340 Cases of the Month: January to March 2004 Cases of the Month: January to March 2004 341

MARCH 2004: A 24YEAROLD WOMAN WITH BIFRONTAL HEADACHES

Contributed by: Chris Englund1; Daniel Silbergeld1,2; Ellsworth C. Alvord, Jr.1; Randy Small1; Robert F. Hevner1

Departments of 1Pathology and 2Neurological Surgery, University of Washington, Seattle.

CLINICAL HISTORYA 24-year-old woman presented with a one-year history of bi-

frontal headaches that had recently worsened. After admission to the hospital, the patient displayed no other symptoms and no acute worsening of the headaches.

NEUROIMAGINGA CT scan was performed and demonstrated a well-circum-

scribed, calcified lesion, approximately 2 cm in diameter, located in the right frontal lobe beneath the coronal suture (Figure 1A). e lesion was isointense on T2-weighted MRI, and showed minimal enhancement on post-contrast sagittal T1-weighted images (Figure 1B).

GROSS AND MICROSCOPIC PATHOLOGYe patient underwent a right frontal craniotomy with Stealth

guidance. e bisected specimen showed a fleshy red/tan tumor, surrounded by a thin rim of normal white matter (Figure 2). e border between tumor and white matter was remarkably distinct on both gross and microscopic inspection (Figure 3).

Hematoxylin and eosin stained sections showed predominantly small round tumor cells, many with perinuclear halos, clustered in groups and surrounded by hypocellular areas, or by microcysts filled with bluish gray material (Figure 4A). Focally, the tumor contained ganglioid cells with larger nuclei, prominent nucleoli, and abundant, basophilic cytoplasm (Figure 4B). Synaptophysin immunoreactivity strongly labeled the hypocellular areas (Figure 4C). e MIB-1 labeling index was less than 1% (not shown). e mature neuronal marker NeuN was variably expressed: in some areas NeuN was expressed by the majority of tumor cells, but in other areas by very few tumor cells (Figure 4D). Ganglioid cells in this tumor were uniformly NeuN+.

To determine if NeuN+ tumor cells were mitotically active or in-active, we performed double immunofluorescence using antibodies against NeuN and Ki-67 (MIB-1 antigen). ere was no co-local-ization of NeuN and Ki-67 in areas of either high (Figure 5A) or low (Figure 5B) NeuN labeling.

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

342 Cases of the Month: January to March 2004 Cases of the Month: January to March 2004 343

FINAL DIAGNOSISExtraventricular neurocytoma.

DISCUSSIONe differential diagnosis of neurocytomas includes oligoden-

droglioma, ganglioglioma, and ependymoma. On radiological, surgical and histopathological examination, extraventricular neurocytomas most frequently resemble oligodendroglioma, but as in the present case, they are generally less infiltrative than glial tumors. e defining marker for the identification of neurocyto-mas has been synaptophysin, since neurocytic tumors show strong immunoreactivity, but glial tumors are mostly negative (10). Extraventricular neurocytomas are histologically identical to the more common central neurocytomas, but are distinguished by their location outside the lateral ventricles. Neurocytomas have been reported in locations as diverse as the spinal cord, cerebellum, and cerebral cortex (1, 2, 4, 5, 7, 8).

NeuN immunoreactivity has not been studied much in neuro-cytomas, central or extraventricular. In this case, we found that the mature neuron marker NeuN was expressed by some neurocytoma cells. NeuN was introduced in 1992 as an antibody that recognized the nuclei (and to a lesser extent the cytoplasm) of differentiated, postmitotic neurons (6). As a marker of neurocytic differentia-tion in tumors, NeuN has been of questionable value, as NeuN immunoreactivity has sometimes been found in tumors that are considered to be glial, such as oligodendrogliomas (3, 10). On the other hand, it has also been suggested that traditional tumor clas-sifications may need to be revised to reflect molecular expression data (5).

Since NeuN is normally found only in postmitotic neurons (6, 9), we hypothesized that even in tumors such as neurocytoma, NeuN might likewise be expressed only by cells that have exited the mitotic cycle. e double labeling results supported this hy-pothesis, since no neurocytoma cells expressed both NeuN and the proliferative cell marker Ki-67. is finding is consistent with the general idea that differentiation and proliferation tend to be alter-native cellular states.

REFERENCES1. Brat DJ, Scheithauer BW, Eberhart CG, Burger PC (2001) Extraventricular neurocytomas: pathologic features and clinical outcome. Am J Surg Pathol 25:1252-1260

2. Brown DM, Karlovits S, Lee LH, Kim K, Rothfus WE, Brown HG (2001) Man-agement of neurocytomas: case report and review of the literature. Am J Clin Oncol 24:272-278

3. Castellano-Sanchez AA, Perry A, Scheithauer BW, Burger PC, Brat DJ (2002) Distinguishing extraventricular neurocytoma from oligodendroglioma: Util-ity of NeuN immunohistochemistry and FISH analysis for 1p and 19q status. J Neuropathol Exp Neurol Abstract 61:452.

4. Giangaspero F, Cenacchi G, Losi L, Cerasoli S, Bisceglia M, Burger PC (1997) Extraventricular neoplasms with neurocytoma features. A clinicopathologi-cal study of 11 cases. Am J Surg Pathol 21:206-212

5. Miller DC, Lang FF, Epstein FJ (1993) Central nervous system ganglioglio-mas Part 1: Pathology. J Neurosurg 79:859-866.

6. Mullen RJ, Buck CR, Smith AM (1992) NeuN, a neuronal specific nuclear protein in vertebrates. Development 116: 201-211.

7. Nishio S, Takeshita I, Kaneko Y, Fukui M (1992) Cerebral neurocytoma: a new subset of benign neuronal tumors of the cerebrum. Cancer 70: 529-537.

8. Tortori-Donati P, Fondelli MP, Rossi A, Cama A, Brisigotti M, Pellicano G (1999) Extraventricular neurocytoma with ganglionic differentiation associ-ated with complex partial seizures. AJNR Am J Neuroradiol 20:724-727.

9. Wolf HK, Buslei R, Schmidt-Kastner R, Schmidt-Kastner PK, Pietsch T, Wies-tler OD, Bluhmke I (1996) NeuN: a useful marker for diagnostic histopathol-ogy. J Histochem Cytochem 44:1167-1171.

10. Wolf HK, Buslei R, Blumcke I, Wiestler OD, Pietsch T (1997) Neural antigens in oligodendrogliomas and dysembryoplastic neuroepithelial tumors. Acta Neuropathol 94:436-443.

342 Cases of the Month: January to March 2004 Cases of the Month: January to March 2004 343

CASE OF THE MONTH: ABSTRACT

JANUARY 2004 CASE OF THE MONTH (COM). A 74-year-old Fili-pino man presented with new-onset partial-complex seizures. Eight months earlier he had a subtotal gastrectomy for adeno-carcinoma classified as T1N0M0 stage IA. He was irradiated. Two months later, he became confused and developed rhythmic, seizure-like movements of the extremities. A head CT revealed a 2 cm. right frontal lobe mass. On MRI, the mass exhibited ring en-hancement and was surrounded by edematous white matter. The patient denied headache, weakness or constitutional symptoms. CT of the chest and abdomen revealed no evidence of metastatic spread or other abnormalities. His seizures were controlled with fosphenytoin and dexamethasone. Preoperatively the frontal lobe lesion was considered most likely to be either a metastatic or primary tumor. Resection of the frontal lobe lesion revealed a firm gliotic cystic mass. Crush preparations and frozen sections showed acute and chronic inflammation, gliosis, fibrosis, and many foreign body giant cells reacting to parasitic larval tissue. Intact and necrotic larval parts were surrounded by gliotic brain tissue containing foreign body giant cells, macrophages, and lymphocytes. However, eosinophils were not seen. Finally a re-fractive fragment resembling a hooklet and a fragmented scolex were identified that made a diagnosis of cysticercosis certain.

FEBRUARY 2004 COM. A 44-year old man presented with a 2-year history of epistaxis and a nodular lesion in the nasopharyn-geal mucosa. Neuroimaging revealed a midline nasopharyngeal tumor extending through the skull base to the clivus. Following surgical resection, histological studies showed a paraganglioma, a tumor with a typical nesting pattern, abundant capillary net-work, and strong immunoreactivity for neuroendocrine mark-ers. Paragangliomas of the head and neck are rare tumors, which may come to the neuropathologist’s attention because of their propensity for intracranial spread. In particular, paragangliomas located in the nasopharynx may generate diagnostic difficulties, as they appear to have no connection with major paraganglia in the region. Morphologic criteria do not allow distinguishing between benign and malignant forms.

MARCH 2004 COM. A 24-year-old woman with bifrontal headaches was found to have a well-circumscribed lesion in the frontal lobe subcortical white matter. Microscopic examination showed clusters of small round cells separated by hypocellular neuropil-like areas, and a distinct border between tumor and surrounding white matter. Synaptophysin was diffusely positive in neuropil-like areas, and many tumor cells expressed NeuN. Based on these findings, a diagnosis of “extraventricular neu-rocytoma” was made. A double-label immunofluorescence stain was performed with NeuN and Ki-67 antibodies to determine if NeuN+ cells remained in the mitotic cycle. No colocalization of these markers was found, thus supporting the hypothesis that neuronal differentiation (as marked by NeuN expression) is in-compatible with continued proliferation of tumor cells, as well as normal neurons.

For a more complete discussion of these cases, additional micrographs, and information regarding submission of cases, please access the Brain Pathology web site at http://www.brainpathology.com. We welcome comments about these or similar cases our readers may have encountered.