Case 3 -

Monomorphous Angiocentric Glioma/Angiocentric Neuroepithelial Tumor Gregory N. Fuller, M.D., Ph.D. M. D. Anderson Cancer Center, Houston, TX

History A 4-year-old girl presented with a 2-month history of intractable seizures. An MRI scan revealed the presence of a 1.5cm diameter non-enhancing mass of the right fronto-parietal cerebral cortex. The mass was gross totally resected. Case 3 - Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer Diagnosis: Monomorphous Angiocentric Glioma/Angiocentric Neuroepithelial Tumor Discussion Historical background This clinicopathologic entity has only recently been described in two reports published independently and simultaneously in October 2005, by Lellouch-Tubiana and colleagues as Angiocentric Neuroepithelial Tumor, and by Wang and colleagues as Monomorphous Angiocentric Glioma – see References. Combining the two series, a total of 18 cases were reported. All of the tumors arose supratentorially in the cerebral hemisphere, and the clinical presentation in all cases was seizure disorder. The age at onset of seizures ranged from 2 – 23 years (mean 8 years old). The age at the time of surgery ranged from 2.3 to 37 years (mean 13 years old). The male:female incidence is equal (9 cases of each gender). The laterality is also equal (9 right cerebral hemisphere; 9 left cerebral hemisphere). The most common location is frontal lobe, with over half of the tumors arising in that location (10 cases, including one fronto-parietal and one fronto-temporal). The second most common site is the temporal lobe (4 cases), with 75% (3 of 4) of these originating in the mesial temporal lobe. The parietal lobe follows the temporal lobe closely in incidence (3 cases). The occipital lobe is the most rare location (only 1 case reported in the combined series of 18 cases). Neuroimaging features All cases reported to date are non-enhancing, cortically-centered tumors that also involve the underlying white matter. Best visualization is provided by T2 or fluid attenuation inversion recovery (FLAIR) sequences, in which the tumor appears uniformly hyperintense compared to the surrounding brain. Lellouch-Tubiana et al. called attention to two distinctive MRI features seen in their cases: a cortical rim of hyperintensity on T1 Spin Echo-weighted sequences, and subcortical hyperintensity extending as a narrow "stalk-like" band to the cerebral ventricle visualized on T2 and FLAIR sequences. Histology Tissue sections show a neoplasm with a monomorphous histologic architecture composed of spindled, bipolar glial tumor cells that diffusely infiltrate brain parenchyma and show a marked predilection for perivascular clustering. Subpial accumulation of tumor cells is also seen. The orientation of the bipolar tumor cells with respect to the surrounded blood vessels is parallel to the vascular wall for some vessels and perpendicular to the vessel wall for others. The latter orientation resembles ependymal perivascular pseudorosettes. An additional feature that is suggestive of ependymal differentiation is the presence of dot-like cytoplasmic positivity for epithelial membrane antigen (EMA), which was shown to correspond at the ultrastructural level to microlumens filled with microvilli, similar to those seen in ependymoma, in the single case studied by electron microscopy (Wang et al.). The tumor cells exhibit strong diffuse positivity for glial fibrillary acidic protein (GFAP). A distinctive perpendicular orientation of the tumor cells to the pial surface is focally present in some cases. Scattered mitotic figures may be present, which are more easily identified with an immunostain directed against the mitosis-specific marker phospho-histone H3 (pHH3). The Ki-67 (MIB-1) labeling index of the cases studied so far is low, ranging from 1-5%. Molecular features Genetic/molecular characterization is not yet available. Differential Diagnosis The clinical differential diagnosis, based on a cortically-based mass presenting in a child, adolescent or young adult with seizures, includes dysembryoplastic neuroepithelial tumor (DNET) and ganglioglioma. The histologic differential diagnosis includes diffuse astrocytoma, ependymoma and glioneuronal tumor. The apparent diffuse infiltration of brain parenchyma suggests diffuse astrocytoma. Focal perivascular pseudorosettes and dot-like EMA positivity suggest ependymoma. The scattered large cortical neurons/ganglion cells suggest glioneuronal tumor. Wang et al have interpreted this histologic feature as diffuse infiltration with entrapped normal cortical neurons, and Lellouch-Tubiana et al have interpreted it as evidence for a neuronal component. The latter authors chose the designation angiocentric neuroepithelial tumor (ANET) to suggest both a parallel and a contrast with dysembryoplastic neuroepithelial tumor (DNET). Both groups of investigators stress the distinctive histologic feature of bipolar tumor cells with pronounced perivascular tropism. Clinical Behavior This tumor appears to have a relatively favorable prognosis. A majority of the cases are reported to be stable without enlargement or recurrence after subtotal or gross total resection, with clinical follow-up ranging from 1 to 13 years (mean follow-up of approximately 4 years). However, a single case did recur, with increased mitotic activity, and was ultimately lethal. Extended follow-up and additional clinical experience with this tumor is needed. Hypothesis of embryologic origin from ependymoglia Based on several distinctive features, including the bipolar cellular morphology, ependymoma-like punctate cytoplasmic positivity for EMA, and apparent contiguity with the subventricular zone as seen on neuroimaging studies, Lellouch-Tubiana et al have speculated about a possible embryologic derivation from the ependymoglia (radial glia and tanycytes). Angiocentric Glioma as a Pitfall in Surgical Neuropathology Ten Common Surgical Pathology Pitfalls* Mistaking normal structures for pathological processes Mistaking non-neoplastic diseases for tumor Mistaking or one tumor type for another Unfamiliarity with rare tumor types Failure to recognize common tumors in uncommon sites Unfamiliarity with recently described disease entities Misleading artifacts Failure to recognize an inadequate or non-representative biopsy Failure to perform an appropriate diagnostic procedure Failure to formulate an appropriate differential diagnosis * Fuller GN, Aldape KD, Molecular genetics and neuropathology of intracranial tumors, in: M D Anderson Cancer Care Series: Tumors of the Brain and Spinal Cord. New York: Springer-Verlag, 2006. 10 New Types of Brain Tumor Described Over the Past 25 Years* Tumor Type Year Described Pleomorphic xanthoastrocytoma 1979 Central neurocytoma 1982 Dysembryoplastic neuroepithelial tumor 1988 Chordoid glioma 1998 Papillary glioneuronal tumor 1998-99 Rosetted glioneuronal tumor 1998-99 Pilomyxoid astrocytoma 1999 Rosette-forming glioneuronal tumor of the 4th ventricle 2002 Papillary tumor of the pineal region 2003 Monomorphous angiocentric bipolar glioma 2005 *Fuller GN, Aldape KD, Molecular genetics and neuropathology of intracranial tumors, In: M D Anderson Cancer Care Series: Tumors of the Brain and Spinal Cord. New York: Springer-Verlag, 2006. Clinical Follow-up of the Present Case The patient is alive and well with no sign of recurrent tumor five years after resection. References Monomorphous Angiocentric Glioma/Angiocentric Neuroepithelial Tumor Lellouch-Tubiana A, Boddaert N, Bourgeois M, Fohlen M, Jouvet A, Delalande O, Seidenwurm D, Brunelle F, Sainte-Rose C. Angiocentric neuroepithelial tumor (ANET): a new epilepsy-related clinicopathological entity with distinctive MRI. Brain Pathol. 2005;15:281-6. Wang M, Tihan T, Rojiani AM, Bodhireddy SR, Prayson RA, Iacuone JJ, Alles AJ, Donahue DJ, Hessler RB, Kim JH, Haas M, Rosenblum MK, Burger PC. Monomorphous angiocentric glioma: a distinctive epileptogenic neoplasm with features of infiltrating astrocytoma and ependymoma. J Neuropathol Exp Neurol. 2005;64:875-81. Burger PC and Scheithauer BW. Tumors of the Central Nervous System. AFIP Atlas of Tumor Pathology, 4th Series. Washington , DC : American Registry of Pathology, 2006. Chordoid Glioma Brat DJ, Scheithauer BW, Staugaitis SM, Cortez SC , Brecher K, Burger PC. Third ventricular chordoid glioma: a distinct clinicopathologic entity. J Neuropathol Exp Neurol. 1998;57:283-90. Leeds NE , Lang FF, Ribalta T, Sawaya R, Fuller GN. Origin of chordoid glioma of the third ventricle. Arch Pathol Lab Med. 2006;130:460-4. Papillary Tumor of the Pineal Region Jouvet A, et al. Papillary tumor of the pineal region. Am J Surg Path 27:505-512, 2003. Kuchelmeister K, Hugens-Penzel M, Jodicke A, Schachenmayr W. Papillary tumour of the pineal region: histodiagnostic considerations. Neuropathol Appl Neurobiol. 2006;32:203-8. Shibahara J, Todo T, Morita A, Mori H, Aoki S, Fukayama M. Papillary neuroepithelial tumor of the pineal region. A case report. Acta Neuropathol (Berl). 108(4):337-40, 2004. Vaquero J, Coca S, Martinez R, Escandon J. Papillary pineocytoma. Case report. J Neurosurg. 1990 Jul;73(1):135-7. Circumventricular Organs Fuller GN, Burger PC: Central nervous system. In: Mills SE, ed. Histology for Pathologists. 3rd ed. New York: Raven Press; 2006. Phospho-histone H3 (pHH3) Colman H, Giannini C, Huang L, Gonzalez J, Hess K, Bruner J, Fuller G, Langford L, Pelloski C, Aaron J, Burger P, Aldape K. Assessment and prognostic significance of mitotic index using the mitosis marker phospho-histone H3 in low-intermediate grade infiltrating astrocytomas. Amer J Surg Pathol 2006; in press. Ribalta T, McCutcheon IE, Aldape KD, Bruner JM, Fuller GN. The mitosis-specific antibody anti-phosphohistone-H3 (PHH3) facilitates rapid reliable grading of meningiomas according to WHO 2000 criteria. Am J Surg Pathol. 2004;28:1532-1536.