G l i a l Tu m o r s wi t h Neuronal D iffere ntiation Chul-Kee Park, MD, PhDa,*, Ji Hoon Phi, MD, PhDb, Sung-Hye Park, MD, PhDc KEYWORDS Neuronal differentiation Rosette-forming glioneuronal tumor of the fourth ventricle Papillary glioneuronal tumor Glioneuronal tumors without pseudopapillary architecture Glioneuronal tumor with neuropil-like islands Malignant glioneuronal tumor
KEY POINTS The rosette-forming glioneuronal tumor of the fourth ventricle (RGNT) frequently develops at a young age, locates in the cerebellum, and is benign in most cases. The papillary glioneuronal tumor (PGNT) is benign, but a high proliferative index should be considered separately to determine the potential of aggressive behavior. The glioneuronal tumor without pseudopapillary architecture (GNT) has the possibility of differentiating behavior compared with PGNT. In pediatric and adolescent patients, spinal glioneuronal tumor with neuropil-like islands (GTNI) shows aggressive clinical behavior regardless of the World Health Organization (WHO) grade of the glial components. The malignant glioneuronal tumor (MGNT) in the form of diffuse leptomeningeal glioneuronal tumors is of interest for possible unique disease entities.
Tumors of neuroepithelial tissues in the central nervous system include diverse mixtures of glial and/or neuronal differentiated tumor cells with variable histologic grades. With more sophisticated immunohistochemical studies, subsets of classic glial or neuronal tumors have been further classified into tumors having both characteristics of glial and neuronal lineages. The glial and neuronal markers can be identified by combined staining of a single type of tumor simultaneously or by use of 2 different stains, exclusively. The clinical significance of these unclassified (ie, gray-zone) tumors is yet to be confirmed. One of the most remarkable changes proposed in the fourth edition of the WHO classification of
tumors of the central nervous system, which was published in 2007, is the incorporation of new entities, variants, and patterns of neuronal and/or glial tumors.1,2 Traditionally, categories of neuronal and mixed neuronal-glial tumors included the diagnosis of dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos), desmoplastic infantile astrocytoma/ganglioglioma, dyembryoplastic neuroepithelial tumor (DNET), gangliocytoma, ganglioglioma, anaplastic ganglioglioma, central neurocytoma, cerebellar liponeurocytoma, and paraganglioma of the filum terminale.1 Three new entities, however, were added to this category in the 2007 WHO classification.1 They are the rosette-forming glioneuronal tumor (RGNT), PGNT, and extraventricular neurocytoma (EVN), which consist of almost entirely benign lesions.1
a Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea; b Division of Pediatric Neurosurgery, Department of Neurosurgery, Seoul National University Children’s Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea; c Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea * Corresponding author. E-mail address: [email protected]
Neurosurg Clin N Am 26 (2015) 117–138 http://dx.doi.org/10.1016/j.nec.2014.09.006 1042-3680/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
neurosurgery.theclinics.com
INTRODUCTION
118
Park et al The main difference between newly introduced glial tumors with neuronal differentiation and conventional ganglioglioma is that the former has cells with a broad spectrum of neuronal differentiation, whereas the ganglioglioma tumor contains mature neurons.3 Controversies still exist, however, concerning the spectrum of glial tumors with neuronal differentiation, and the definition of their clinical significance should be further established.3 Candidates of particular interest, which have yet to be included in this disease spectrum, include the GNTs, and GTNIs. Previous studies described GTNI synonymously with rosette-forming glioneuronal tumors, which should not be confused with RGNTs. In addition, atypical or aggressive forms of PGNT and GNT need to be studied, and the extreme variants of malignant glioneuronal tumors (MGNTs) should also be further evaluated.3 This article reviews the literature as well as several series reports on RGNT, PGNT, GNT, GTNI, and MGNT, focusing on clinical aspects of these diseases.
ROSETTE-FORMING GLIONEURONAL TUMORS OF THE FOURTH VENTRICLE RGNTs are a rare benign tumor type arising in the cerebellum adjacent to the fourth ventricle. In 1995, a case of a benign-appearing tumor in the inferior vermis of a 28-year-old patient, consisting of oligodendrocyte-like cells with prominent rosette formation and microcystic astrocytoma, was reported.4 The clinicians diagnosed the lesion as a DNET of the cerebellum.4 This case was the first description of RGNT, with typical characteristics of location in the cerebellum, young age onset, benign histology and clinical course, rosette formation, and a neuronal/glial differentiation pattern. Komori and colleagues5 described a series of 11 patients with similar lesions and termed the disease RGNT. The number of reported cases has steadily increased, especially after the adoption of RGNT as a new entity in the 2007 WHO classification of brain tumors.1,2 Recently published meta-analyses of the RGNT included 85 cases of RGNT reported from 1998 to 2012.6 The median age at diagnosis was 27 years (range 6–79 years), and there was a slight female predominance.6 The tumor location was one of the defining features of the tumor type; hence, the name includes the phrase, “of the fourth ventricle.” RGNT is typically located in the fourth ventricle, with possible extension into the cerebellar vermis, cerebellar hemisphere, and brainstem. However, atypical tumor locations of RGNT in the tectal/pineal region, septum pellucidum, and spinal cord have been reported.7–9 In the meta-analyses of
85 patients, typical posterior fossa locations were found in 68 patients (80%), 13 patients (15%) had supratentorial tumors, and 1 patient had a spinal tumor.6 Multifocal tumor locations have also been reported.5,10,11 A patient with multifocal masses in the cerebellum and cerebellopontine angle also showed spinal intramedullary lesions and spinal leptomeningeal enhancement, suggesting the possibility of widespread seeding (metastasis) of RGNT.11 In the authors’ clinic, 3 patients with RGNT were all female, and the ages at initial diagnosis were 6, 13, and 15 years. The tumors were located in the cerebellar vermis (1 patient) or cerebellar hemisphere (2 patients). In 2000, a 13-year-old girl with a large cystic rim-enhancing mass in the vermis had surgical removal, and, at that time, her pathologic diagnosis was pilocytic astrocytoma (Fig. 1A). Ten years later, follow-up imaging revealed a nonenhancing lesion growing in the operative bed. Reoperation and pathologic classification, according to the current knowledge base, indicated it was RGNT rather than pilocytic astrocytoma (see Fig. 1B). The case illustrated the challenges of rapidly changing diagnostic criteria and classification imposed on neurosurgeons and pathologists. The majority of RGNT was situated in the posterior fossa. Therefore, headache was the most common symptom due to the obstructive hydrocephalus.2 Nausea/vomiting, ataxia, and visual disturbances were also common manifestationsd.6 Radiologic characteristics on MRI of RGNT revealed a relatively circumscribed tumor with discernible margins.6 MRI usually showed low signal intensity in T1-weighted images and high signal intensity in T2-weighted images.6 The tumors frequently showed gadolinium enhancement and could be solid, cystic, or mixed solid and/or cystic in type.5 Intratumoral calcification was inconsistently found.6 RGNT is a benign and indolent tumor, and, based on reported clinical experience and the current WHO classification, it corresponds to a grade 1 tumor.2 As is common for low-grade brain tumors, surgery is the primary treatment. In the meta-analyses results, complete tumor resection was reported in 36 of 63 evaluated cases.6 The results of radiation therapy for RGNT were limited because only a few patients received adjuvant radiation after surgery. Recurrence of RGNT was an uncommon event and only 4 of 52 patients experienced tumor recurrence.6 In the authors’ study, however, 1 patient experienced a recurred RGNT at 10 years after the initial operation (see Fig. 1). Therefore, long-term follow-up is mandatory after surgery. Results from the patient with
Glial Tumors with Neuronal Differentiation
Fig. 1. A case of recurrence of a rosette-forming glioneuronal tumor (RGNT). (A) Initial presentation at 13 years of age shows a huge cystic mass in the vermis accompanied by hydrocephalus (left). The tumor was completely removed and the diagnosis at that time was pilocytic astrocytoma. Ten years later, a recurred nonenhancing mass (arrow, right) was found at the operative bed on routine surveillance imaging (right). It was removed again and found to be RGNT based on the revised 2007 WHO classification. (B) Histologic features show characteristics of RGNT in a recurrent tumor. Light microscopy of RGNT, showing numerous small rosettes with central pink neuropillike cores. The tumor cells have uniform small round nuclei and clear cytoplasm (hematoxylin-eosin stain, 400). The cores of the rosettes are robustly positive for synaptophysin and microtubule-associated protein 2 (MAP2).
leptomeningeal seeding (discussed previously) also raised concerns about the nature of the RGNT, because there may be more genetic/clinical heterogeneity in this benign neoplasm.11
PAPILLARY GLIONEURONAL TUMOR The first established study of PGNT reported a series of 9 cases.12 Original studies were published in 1997, however, under the description, “pseudopapillary neurocytoma with glial differentiation.”13 Since then, a total of 69 cases have been reported in the literature.12–56 For the purpose of metaanalyses, 12 cases from the authors’ institute, including 5 previously reported cases, were combined with the reported cases for a total 76 cases (Table 1).47,49 Histologic features of PGNT include
the pseudopapillary architecture of glial cells with interpapillary collections of oligodendroglia-like neurocytic cells (Fig. 2).57 No prominent mitosis, necrosis, and vascular proliferation were observed. In general, the proliferative index was low, but there were subsets of cases with an increased Ki-67 index.29,32–34,36,40,44,49,50,55 There was no difference in male-to-female ratio. The age distribution ranged from 3 to 75 years (mean, 26.3 years). A strong preponderance for affecting young adults and children was observed, however, and 82.9% of the patients were younger than 40 years of age (see Fig. 2). The relative proportion of patients with a high proliferative index (Ki-67 5%), however, was greater in the older age group (62.5% in age 40 years) than in the younger age group (26.0% in age
KEY POINTS The rosette-forming glioneuronal tumor of the fourth ventricle (RGNT) frequently develops at a young age, locates in the cerebellum, and is benign in most cases. The papillary glioneuronal tumor (PGNT) is benign, but a high proliferative index should be considered separately to determine the potential of aggressive behavior. The glioneuronal tumor without pseudopapillary architecture (GNT) has the possibility of differentiating behavior compared with PGNT. In pediatric and adolescent patients, spinal glioneuronal tumor with neuropil-like islands (GTNI) shows aggressive clinical behavior regardless of the World Health Organization (WHO) grade of the glial components. The malignant glioneuronal tumor (MGNT) in the form of diffuse leptomeningeal glioneuronal tumors is of interest for possible unique disease entities.
Tumors of neuroepithelial tissues in the central nervous system include diverse mixtures of glial and/or neuronal differentiated tumor cells with variable histologic grades. With more sophisticated immunohistochemical studies, subsets of classic glial or neuronal tumors have been further classified into tumors having both characteristics of glial and neuronal lineages. The glial and neuronal markers can be identified by combined staining of a single type of tumor simultaneously or by use of 2 different stains, exclusively. The clinical significance of these unclassified (ie, gray-zone) tumors is yet to be confirmed. One of the most remarkable changes proposed in the fourth edition of the WHO classification of
tumors of the central nervous system, which was published in 2007, is the incorporation of new entities, variants, and patterns of neuronal and/or glial tumors.1,2 Traditionally, categories of neuronal and mixed neuronal-glial tumors included the diagnosis of dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos), desmoplastic infantile astrocytoma/ganglioglioma, dyembryoplastic neuroepithelial tumor (DNET), gangliocytoma, ganglioglioma, anaplastic ganglioglioma, central neurocytoma, cerebellar liponeurocytoma, and paraganglioma of the filum terminale.1 Three new entities, however, were added to this category in the 2007 WHO classification.1 They are the rosette-forming glioneuronal tumor (RGNT), PGNT, and extraventricular neurocytoma (EVN), which consist of almost entirely benign lesions.1
a Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea; b Division of Pediatric Neurosurgery, Department of Neurosurgery, Seoul National University Children’s Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea; c Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea * Corresponding author. E-mail address: [email protected]
Neurosurg Clin N Am 26 (2015) 117–138 http://dx.doi.org/10.1016/j.nec.2014.09.006 1042-3680/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
neurosurgery.theclinics.com
INTRODUCTION
118
Park et al The main difference between newly introduced glial tumors with neuronal differentiation and conventional ganglioglioma is that the former has cells with a broad spectrum of neuronal differentiation, whereas the ganglioglioma tumor contains mature neurons.3 Controversies still exist, however, concerning the spectrum of glial tumors with neuronal differentiation, and the definition of their clinical significance should be further established.3 Candidates of particular interest, which have yet to be included in this disease spectrum, include the GNTs, and GTNIs. Previous studies described GTNI synonymously with rosette-forming glioneuronal tumors, which should not be confused with RGNTs. In addition, atypical or aggressive forms of PGNT and GNT need to be studied, and the extreme variants of malignant glioneuronal tumors (MGNTs) should also be further evaluated.3 This article reviews the literature as well as several series reports on RGNT, PGNT, GNT, GTNI, and MGNT, focusing on clinical aspects of these diseases.
ROSETTE-FORMING GLIONEURONAL TUMORS OF THE FOURTH VENTRICLE RGNTs are a rare benign tumor type arising in the cerebellum adjacent to the fourth ventricle. In 1995, a case of a benign-appearing tumor in the inferior vermis of a 28-year-old patient, consisting of oligodendrocyte-like cells with prominent rosette formation and microcystic astrocytoma, was reported.4 The clinicians diagnosed the lesion as a DNET of the cerebellum.4 This case was the first description of RGNT, with typical characteristics of location in the cerebellum, young age onset, benign histology and clinical course, rosette formation, and a neuronal/glial differentiation pattern. Komori and colleagues5 described a series of 11 patients with similar lesions and termed the disease RGNT. The number of reported cases has steadily increased, especially after the adoption of RGNT as a new entity in the 2007 WHO classification of brain tumors.1,2 Recently published meta-analyses of the RGNT included 85 cases of RGNT reported from 1998 to 2012.6 The median age at diagnosis was 27 years (range 6–79 years), and there was a slight female predominance.6 The tumor location was one of the defining features of the tumor type; hence, the name includes the phrase, “of the fourth ventricle.” RGNT is typically located in the fourth ventricle, with possible extension into the cerebellar vermis, cerebellar hemisphere, and brainstem. However, atypical tumor locations of RGNT in the tectal/pineal region, septum pellucidum, and spinal cord have been reported.7–9 In the meta-analyses of
85 patients, typical posterior fossa locations were found in 68 patients (80%), 13 patients (15%) had supratentorial tumors, and 1 patient had a spinal tumor.6 Multifocal tumor locations have also been reported.5,10,11 A patient with multifocal masses in the cerebellum and cerebellopontine angle also showed spinal intramedullary lesions and spinal leptomeningeal enhancement, suggesting the possibility of widespread seeding (metastasis) of RGNT.11 In the authors’ clinic, 3 patients with RGNT were all female, and the ages at initial diagnosis were 6, 13, and 15 years. The tumors were located in the cerebellar vermis (1 patient) or cerebellar hemisphere (2 patients). In 2000, a 13-year-old girl with a large cystic rim-enhancing mass in the vermis had surgical removal, and, at that time, her pathologic diagnosis was pilocytic astrocytoma (Fig. 1A). Ten years later, follow-up imaging revealed a nonenhancing lesion growing in the operative bed. Reoperation and pathologic classification, according to the current knowledge base, indicated it was RGNT rather than pilocytic astrocytoma (see Fig. 1B). The case illustrated the challenges of rapidly changing diagnostic criteria and classification imposed on neurosurgeons and pathologists. The majority of RGNT was situated in the posterior fossa. Therefore, headache was the most common symptom due to the obstructive hydrocephalus.2 Nausea/vomiting, ataxia, and visual disturbances were also common manifestationsd.6 Radiologic characteristics on MRI of RGNT revealed a relatively circumscribed tumor with discernible margins.6 MRI usually showed low signal intensity in T1-weighted images and high signal intensity in T2-weighted images.6 The tumors frequently showed gadolinium enhancement and could be solid, cystic, or mixed solid and/or cystic in type.5 Intratumoral calcification was inconsistently found.6 RGNT is a benign and indolent tumor, and, based on reported clinical experience and the current WHO classification, it corresponds to a grade 1 tumor.2 As is common for low-grade brain tumors, surgery is the primary treatment. In the meta-analyses results, complete tumor resection was reported in 36 of 63 evaluated cases.6 The results of radiation therapy for RGNT were limited because only a few patients received adjuvant radiation after surgery. Recurrence of RGNT was an uncommon event and only 4 of 52 patients experienced tumor recurrence.6 In the authors’ study, however, 1 patient experienced a recurred RGNT at 10 years after the initial operation (see Fig. 1). Therefore, long-term follow-up is mandatory after surgery. Results from the patient with
Glial Tumors with Neuronal Differentiation
Fig. 1. A case of recurrence of a rosette-forming glioneuronal tumor (RGNT). (A) Initial presentation at 13 years of age shows a huge cystic mass in the vermis accompanied by hydrocephalus (left). The tumor was completely removed and the diagnosis at that time was pilocytic astrocytoma. Ten years later, a recurred nonenhancing mass (arrow, right) was found at the operative bed on routine surveillance imaging (right). It was removed again and found to be RGNT based on the revised 2007 WHO classification. (B) Histologic features show characteristics of RGNT in a recurrent tumor. Light microscopy of RGNT, showing numerous small rosettes with central pink neuropillike cores. The tumor cells have uniform small round nuclei and clear cytoplasm (hematoxylin-eosin stain, 400). The cores of the rosettes are robustly positive for synaptophysin and microtubule-associated protein 2 (MAP2).
leptomeningeal seeding (discussed previously) also raised concerns about the nature of the RGNT, because there may be more genetic/clinical heterogeneity in this benign neoplasm.11
PAPILLARY GLIONEURONAL TUMOR The first established study of PGNT reported a series of 9 cases.12 Original studies were published in 1997, however, under the description, “pseudopapillary neurocytoma with glial differentiation.”13 Since then, a total of 69 cases have been reported in the literature.12–56 For the purpose of metaanalyses, 12 cases from the authors’ institute, including 5 previously reported cases, were combined with the reported cases for a total 76 cases (Table 1).47,49 Histologic features of PGNT include
the pseudopapillary architecture of glial cells with interpapillary collections of oligodendroglia-like neurocytic cells (Fig. 2).57 No prominent mitosis, necrosis, and vascular proliferation were observed. In general, the proliferative index was low, but there were subsets of cases with an increased Ki-67 index.29,32–34,36,40,44,49,50,55 There was no difference in male-to-female ratio. The age distribution ranged from 3 to 75 years (mean, 26.3 years). A strong preponderance for affecting young adults and children was observed, however, and 82.9% of the patients were younger than 40 years of age (see Fig. 2). The relative proportion of patients with a high proliferative index (Ki-67 5%), however, was greater in the older age group (62.5% in age 40 years) than in the younger age group (26.0% in age
