
Svensson, Pang, and Tindle) and Radiology (Dr Moore), University of
Vermont and Fletcher Allen Health Care, Burlington, Vt.                evaluation revealed that the cells were positive for neuron-
   The authors have no relevant financial interest in the products or   specific enolase, negative for epithelial membrane antigen,
companies described in this article.                                   and negative for CD10. The cystic fluid specimen was
   Corresponding author: Annika M. Svensson, MD, PhD, Department       composed of blood containing lymphocytes and megalo-
of Pathology and Laboratory Medicine, University of Vermont and
Fletcher Allen Health Care, 111 Colchester Ave, Burlington, VT 05401   blastic erythropoiesis (Figure 4). There was no evidence of
(e-mail: Annika.Svensson@uvm.edu).                                     myelopoiesis or megakaryopoiesis.
   Reprints not available from the authors.                               What is your diagnosis?




886 Arch Pathol Lab Med—Vol 130, June 2006                                               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               roendocrine, and smooth muscle differentiation.3 Electron
             Megaloblastic Hematopoiesis                       microscopy has demonstrated a clear relationship of stro-
                                                               mal cells with endothelial cells, smooth muscle cells, and
                         Abstract                              pericytes.3 The current World Health Organization classi-
   Cerebellar hemangioblastomas constitute 1% to 2% of         fication of brain tumors lists hemangioblastoma as a single
all primary nervous system tumors and are generally            entity in the tumors of uncertain histogenesis.4
considered to be benign. Hemangioblastoma is the most             The main differential diagnosis is metastatic renal cell
common presenting manifestation of von Hippel-Lindau           carcinoma, which shares the clear cell features of the hem-
disease. However, most cerebellar hemangioblastomas            angioblastoma cells. Compared with the tumor cells of re-
are not associated with von Hippel-Lindau disease. The         nal cell carcinoma, the hemangioblastoma cells tend to
main differential diagnosis is metastatic renal cell car-      have more uniform nuclear chromatin, smaller nucleoli,
cinoma, which may be distinguished from hemangio-              and a more intimate arrangement of capillaries and stro-
blastoma by staining with glucose transporter 1 or, as         mal cells. The absence of necrosis is also a distinguishing
recently described, by inhibin -subunit (inhibin A).           feature. Immunohistochemically, glucose transporter 1 im-
Although extramedullary hematopoiesis is a rare finding         munoreactivity has been used to distinguish hemangio-
in tumors of the central nervous system, several cases of      blastoma from metastatic renal cell carcinoma.5 In addi-
hemangioblastoma with hematopoiesis in the central             tion, immunohistochemical staining of inhibin A, which is
nervous system have been described previously. How-            expressed in the stromal cells of hemangioblastoma but
ever, to our knowledge this is the first observation of         rarely in renal clear cell carcinoma, has recently been used
megaloblastic erythropoiesis in a cerebellar hemangio-         for this purpose.6,7 In the present case, a panel consisting
blastoma.                                                      of neuron-specific enolase, epithelial membrane antigen,
                                                               and CD10 was used for diagnosis. Hemangioblastoma, in
   Cerebellar hemangioblastomas represent 1% to 2% of all      contrast to renal cell carcinoma, tends to stain for neuron-
primary tumors of the central nervous system. They are         specific enolase but not for epithelial membrane antigen.
considered to be benign neoplasms, but may cause major         The tumor in this case was positive for neuron-specific
morbidity. Hemangioblastoma is the most common pre-            enolase but negative for epithelial membrane antigen. In
senting manifestation of the autosomal-dominant VHL            addition, the tumor was negative for CD10 (whereas it
disease (OMIM 193300), which is associated with a germ-        was positive in more than 90% of renal cell carcinomas).8
line mutation of the VHL tumor suppressor gene.1,2 This        Sampling of the cyst wall of hemangioblastomas may
diagnosis should be considered in patients with more than      show gliosis, and Rosenthal fibers may be prominent,
one tumor or a tumor in an unusual location. In this case,     mimicking pilocytic astrocytoma. Furthermore, during
computed tomographic imaging of the thorax, abdomen,           processing for frozen section, lipid contained in the vac-
and pelvis to rule out VHL lesions was unremarkable. The       uoles may vanish. In cases in which frozen sections show
majority of cerebellar hemangiomas are not associated          cyst wall with fibroid cells, the surgeon should be asked
with VHL. Somatic inactivation of the VHL gene has been        to inspect for mural nodules. In this case, the nodule had
shown in sporadic cases of hemangioblastoma.1,2 Cerebel-       already been observed on the neuroimaging studies and
lar hemangioblastomas occur most often in adults aged 30       tissue was submitted for routine processing.
to 50 years; there is a slight male predominance. Symp-           Extramedullary hematopoiesis is rarely found in pri-
toms depend on localization and size, and may include          mary brain tumors.9 Cases described include a pilocytic
signs of cerebellar dysfunction as well as hydrocephalus.      astrocytoma.10 However, hemangioblastoma is the central
Major hemorrhages are rare.2 Although hemangioblasto-          nervous system tumor that is most commonly associated
mas associated with VHL are often multiple, and may pre-       with extramedullary hematopoiesis, with approximately
sent significant surgical challenges, the prognosis for a       10 cases documented in the literature.9 For instance, a pre-
radically excised solitary, sporadic cerebellar hemangio-      vious study revealed hematopoiesis in 4 of 26 hemangio-
blastoma is considered favorable.                              blastoma specimens examined. One case was associated
   Four types of hemangioblastoma have been described:         with erythrocytosis.10 Approximately 20% of cerebellar
type 1 (6%), simple cyst form with no macroscopic evi-         hemangioblastomas display polycythemia caused by local
dence of mural nodule; type 2 (65%), macrocystic form,         production of erythropoietin.2,10 Disruption of VHL-me-
consisting of a variably sized cyst with a mural nodule        diated degradation of hypoxia-inducible factors may in-
0.502.5 cm in size; type 3 (25%), solid tumor; and type 4      crease the expression of erythropoietin.1 Hypoxia-induc-
(4%), predominantly solid with several small cysts.2 His-      ible factors may also act to stimulate angiogenesis by in-
tologically, hemangioblastomas typically show a mixture        creased levels of vascular endothelial growth factor and
of variably sized capillary vessels and epitheloid stroma      platelet-derived growth factor- .1 Our patient, however,
cells containing lipid vacuoles, the latter feature allowing   did not display erythrocytosis (data not shown).
for differentiation from angioma. Hemangioblastomas are           Megaloblastic erythropoiesis is characterized by eryth-
slow-growing and typically display no mitotic figures.          roblasts larger than normal at all stages of maturation,
The origin of the neoplastic stromal cells is not well de-     dissociation between nuclear and cytoplasmic maturation,
fined. These cells seem to represent a heterogeneous pop-       and the presence of macrocytes in the peripheral blood.
ulation of mesenchymal cells of angiogenic lineage.3 Im-       Although the erythropoietic cells found in the cyst fluid
munohistochemical studies have shown frequent expres-          in this case were clearly megaloblastic, the patient did not
sion of vimentin, S100 protein, neuron-specific enolase,        display megaloblastosis of the peripheral blood (mean
and cytokeratins; less expression of desmin, factor XIIIa      corpuscular volume, 85 fl [reference range, 81–95 fl] with
and Ricinus communis lectin receptors; occasional expres-      normal red cell morphology). The megaloblastosis was
sion of factor VIII and ulex europaeus lectin; and negativ-    thus restricted to the tumor area. To our knowledge,
ity for other markers of endothelial, neuronal, glial, neu-    megaloblastic erythropoiesis has not previously been ob-
888 Arch Pathol Lab Med—Vol 130, June 2006                                       Cystic Tumor of the Cerebellum—Svensson et al
served in hemangioblastomas. Reporting hematopoiesis in                           eds. Pathology and Genetics of Tumours of the Nervous System. 2nd ed. Lyon,
                                                                                  France: IARC Press; 2000:223–230. World Health Organization Classification
hemangioblastomas is important in light of frequent re-                           of Tumors.
currences of the tumor. New treatments, including growth                             5. North PE, Mizeracki A, Mihm MC Jr, Mrak RE. GLUT1 immunoreaction
factors, may work to expand intracranial extramedullary                           patterns reliably distinguish hemangioblastoma from metastatic renal cell carci-
                                                                                  noma. Clin Neuropathol. 2000;19:131–137.
hematopoiesis.9                                                                      6. Hoang MP, Amirkhan RH. Inhibin alpha distinguishes hemangioblastoma
                                                                                  from clear cell renal cell carcinoma. Am J Surg Pathol. 2003;27:1152–1156.
                                 References                                          7. Jung SM, Kuo TT. Immunoreactivity of CD10 and inhibin alpha in differ-
   1. Lonser RR, Glenn GM, Walther M, et al. Von Hippel-Lindau disease. Lancet.   entiating hemangioblastoma of central nervous system from metastatic clear cell
2003;361:2059–2067.                                                               renal cell carcinoma. Mod Pathol. 2005;18:788–794.
   2. Richard S, David P, Marsot-Dupuch K, Giraud S, Beroud C, Resche F. Cen-        8. Avery AK, Beckstead J, Renshaw AA, Corless CL. Use of antibodies to RCC
tral nervous system hemangioblastomas, endolymphatic sac tumors, and von Hip-     and CD10 in the differential diagnosis of renal neoplasms. Am J Surg Pathol.
pel-Lindau disease. Neurosurg Rev. 2000;23:1–22.                                  2000;24:203–210.
   3. Lach B, Gregor A, Rippstein P, Omulecka A. Angiogenic histogenesis of          9. Beckner ME, Lee JYK, Schochet SS Jr, Chu CT. Intracranial extramedullary
stromal cells in hemangioblastoma: ultrastructural and immunohistochemical        hematopoiesis associated with pilocytic astrocytoma: a case report. Acta Neu-
study. Ultrastruct Pathol. 1999;23:299–310.                                       ropathol. 2003;106:584–587.
   4. Bohling T, Plate KL, Hatia MJ, Alitalo K, Neumann HPH. Von Hippel-             10. Zec N, Cera P, Twofighi J. Extramedullary hematopoiesis in cerebellar hem-
Lindau disease and capillary hemangioblastoma. In: Kleihues P, Cavanee WK,        angioblastoma. Neurosurgery. 1991;29:34–37.




Arch Pathol Lab Med—Vol 130, June 2006                                                             Cystic Tumor of the Cerebellum—Svensson et al 889

				
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