In 2005, Wang and coworkers 1 described a report of 8

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1 Angiocentric Glioma A Clinicopathologic Review of 5 Tumors With Identification of Associated Cortical Dysplasia Trent Marburger, MD; Richard Prayson, MD N Context. Angiocentric glioma is a rare, epilepsy-associated, low-grade neoplasm with a characteristic perivascular growth pattern. Objective. To describe the clinicopathologic features of 5 angiocentric gliomas and to evaluate for coexistent malformation of cortical development/cortical dysplasia. Design. Retrospective review of the clinicopathologic features of 5 angiocentric gliomas (3 males and females; median age at surgery, 10 years; range, 3 19 years). Results. Seizures were the most common presenting symptom (n = 4); 1 patient presented with headaches. Four of the tumors were located in the parieto-occipital, parietal, or temporal cortex and 1 case arose in the thalamus. All tumors consisted of an angiocentric growth pattern of bipolar spindle cells with mild pleomorphism. Three tumors also demonstrated a focal solid growth pattern. Evidence of adjacent malformation of cortical development/focal cortical dysplasia was observed in 4 of 4 cases with sufficient tissue for evaluation; all were Palmini et al type I lesions (type IA, n = 1; type, n = 3). All patients were alive at last known follow-up ( months). Conclusions. The thalamic location of 1 tumor represents an undescribed location for this typically superficial cortical tumor. A subset of angiocentric gliomas, similar to other low-grade chronic epilepsy-related tumors of childhood, are associated with coexistent malformation of cortical development, suggesting a developmental basis to their origin. (Arch Pathol Lab Med. 011;135: ) In 005, Wang and coworkers 1 described a report of 8 cases of a superficial cerebral tumor with elements of both ependyma and astrocytoma and marked by an angiocentric growth pattern. They coined the term monomorphous angiocentric glioma for this tumor. Lellouch-Tubiana et al published a report at about the same time that described 10 cases of nearly identical tumors, which they designated angiocentric neuroepithelial tumors. These tumors were subsequently codified as a distinct clinicopathologic entity in the 007 World Health Organization (WHO) Classification of Tumours of the Central Nervous System 3 and were given the name angiocentric glioma. These low-grade neoplasms (WHO grade I) typically present with chronic epilepsy and demonstrate a characteristic angiocentric growth pattern, an infiltrative border, and ultrastructural features of ependymal differentiation. A recent review of the literature by Mott et al 4 affirmed that these cortical-based tumors are primarily found in the pediatric population with no sex predilection. More than 90% of reported patients with angiocentric gliomas have presented with seizures. 4 Many of the pediatric tumors that present with chronic epilepsy, such Accepted for publication December 1, 010. From the Department of Pathology, Cleveland Clinic, Cleveland, Ohio. The authors have no relevant financial interest in the products or companies described in this article. Correspondence: Trent Marburger, MD, Anatomic & Clinical Pathology, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH ( marburt@ccf.org). as ganglioglioma and dysembryoplastic neuroepithelial tumor, are associated with adjacent abnormal cortical architecture (malformation of cortical development [MCD] or focal cortical dysplasia). 5 8 The purpose of this study is to review the clinicopathologic features of 5 angiocentric gliomas and to evaluate for adjacent coexistent MCD or focal cortical dysplasia. MATERIALS AND METHODS Institutional review board approval was attained prior to commencement of the study. The pathology files were searched during a 0-year period of time ( ) for tumors diagnosed as angiocentric glioma or tumors with pathologic descriptions potentially representing angiocentric glioma. Five patients were identified and all available pathologic materials were reviewed; a diagnosis was confirmed in all 5 cases. These 5 patients (3 males and females; median age at surgery, 10 years; range, 3 19 years) comprised the study group. Criteria used for diagnosis included those outlined by the 007 WHO Classification of Tumours of the Central Nervous System. 3 Histologic features evaluated included the extent of solid versus angiocentric growth pattern, cell morphology, calcifications, mitoses, necrosis, and vascular proliferation. Immunohistochemical analyses were performed using formalin-fixed, paraffin-embedded tissue sections, avidin-biotin-peroxidase methodology, and an automated immunostainer (BenchMark XT system, Ventana Medical Systems, Tucson, Arizona). Ki-67 (prediluted; Ventana) labeling indices were determined for cases in which staining had been performed. Labeling indices were determined by assessing 1000 tumor cell nuclei in the area of tumor with the most staining and expressing positive-staining tumor nuclei as a percentage. In tumors for which there was sufficient adjacent nontumor tissue resected, an assessment for MCD/focal cortical dysplasia Arch Pathol Lab Med Vol 135, August 011 Angiocentric Glioma Marburger & Prayson 1037

2 was made using the Palmini et al 9 classification. Palmini et al 9 focal cortical dysplasia type IA is marked by isolated architectural abnormalities (dyslamination that may or may not be accompanied by ectopically placed neurons in or adjacent to cortical layer I and/or microscopic neuronal heterotopia outside layer I). Focal cortical dysplasia type is additionally marked by giant or immature neurons. Type IIA focal cortical dysplasia additionally shows evidence of dysmorphic neurons, and type I is marked by the presence of balloon cells. The medical record was reviewed in each case for clinical information, including patient age and sex, clinical presentation, location of tumor, extent of, use of adjuvant radiation or chemotherapy, and status at last known follow-up. RESULTS A summary of the clinical features of all 5 patients in the current series is contained in Table 1. The 5 patients consisted of 3 males and females with a median age at surgery of 10 years (range, 3 19 years). Seizures were the most common presenting symptom (n 5 4); 1 patient presented with headaches. The duration of presurgical neurologic symptoms was known for 3 patients and was 1 year, years, and greater than 8 years. Four of the tumors were located in superficial cerebrocortical locations ( parieto-occipital cortex, 1 parietal cortex, and 1 temporal cortex; Figure 1, A) and 1 case arose in the thalamus. Three patients underwent a gross total of the tumor and 1 patient underwent a subtotal of his tumor. A biopsy only of the thalamic tumor was taken. No adjuvant chemotherapy or radiotherapy was administered following surgery. Each patient s postoperative seizure activity was compared to his or her preoperative activity and categorized using the Engel classification 10 to assess the efficacy of these surgical interventions. All cases with gross total (3 of 3) showed complete cessation of seizure symptoms (Engel class I) or only nondisabling simple partial seizures. In the single case with subtotal, only mild improvement in seizure symptoms with no worthwhile improvement was reported (Engel class IV). Clinical follow-up revealed a favorable prognosis, with all patients alive at last known follow-up (median follow-up of 3 years; range,,1 10 years). No tumor recurrence following gross total (n 5 3) was observed. Histologic features of the tumors studied are summarized in Table. All 5 tumors consisted of an angiocentric growth pattern of bipolar spindle cells with slender nuclei that radiate from a central vessel to form pseudorosette structures (Figure 1, B). Three tumors also demonstrated a focal solid growth pattern with areas of nested epithelioid cells and compacted perivascular pseudorosette formations of spindled cells, similar to those in the remainder of the tumor (Figure 1, C). An infiltrative border was discernable in 3 of 4 cases with sufficient tissue for evaluation (Figure 1, D). Subpial aggregation of streaming spindled tumor cells was observed in 4 of 4 cases with sufficient tissue for evaluation (Figure 1, E). Two cases exhibited a population of cells resembling oligodendroglial cells with rounded nuclei, scant cytoplasm, and focal pericellular clearing. Calcifications (n 5 ) and microcystic change (n 5 1; Figure 1, C) were observed in a minority of cases. Mitotic activity, necrosis, vascular proliferation, and meningeal extension were not observed. Ki-67 labeling indices were less than 4% in all cases (Figure 1, F). Evidence of adjacent MCD/focal cortical dysplasia was observed in 4 of 4 cases with sufficient tissue for evaluation; all were Palmini et al 9 type I lesions. One case demonstrated abnormal cortical layering with an absence of layer II (Figure, A through C). A malpositioning of pyramidal-type neurons was rarely observed in the molecular layer and was focally evident at the interface of the molecular layer and the subjacent layer III. A misalignment of large pyramidal neurons within layers III and IV was observed. These findings are consistent with a Palmini et al 9 type IA focal cortical dysplasia. The remaining 3 cases of focal cortical dysplasia were marked by an absence of layer II, occasional large pyramidal-type neurons (neuronal cytomegaly) malpositioned in cortical layer I or superficial layer III, and a malalignment of pyramidal-type neurons within cortical layers III and V. These findings are consistent with a Palmini et al 9 type focal cortical dysplasia. One of these cases additionally showed abnormal neuronal cytoplasmic processes Case No. Table 1. Summary of Angiocentric Glioma Clinical Features Age At Diagnosis, y/sex Presentation a Location Laterality Surgery 1 10/F Seizures (class I) Parieto-occipital cortex 15/M Seizures (class IV), visual disturbance, headaches 3 19/M Seizures (class I) Parietal cortex Left Total 4 3/F Seizures (class I) Temporal cortex Left Total 5 15/M Headache and visual disturbance Abbreviations: ANET, alive with no evidence of tumor; AWT, alive with tumor. a Engel classification of seizures is given in parentheses. Adjuvant Therapy Time, mo Follow-up Status Left Total None 131 ANET Temporal cortex Left Subtotal None 103 AWT Seizures, headaches None 44 ANET (when taking medications) None 7 ANET (unmedicated) Thalamus Right Biopsy None 17 AWT Headaches, seizure-free 1038 Arch Pathol Lab Med Vol 135, August 011 Angiocentric Glioma Marburger & Prayson

3 Figure 1. A, This T-weighted magnetic resonance imaging of an angiocentric glioma in the left parieto-occipital region demonstrates the typical superficial nature of these predominantly cortical-based tumors. B, Angiocentric glioma with bipolar spindled cells demonstrating a characteristic perivascular pseudorosette growth pattern. C, Angiocentric glioma demonstrating a solid growth pattern with microcyst formation and perivascular rosettes. D, Angiocentric glioma (upper right corner) demonstrating an infiltrative border with adjacent cortical tissue (lower left corner). E, Area adjacent to angiocentric glioma marked by a subpial aggregation of infiltrating tumor cells. F, Ki-67 labeling of angiocentric glioma showing a paucity of reactive cells. This case demonstrated Ki-67 labeling indices of less than 1% (hematoxylin-eosin, original magnifications 300 [B, C, and D] and 3100 [E]; Ki-67, original magnification 3400 [F]). Arch Pathol Lab Med Vol 135, August 011 Angiocentric Glioma Marburger & Prayson 1039

4 Table. Case Calcification Solid Component Summary of Angiocentric Glioma Pathologic Featuresa Pleomorphism Ki-67 Labeling Index Subpial Aggregation 0% 4% Infiltrative Border Focal Cortical Dysplasia Typeb IA Abbreviation:, not available. a b Mitotic activity, necrosis, vascular proliferation, and meningeal extension were not observed. Palmini et al9 classification. suggestive of a dysmorphic neuron (possible Palmini et al9 type IIA focal cortical dysplasia; Figure, D). COMMENT Angiocentric glioma is a low-grade (WHO grade I) cerebrocortical tumor of childhood with a characteristic angiocentric growth pattern.3 More than 90% of reported angiocentric gliomas have presented with chronic epilepsy, and excision alone has most often proved curative.4 Imaging studies of these tumors demonstrate hyperintensity on T-weighted and fluid-attenuated inversion recovery magnetic resonance imaging without contrast enhancement. Clinically, our 5 patients closely resemble those previously reported. Our identification of a thalamic angiocentric glioma and the recent report of an Angiocentric Glioma-like Tumor of the Midbrain by Covington et al11 suggest that they may less commonly arise in other locations in the brain. Figure. A, Section taken from the right temporal lobe of an autopsy case showing the normal layering pattern of the superficial cortex. B, Area adjacent to angiocentric glioma marked by a malformation of cortical development (Palmini et al9 focal cortical dysplasia type IA) characterized by an absence of cortical layer II. C, Higher-magnification appearance of B highlighting the interface between the molecular layer of the cortex and the large pyramidal-type neurons that typically make up part of cortical layer III (external pyramidal layer). D, A Bodian stain highlighting the abnormal cell processes of a large neuron situated at the deep aspect of cortical layer I, suggestive of a dysmorphic neuron (hematoxylin-eosin, original magnifications 3100 [A and B] and 300 [C]; Bodian, original magnification 300 [D]) Arch Pathol Lab Med Vol 135, August 011 Angiocentric Glioma Marburger & Prayson

5 Histopathologically, angiocentric glioma exhibits a perivascular growth pattern of bipolar spindle cells with mild pleomorphism, an infiltrative border, and lack of high-grade features such as elevated mitotic activity, necrosis, vascular proliferation, and meningeal extension. All 5 tumors in the current study consisted predominantly of this characteristic angiocentric growth pattern. An infiltrative border was discernable in 3 of 4 cases with sufficient tissue for evaluation. Immunohistochemical staining of angiocentric gliomas is typically positive with antibodies to glial fibrillary acidic protein, S-100 protein, and vimentin. 3 A dotlike pattern of immunoreactivity to epithelial membrane antigen, similar to what may be encountered in some ependymomas, has also been described. 3 Ki-67 labeling indices were less than 4% in all 5 cases presented here, which is well within the 1% to 5% range previously reported for angiocentric glioma and in keeping with the low-grade nature of the tumor. 3 Ultrastructurally, these tumors reportedly show evidence of ependymal differentiation, with cilia and microvillifilled microlumens bounded by elongated intermediate junctions. 1 The prognosis of these stable or very slow-growing tumors is excellent, following complete surgical excision. In the 5 tumors reported here, all cases with gross total (3 of 3) showed complete cessation of seizure symptoms (Engel class I) or only nondisabling simple partial seizures. No tumor recurrence following gross total (n 5 3) was observed. 10 In the single case with subtotal, only mild improvement in seizure symptoms was reported (Engel class IV). 10 Evaluation of coexistent pathology in chronic epilepsy patients with neoplasms has revealed MCD/cortical dysplasia associated with a number of tumor types. Many of the pediatric tumors that present with chronic epilepsy, such as ganglioglioma and dysembryoplastic neuroepithelial tumor, are associated with adjacent abnormal cortical architecture (MCD or focal cortical dysplasia). 5 8 A recently published study 1 found that MCD or focal cortical dysplasia was identified in 40 of 50 patients with chronic epilepsy-associated tumors and demonstrated that the majority of these displayed Palmini et al 9 type I lesions. Evaluation for coexistent MCD/cortical dysplasia in the 5 tumors reported here revealed the presence of these abnormalities in 4 of 4 cases with sufficient tissue for evaluation; all were Palmini et al 9 type I lesions. The nature of the relationship between angiocentric gliomas and MCD/cortical dysplasia is not known. The coexistence here, as with the gangliogliomas and dysembryoplastic neuroepithelial tumor, suggests a probable developmental basis to the origin of these tumors. The histogenesis of angiocentric glioma is a subject of debate, with postulated ependymal or radial glial cell origin. The differentiation of these tumors appears ependymal in nature when one considers the angiocentric growth pattern, immunohistochemical profile including a dotlike pattern of immunoreactivity to epithelial membrane antigen, and ultrastructural findings. 3 The cortical location of the great majority of these tumors, however, argues against derivation from native ependymocytes or tanycytes. 3 Lellouch-Tubiana et al proposed a dysembryoplastic process with a radial glial cell origin for angiocentric gliomas, citing a cytologic resemblance of radial glial cells to those of angiocentric glioma. The differential diagnosis of angiocentric glioma should include ependymoma and pilomyxoid astrocytoma. Ependymomas share a number of features with angiocentric gliomas, including a predilection for the pediatric patient population, an angiocentric growth pattern with pseudorosette formation, immunohistochemical reactivity with epithelial membrane antigen in a dotlike pattern, and ultrastructural studies demonstrating cilia and microvilli-filled microlumens bounded by elongated intermediate junctions. 1 Angiocentric glioma differs from ependymoma by its cortical location, diffuse and infiltrative growth pattern, and prominent bipolar spindle cell morphology, not typical of ependymoma. 1 Pilomyxoid astrocytomas arise predominantly in a pediatric patient population, most often occur in the hypothalamic/ chiasmatic region, and demonstrate contrast enhancement on imaging studies. 13 Pilomyxoid astrocytomas may histologically resemble angiocentric gliomas with a vasculocentric arrangement of bipolar spindled tumor cells, but demonstrate a noninfiltrative growth pattern and prominent mucinous background, not typical of angiocentric glioma. 1 In summary, we report a retrospective review of 5 angiocentric gliomas that exhibit similar features to previously reported cases of this low-grade epilepsyassociated pediatric tumor. The thalamic location of 1 tumor represents an undescribed location for this typically cerebrocortical tumor. A subset of angiocentric gliomas, similar to other low-grade chronic epilepsy-related tumors of childhood, are associated with coexistent MCD/ focal cortical dysplasia, suggesting a developmental basis to their origin. References 1. Wang M, Tihan T, Rojiani AM, et al. Monomorphous angiocentric glioma: a distinctive epileptogenic neoplasm with features of infiltrating astrocytoma and ependymoma. J Neuropathol Exp Neurol. 005;64(10): Lellouch-Tubiana A, Boddaert N, Bourgeois M, et al. Angiocentric neuroepithelial tumor (ANET): a new epilepsy-related clinicopathological entity with distinctive MRI. Brain Pathol. 005;15(4): Burger PC, Jouvet A, Preusser M, Hans VH, Rosenblum MK, Lellouch- Tubiana A. Angiocentric glioma. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, eds. WHO Classification of Tumours of the Central Nervous System. 4th ed. 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Neurology. 004;6(6)(suppl 3):S S Engel J Jr, Van Ness PC, Rasmussen TB. Outcome with respect to epileptic seizures. In: Engel J Jr, ed. Surgical Treatment of the Epilepsies. nd ed. New York, NY: Raven Press Ltd; 1993: Covington DB, Rosenblum MK, Brathwaite CD, Sandberg DI. Angiocentric glioma-like tumor of the midbrain. Pediatr Neurosurg. 009;45(6): Prayson RA, Fong J, Najm I. Coexistent pathology in chronic epilepsy patients with neoplasms. Mod Pathol. 010;3(8): Scheithauer BW, Hawkins C, Tihan T, VandenBerg SR, Burger PC. Pilocytic astrocytoma. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, eds. WHO Classification of Tumours of the Central Nervous System. Lyon, France: IARC Press; 007:14 1. Arch Pathol Lab Med Vol 135, August 011 Angiocentric Glioma Marburger & Prayson 1041