Angiocentric glioma has been recently recognized. Malignant glioma with angiocentric features. Case report

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1 J Neurosurg Pediatrics 11: , 2013 AANS, 2013 Malignant glioma with angiocentric features Case report Jian-Qiang Lu, M.D., Ph.D., 1 Samir Patel, M.D., 2 Beverly A. Wilson, M.D., 3 Jeffrey Pugh, M.D., 4 and Vivek Mehta, M.D. 4 Departments of 1 Laboratory Medicine and Pathology, 2 Oncology, 3 Pediatrics, and 4 Surgery, University of Alberta, Edmonton, Alberta, Canada Angiocentric glioma is a recently recognized benign brain tumor with unknown histogenesis. Most of these tumors are mitotically low in activity in accord with their benign clinical course. However, increased mitotic activity has been noted in several cases, one of which had an ultimately fatal outcome. Here, the authors present a tumor showing angiocentric glioma and glioblastoma-like features, with recurrence of the lower-grade component after radiotherapy. A 15-year-old boy presented with a 3-month history of progressive left-sided weakness and headache. Magnetic resonance imaging showed a large heterogeneous mass in the right frontal lobe, with mild post-gd enhancement. A gross-total resection was obtained. Histopathological examination of the resected tissue revealed a tumor with 2 distinct appearances: 1) a mildly to moderately cellular infiltrating tumor with angiocentric glioma characteristics, and 2) a markedly cellular glioblastoma-like tissue with necrosis and microvascular proliferation. The patient received a course of postoperative radiotherapy to 59.4 Gy in 33 fractions administered over the course of 6.5 weeks, but his tumor recurred 4 months after resection. A second resection was then performed. The recurrent tumor exhibited radiation-induced changes and persistent characteristics of angiocentric glioma, but it had fewer malignant features; the mitotic activity was lower, and there was no necrosis or microvascular proliferation. The findings in this case, along with those in several previously reported cases, suggest that angiocentric gliomas may have a malignant variant or malignant transformation. Angiocentric gliomas with malignant features tend to recur, for which surgical intervention followed by radiotherapy and chemotherapy should be offered as a therapeutic option. ( Key Words angiocentric glioma malignant transformation pathology radiotherapy anaplastic ependymoma glioblastoma oncology Angiocentric glioma has been recently recognized as a distinct clinicopathological entity in the revised 2007 WHO Classification of Tumours of the Central Nervous System. 2 It has been described as an epileptogenic benign (WHO Grade I) brain tumor that may be cured by excision alone. Its histogenesis remains unknown, but there are clearly features of ependymal differentiation. 6,17 Several dozen angiocentric gliomas have been reported to date, 6 8,12,14,15,17 but in only a few cases have mitoses been noted. 6,15,17 Several angiocentric Abbreviations used in this paper: EMA = epithelial membrane antigen; GTR = gross-total resection. gliomas, including those with mitoses, have been treated with radiotherapy, but the effects of radiotherapy have not been evaluated histologically. 6 8,15,17 Here, we present a unique tumor containing both angiocentric glioma and glioblastoma-like features, in which the anaplastic component was largely absent in the recurrent, posttreatment lesion. Case Report Presentation and Examination. This 15-year-old boy presented with a 3-month history of progressive left-sided 350 J Neurosurg: Pediatrics / Volume 11 / March 2013

2 Malignant glioma with angiocentric features weakness starting with his left hand. He also complained of headache, vomiting, and decreased visual acuity. Physical examination at admission revealed left hemiparesis. Craniospinal MRI showed a large ( cm) mass in the right frontal lobe. The mass was heterogeneously hypointense on T1-weighted images and heterogeneously hyperintense on T2-weighted images (Fig. 1A), and it mildly enhanced after Gd administration (Fig. 1B), which was associated with a 1.2-cm right-to-left midline shift and T2 hyperintense signal abnormality in the adjacent white matter. On diffusion-weighted imaging, the apparent diffusion coefficient of the mass was approximately mm 2 /sec and predominantly similar to that of the brain tissue (Fig. 1C). The mass on MR spectroscopy demonstrated a high choline content. Initial Resection. The patient underwent an emergency right frontal craniotomy. After the dura mater was incised, the mass was easily identified. Circumferential dissection of the planes was performed, and the mass was internally debulked and removed using the Cavitron ultrasonic aspirator. An intraoperative frozen section obtained from the periphery of that mass showed morphological features consistent with a glioma. A GTR was achieved. Histopathological Examination. On gross examination, the cm surgically excised tissue was soft, rubbery, and heterogeneous. Histopathological examination revealed a tumor with varying hypercellularity (Fig. 2). Most areas had mild to moderate hypercellularity with predominantly spindle-shaped cells and angiocentric growth pattern (Fig. 2A F), in which many tumor cells were radially and longitudinally aligned along the cerebral blood vessels (Fig. 2A). The subpial aggregation of neoplastic cells was also present (Fig. 2B, arrows). Infiltrating growth of this tumor into the adjacent brain parenchyma was obvious, with occasional entrapped neurons (Fig. 2C, arrow). Neurofilament protein immunoreactive axons were abundant in the tumor except for in the perivascular areas (Fig. 2D). This tumor was diffusely immunoreactive for GFAP (Fig. 2E) and vimentin. Epithelial membrane antigen immunostaining exhibited dotlike and ringlike positivity (Fig. 2F), suggestive of ependymal differentiation. In contrast, other areas of the tumor were markedly hypercellular, with scattered mitoses, microvascular proliferation (Fig. 2G), and necrosis (Fig. 2H). The MIB-1 labeling index of proliferation was moderately high (Fig. 2I), and IDH1 (R132H) immunostaining was negative. 9 Focal immunoreactivity for epidermal growth factor receptor was seen in this tumor (not shown). 5 Postoperative Radiotherapy. The resection resulted in improvement of the patient s facial asymmetry and strength on the left side (Fig. 3A). Postoperatively, it was noted that he had persistent visual loss. Ophthalmological examination revealed severe bilateral central visual loss. Moderate bilateral papilledema was found, which was suspected to exist prior to the resection. Cranial radiation (59.4 Gy in 33 fractions) was administered over a course of 6.5 weeks. During radiotherapy, the patient had continuous improvement in his left hemiparesis, but visual loss persisted. His family had noted a few episodes of possible seizures. An electroencephalographic study revealed moderate abnormalities and recorded 2 subclinical electrographic seizures, for which he started receiving Tegretol. Tumor Recurrence. A follow-up MRI study performed 5 weeks after radiation therapy (16 weeks after the resection) showed thickened enhancement after Gd administration in the medial aspect of the surgical margins (Fig. 3B), compared with the preradiation MRI study (Fig. 3A), which was highly suspicious for the tumor recurrence. Repeat MRI performed 11 weeks later revealed increased nodular tissue and more thickened enhancement post-gd preferentially along the resection cavity (Fig. 3C). The patient had increased left-sided weakness. Second Resection. After opening the dura, the tumor was relatively distinct from the brain tissue. Tumor lobules were dissected without difficulty, and superior frontal quadrant resection (GTR) was achieved. Histopathological Examination. The resected tissue, examined totally, measured cm in aggregate. Its histopathological features were somewhat similar to those of the primary resected tumor described earlier. Spindle-shaped cells (Fig. 4A) and an angiocentric growth pattern (Fig. 4A C) persisted in most areas. Radiation-induced changes, including cytological atypia particularly with increased eosinophilic cytoplasm (Fig. 4B) and tissue rarefaction (Fig. 4C), were focally prom- Fig. 1. Preoperative T2-weighted (A), Gd-enhanced T1-weighted (B), and diffusion-weighted (C) MR images revealing a heterogeneous tumor in the right frontal lobe. J Neurosurg: Pediatrics / Volume 11 / March

3 J. Q. Lu et al. Fig. 2. Photomicrographs of a tumor demonstrating the morphology of spindle-shaped cells preferentially aligned along the cerebral blood vessels (A), the subpial aggregation (B, arrows), and infiltrating growth with occasional entrapped neurons (C, arrow) and abundant neurofilament protein immunoreactive axons except the perivascular areas (D), immunoreactivity for GFAP (E), dotlike and ringlike immunoreactivity for EMA (F, arrow indicates ringlike positivity). The tumor shows focally malignant features with increased cellularity, microvascular proliferation (G), necrosis (H), and a high MIB-1 labeling index of proliferation (I). Original magnification 200 (A, B, and G), 400 (C, E, F, and I), and 100 (D and H). inent.3 Tumor cells were strongly immunoreactive for GFAP. Dotlike and ringlike EMA immunoreactivity was again present, which was consistent with the electron microscopy finding of microvilli in the cytoplasm of cells (Fig. 4D). Mitoses were rarely identified, and the MIB-1 labeling index was much lower than that of the primary tumor (Fig. 4E). Neither necrosis nor microvascular proliferation was found. This tumor was negative for p53, but it was largely immunoreactive for p16 (Fig. 4F). Postoperative Course. After the second resection, the patient developed increasing fatigue and left foot drop. Four weeks later, he was started on chemotherapy with oral temozolomide (400 mg daily for 5 days every month), which was scheduled for 10 cycles or months. The MRI studies performed at the 9-, 14-, and 30-week follow-up visits after the second resection revealed no tumor recurrence other than the postsurgical changes and no evidence of a metastatic lesion (Fig. 3D). Discussion To our knowledge this is the first report of a glioblastoma-like tumor containing the characteristic features of an angiocentric glioma. Angiocentric gliomas with increased mitotic activity have been previously reported in 3 case 352 studies. Table 1 summarizes the clinical, radiological, and pathological features, as well as the outcomes of those cases, in comparison with the present case. The present case, along with these 3 angiocentric glioma cases with anaplastic features, suggests that angiocentric glioma may have a malignant variant or malignant transformation. The cell origin of angiocentric glioma is unknown, but the presence of ependymal features has been noted by all authors.2,6 8,12,14,15,17 One suggestion is that angiocentric gliomas are variants of cortical ependymomas.16 Ependymal differentiation is expressed as an ultrastructural finding of the ependymal characteristics and immunohistochemical dotlike immunoreactivity for EMA.2,6 8,12,14,15,17 The diffusely infiltrating quality, often with prominent subpial accumulation, is, in contrast, not usually a feature of ependymomas. Our present case was otherwise consistent with a glioblastoma, except that angiocentric glioma and ependymal characteristics were also identified. Interestingly, our present case demonstrated 2 additional features: a modest value of the apparent diffusion coefficient on diffusion-weighted imaging in favor of ependymal differentiation,1,13 and the immunoreactivity for p16 tumor suppressor gene protein, which is more often seen with malignant astrocytomas than ependymal tumors.4,10,11 The absence of mutant IDH1 (R132H) protein expression, as reported in angiocentric gliomas, helps further distinj Neurosurg: Pediatrics / Volume 11 / March 2013

4 Malignant glioma with angiocentric features Fig. 3. Gadolinium-enhanced T1-weighted MR images obtained 3 weeks after the primary resection (A, preradiotherapy), 16 weeks after the primary resection (B, 5 weeks postradiotherapy, highly suspicious for tumor recurrence), and 27 weeks after the primary resection (C, 16 weeks postradiotherapy, confirming the tumor recurrence leading to its second resection). A further follow-up image obtained 30 weeks after the second resection (D, 58 weeks after the primary resection) shows no tumor recurrence. guish the present tumor from infiltrative astrocytomas (except for primary glioblastomas).9 Although angiocentric glioma has been regarded as an epileptogenic tumor, several previously reported patients with angiocentric gliomas did not initially present with seizures but with other symptoms, especially headache.7,12,17 In the present case, the presenting symptoms were leftsided weakness and headache, which may correspond to the patient s rapidly growing tumor with glioblastoma-like features. Although chronic atrophic papilledema may have contributed to the visual field loss, the cause of persistent visual loss in the present case is unknown. With regard to the prognosis, 2 previously reported angiocentric gliomas with anaplastic features recurred 12 and 21 months after their primary resection.6,17 The tumor in the present patient recurred 4 months after the primary resection and a second resection was performed. No recurrence was observed 7 months after the second resection. The histopathological features of the second resected tumor (lower mitotic activity and absence of necrosis and microvascular proliferation) were much less malignant than those of the primary resected tumor. These histopathological changes in the second resection may reflect the beneficial effects of the radiotherapy following the primary resection. No recurrence in the next 7 months after the second resection may also be accredited to the addition of high-dose temozolomide. Conclusions Angiocentric gliomas may undergo malignant transformation or include a malignant variant. The biological behavior of such lesions is unclear given the paucity of cases. Angiocentric gliomas with malignant features tend to recur, and their prognosis might be equivalent to that of glioblastoma or anaplastic ependymoma. These angio- Fig. 4. Photomicrographs of the recurrent tumor showing the retained morphology of the angiocentric growth of tumor cells (A C) and spindle-shaped cells (A), as well as radiation-induced changes including cytological atypia (B) and tissue rarefaction (C). D: Electron microscopy image demonstrating microvilli (arrow) in the cytoplasm of cells around the blood vessel. v = vascular lumen. E and F: The recurrent tumor exhibits lower MIB-1 labeling index of proliferation (E) but is largely immunoreactive for the p16 tumor suppressor gene protein (F). Original magnification 200 (A and B), 100 (C), 33,600 (D), and 400 (E and F). J Neurosurg: Pediatrics / Volume 11 / March

5 J. Q. Lu et al. TABLE 1: Reported cases with the features of angiocentric glioma and malignancy* Age at Op (yrs), Sex Clinical Presentation Location on Preop MRI Pathology Treatment Outcome Authors & Year recurrence (w/ seizures) at 21 mos; died of disease 62 mos after initial op initial PR; for recurrence, PR followed by 60 Gy RT over 6 wks in 30 fractions, & chemo (procarbazine, carmustine, & vincristine) features of AG & initially low-grade astrocytoma; recurrence w/ mitoses, diagnosed as anaplastic astrocytoma 26, M 2-yr Hx seizures lt frontal lobe, initially non contrastenhancing lesion Wang et al., 2005 no recurrence at 9-mo follow-up resection of lesion & surrounding epileptogenic cortex features of AG & mitoses (1/50 hpf; MIB-1 labeling index 8%) 6, M 5-mo Hx seizures rt occipitoparietal cortex, ill-defined high-signal lesion on FLAIR & T2- weighted MRI Sugita et al., 2008 recurrence (w/ irregularly enhanced lesion) after ~1 yr & growing gradually in deep white matter PR followed by RT & chemo (temozolomide) 2 different morphologies: features of AG; astrocytoma w/ mitoses & MIB-1 labeling index >5% rt insular gyri/anterior temporal lobe, large hyperintense lesion on FLAIR & T2-weighted MRI w/ postcontrast enhancement in insular region 66, F 6-yr Hx intermittent headaches, newonset seizures Miyahara et al., 2011 recurrence 16 wks after initial op; after 2nd op, no more recurrence at 30-wk follow-up initial GTR, followed by 59.4 Gy RT over 6.5 wks in 33 fractions; for recurrence, GTR followed by chemo (high-dose temozolomide) 2 distinct appearances: features of AG; malignant astrocytoma w/ mitoses, necrosis, & microvascular proliferation rt frontal lobe large ( cm) heterogeneously hyperintense lesion on T2-weighted MRI w/ mild postcontrast enhancement 15, M 3-mo Hx headaches & lt-sided weakness present case * AG = angiocentric glioma; chemo = chemotherapy; Hx = history of; PR = partial resection; RT = radiotherapy. centric gliomas with malignant features should be treated with radiotherapy and chemotherapy following GTR. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: all authors. Acquisition of data: all authors. Analysis and interpretation of data: all authors. Drafting the article: Lu, Patel, Wilson, Mehta. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Lu. Administrative/technical/material support: all authors. Study supervision: Lu, Mehta. Acknowledgments The authors thank Peter C. Burger, M.D., of the Department of Pathology at Johns Hopkins University, Baltimore, Maryland, for his help with the pathology diagnosis in this case and critical review of the manuscript, and Cynthia Hawkins, M.D., at The Hospital for Sick Children, Toronto, Ontario, Canada, for her help with preforming IDH1 and EGFR immunohistochemical studies. References 1. Bull JG, Saunders DE, Clark CA: Discrimination of paediatric brain tumours using apparent diffusion coefficient histograms. Eur Radiol 22: , Burger PC, Jouvet A, Preusser M, Hans VH, Rosenblum MK, Lellouch-Tubiana A: Angiocentric glioma, in Louis DN, Ohgaki H, Weistler OD, et al (eds): WHO Classification of Tumours of the Central Nervous System, ed 4. Lyon: IARC Press, 2007, pp Ellison DW, Perry A, Rosenblum M, Asa S, Reid R, Louis DN: Tumors: non-neuroepithelial tumors and secondary effects, in Love S, Louis DN, Ellison DW (eds): Greenfield s Neuropathology, ed 8. 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Am J Surg Pathol 31: , Raghunathan A, Olar A, Vogel H, Parker JR, Coventry SC, Debski R, et al: Isocitrate dehydrogenase 1 R132H mutation is not detected in angiocentric glioma. Ann Diagn Pathol 16: , Rajaram V, Leuthardt EC, Singh PK, Ojemann JG, Brat DJ, Prayson RA, et al: 9p21 and 13q14 dosages in ependymomas. A clinicopathologic study of 101 cases. Mod Pathol 17:9 14, Rao LS, Miller DC, Newcomb EW: Correlative immunohistochemistry and molecular genetic study of the inactivation of 354 J Neurosurg: Pediatrics / Volume 11 / March 2013

6 Malignant glioma with angiocentric features the p16ink4a genes in astrocytomas. Diagn Mol Pathol 6: , Rho GJ, Kim H, Kim HI, Ju MJ: A case of angiocentric glioma with unusual clinical and radiological features. J Korean Neurosurg Soc 49: , Rumboldt Z, Camacho DL, Lake D, Welsh CT, Castillo M: Apparent diffusion coefficients for differentiation of cerebellar tumors in children. AJNR Am J Neuroradiol 27: , Shakur SF, McGirt MJ, Johnson MW, Burger PC, Ahn E, Carson BS, et al: Angiocentric glioma: a case series. Clinical article. J Neurosurg Pediatr 3: , Sugita Y, Ono T, Ohshima K, Niino D, Ito M, Toda K, et al: Brain surface spindle cell glioma in a patient with medically intractable partial epilepsy: a variant of monomorphous angiocentric glioma? Neuropathology 28: , Van Gompel JJ, Koeller KK, Meyer FB, Marsh WR, Burger PC, Roncaroli F, et al: Cortical ependymoma: an unusual epileptogenic lesion. Clinical article. J Neurosurg 114: , Wang M, Tihan T, Rojiani AM, Bodhireddy SR, Prayson RA, Iacuone JJ, et al: Monomorphous angiocentric glioma: a distinctive epileptogenic neoplasm with features of infiltrating astrocytoma and ependymoma. J Neuropathol Exp Neurol 64: , 2005 Manuscript submitted April 29, Accepted November 12, Please include this information when citing this paper: published online December 14, 2012; DOI: / PEDS Address correspondence to: Jian-Qiang Lu, M.D., Ph.D., Neuropathology Section, 5B2.24 WCM Health Sciences Centre, University of Alberta, Street, Edmonton, Alberta, Canada T6G 2B7. jian-qiang.lu@ualberta.ca. J Neurosurg: Pediatrics / Volume 11 / March