ABSTRACT
Subependymomas are rare, intraventricular glial tumors histologically characterized by clusters of small uniform cells distributed in an abundant fibrillary matrix. These tumors can arise in the parenchyma of the cerebrum, cerebellum, or spinal cord. Herein, we report an extremely rare case of cerebellar intraparenchymal subependymoma in a 62-year-old woman. The patient presented with dizziness for several years, and brain magnetic resonance imaging revealed a well-defined solid mass in the right cerebellum, upon which a stereotactic biopsy was performed. Histologically, the tumor showed a distinctive multinodular pattern with unevenly distributed glial cells and an abundant fibrillary matrix. Next-generation sequencing analysis showed balanced genomes without genetic alterations, including single-nucleotide variants, small insertions, deletions, or copy number alterations. Follow-up magnetic resonance imaging revealed that the size of the mass has not changed; the patient has not received any surgical treatments since the pathologic diagnosis and is living healthily.
Subject(s)
Glioma, Subependymal , Glioma , Female , Humans , Middle Aged , Glioma, Subependymal/diagnosis , Glioma, Subependymal/genetics , Glioma, Subependymal/surgery , Spinal Cord/pathology , Glioma/pathology , Cerebellum/pathology , Magnetic Resonance Imaging , High-Throughput Nucleotide SequencingABSTRACT
Subependymomas of the spinal cord are rare, do not often involve multiple levels, and very rarely recur. Here, we present a series of spinal cord subependymomas with a detailed description of the clinical, radiological and pathological features, and characterization by chromosomal microarray analysis. Briefly, the four patients included two men and two women, between the ages of 22 and 48 years. The most common presenting symptoms were neck and arm pain with upper extremity weakness. By imaging, the tumors were found to involve multiple spinal levels, including cervical/ cervico-thoracic (three patients) and thoracic (one patient), were all eccentric, and had minimal to no post-contrast enhancement. Two patients underwent gross total resection, one had a sub-total resection, and one underwent biopsy alone with a decompressive laminectomy. Follow up ranged from 6 months to 22 years. One patient (case 4) had recurrence 15 years following gross total resection and chromosomal microarray analysis revealed deletions on the long arm of chromosome 6. Our limited series suggests that spinal cord subependymomas can rarely recur, even following gross total resection, suggesting a possible role for long-term surveillance for these rare tumors.
Subject(s)
Chromosome Aberrations , Chromosomes, Human, Pair 6/genetics , Glioma, Subependymal/genetics , Glioma, Subependymal/pathology , Spinal Cord Neoplasms/genetics , Spinal Cord Neoplasms/pathology , Adult , Female , Gene Deletion , Humans , Male , Microarray Analysis , Middle Aged , Young AdultABSTRACT
Subependymomas are rare, slow-growing, grade I glial tumors of the central nervous system. Recently, diffuse midline gliomas with mutations in the H3.1 or H3.3 genes at the position of amino acid 27, resulting in the replacement of lysine by methionine (K27M), were defined as the new grade IV entity. As H3K27M mutations have been reported in midline gliomas, gangliogliomas, and pilocytic astrocytomas, whether they occur in midline subependymomas has been unclear. We determined whether any such mutations can be found in them and analyzed the prognostic relevance of any such mutations in subependymomas. Four subependymomas, all in the brain stem, harbored H3K27M mutations. No such mutation was found in any of the subependymomas from other locations. The mutations were identified by immunohistochemical stains and confirmed with Sanger sequencing. The median follow-up of the patients with the mutations in their tumors was 3.2 years, and 3 are still alive, having received no adjuvant therapy. We demonstrate that H3K27M mutation can occur in brainstem subependymomas; despite the presence of H3K27M mutation, these cases should not be diagnosed or treated as grade IV tumors because they showed a better outcome than the outcome of diffuse midline H3K27M mutant glioma. Our conclusion is not only that brainstem subependymomas can have H3K27M mutations but that they do not carry the rapidly lethal prognosis with which these mutations are usually associated because of their discovery in diffuse intrinsic pontine gliomas.
Subject(s)
Brain Stem Neoplasms/pathology , Glioma, Subependymal/genetics , Glioma, Subependymal/pathology , Histones/genetics , Adolescent , Adult , Brain Stem Neoplasms/genetics , Female , Humans , Male , Middle Aged , Mutation , Young AdultABSTRACT
Subependymoma is a rare primary brain tumor, constituting 0.07-0.51% of brain tumors. Genetic alterations in subependymoma are largely unknown, but familial occurrences have been reported. Trichorhinophalangeal syndrome type 1 (TRPS1) is a rare hereditary malformation complex caused by mutations in a gene identified in the year 2000 on 8q24.12. We report two patients with TRPS I and surgically treated subependymomas, one of whom has a first degree relative, now deceased, who was affected and also had a subependymoma. We therefore sought a role for the TRPS1 gene in the molecular oncogenesis of subependymoma. Formalin fixed tumor specimens and saliva samples were obtained from the two index patients as well as tumor samples from six sporadic subependymoma surgical specimens. A heterozygous TRPS1 germ line mutation predicted to cause a frame shift leading to a premature stop codon was found in the first index patient and also present in the associated tumor. No germline mutation was found in the second index patient, but his tumor displayed copy number neutral loss of heterozygosity in TRPS1. TRPS1 mutation analysis of the sporadic subependymomas revealed genetic, mostly loss of function alterations in one-third (two of six) of samples. Genetic alterations in TRPS1 likely play a role in at least a subgroup of subependymomas. Confirmation and further (epi)genetic investigations, ideally in newly acquired, fresh-frozen tumor samples, are warranted.
Subject(s)
Brain Neoplasms/genetics , Brain Neoplasms/physiopathology , DNA-Binding Proteins/genetics , Glioma, Subependymal/genetics , Glioma, Subependymal/physiopathology , Mutation/genetics , Transcription Factors/genetics , Adult , DNA Mutational Analysis , Female , Humans , Male , Repressor ProteinsABSTRACT
Ependymomas are rare primary tumors of the central nervous system in children and adults that comprise histologically similar but genetically distinct subgroups. The tumor biology is typically more associated with the site of origin rather than being age-specific. Genetically distinct subgroups have been identified by genomic studies based on locations in classic grade II and III ependymomas. They are supratentorial ependymomas with C11orf95-RELA fusion or YAP1 fusion, infratentorial ependymomas with or without a hypermethylated phenotype (CIMP), and spinal cord ependymomas. Myxopapillary ependymomas and subependymomas have different biology than ependymomas with typical WHO grade II or III histology. Surgery and radiotherapy are the mainstays of treatment, while the role of chemotherapy has not yet been established. An in-depth understanding of tumor biology, developing reliable animal models that accurately reflect tumor molecule features, and high throughput drug screening are essential for developing new therapies. Collaborative efforts between scientists, physicians, and advocacy groups will enhance the translation of laboratory findings into clinical trials. Improvements in disease control underscore the need to incorporate assessment and management of patients' symptoms to ensure that treatment advances translate into improvement in quality of life.
Subject(s)
Brain Neoplasms/pathology , Ependymoma/pathology , Glioma, Subependymal/pathology , Spinal Cord Neoplasms/pathology , Animals , Brain Neoplasms/genetics , Disease Models, Animal , Ependymoma/genetics , Glioma, Subependymal/genetics , Humans , Quality of Life , Spinal Cord Neoplasms/diagnosisABSTRACT
In this paper, a rare case of subependymoma of the fourth ventricle in identical female twins is reported. Magnetic resonance imaging and CT showed nearly identical locations of the tumors in the fourth ventricle and similar growth patterns of the tumors in both sisters. Likewise, postoperative histopathological analysis of both tumors revealed the typical histological appearance of subependymomas. Subependymoma is a rare, low-grade glioma of the CNS, slowly growing and usually asymptomatic. If symptomatic, a subependymoma can in some cases lead to sudden death caused by pressure on the brainstem or decompensated secondary hydrocephalus. This case demonstrates the importance of detecting tumors early and thereby preventing symptoms arising from increasing intracranial pressure, and optimizing therapy options.
Subject(s)
Cerebral Ventricle Neoplasms/diagnosis , Cerebral Ventricle Neoplasms/genetics , Diseases in Twins , Glioma, Subependymal/diagnosis , Glioma, Subependymal/genetics , Twins, Monozygotic , Adult , Cerebral Ventricle Neoplasms/surgery , DNA Copy Number Variations , Female , Fourth Ventricle/diagnostic imaging , Fourth Ventricle/pathology , Fourth Ventricle/surgery , Glioma, Subependymal/surgery , Humans , Magnetic Resonance Imaging , Neurosurgical Procedures , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
Tuberous sclerosis complex is an autosomal dominant disease, with variable expressivity and multisystemic involvement, which is characterised by the growth of benign tumours called hamartomas. The organs that are most commonly affected are the brain, skin, kidneys, eyes, heart and lungs. Of all the children with this disease, 85% present neurological manifestations that, due to their severity, are the main cause of morbidity and mortality. The most significant neurological manifestations are epilepsy, autism spectrum disorders and mental retardation. It has been shown that in tuberous sclerosis complex the genes TSC1 and TSC2 alter the mTOR enzyme cascade, which sets off inhibition of this pathway. The possibility of resorting to treatments applied at the origin, thus inhibiting this pathway, is currently being evaluated.
Subject(s)
Molecular Targeted Therapy , Sirolimus/analogs & derivatives , Sirolimus/therapeutic use , TOR Serine-Threonine Kinases/antagonists & inhibitors , Tuberous Sclerosis/drug therapy , Anticonvulsants/therapeutic use , Astrocytoma/genetics , Autistic Disorder/genetics , Brain Diseases/genetics , Brain Neoplasms/genetics , Drug Design , Epilepsy/drug therapy , Epilepsy/genetics , Epilepsy/surgery , Epilepsy/therapy , Everolimus , Glioma, Subependymal/genetics , Hamartoma/genetics , Humans , Intellectual Disability/genetics , Learning Disabilities/genetics , Learning Disabilities/prevention & control , Signal Transduction/drug effects , Sirolimus/pharmacology , TOR Serine-Threonine Kinases/physiology , Tuberous Sclerosis/genetics , Tuberous Sclerosis/pathology , Tuberous Sclerosis/psychology , Tuberous Sclerosis Complex 1 Protein , Tuberous Sclerosis Complex 2 Protein , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/physiologyABSTRACT
Subependymomas (SE) are slow-growing brain tumors that tend to occur within the ventricles of middle-aged and elderly adults. The World Health Organization classifies these tumors within the ependymoma group. Previous limited analysis of this tumor type had not revealed significant underlying cytogenetic abnormalities. We have used microarray comparative genomic hybridization to study a series of SE (n = 12). A whole-genome array at 0.97-Mb resolution showed copy number abnormalities in five of 12 cases (42%). Two cases (17%) showed regions of loss on chromosome 6. More detailed analysis of all cases using a chromosome 6 tile-path array confirmed the presence of overlapping regions of loss in only these two cases. One of these cases also showed trisomy chromosome 7. Monosomy of chromosome 8 was seen in a further two cases (17%), and a partial loss on chromosome 14 was observed in one additional case. This is the first array-based, genome-wide study of SE. The observation that five of 12 cases examined (42%) at 0.97-Mb resolution showed chromosomal copy number abnormalities is a novel finding in this tumor type.
Subject(s)
Cerebral Ventricle Neoplasms/genetics , Chromosomes, Human/genetics , Gene Dosage/genetics , Genetic Predisposition to Disease/genetics , Glioma, Subependymal/genetics , Monosomy , Trisomy , Adult , Aged , Cerebral Ventricle Neoplasms/metabolism , Cerebral Ventricle Neoplasms/pathology , Chromosomes, Human, Pair 14/genetics , Chromosomes, Human, Pair 6/genetics , Chromosomes, Human, Pair 7/genetics , Chromosomes, Human, Pair 8/genetics , DNA Mutational Analysis , Female , Gene Expression Profiling , Genomic Library , Genotype , Glioma, Subependymal/metabolism , Glioma, Subependymal/pathology , Humans , Male , Middle Aged , Mutation/genetics , Oligonucleotide Array Sequence Analysis , Sequence DeletionSubject(s)
Cerebral Ventricle Neoplasms/diagnosis , Glioma, Subependymal/diagnosis , Image Enhancement , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Tuberous Sclerosis/diagnosis , Adenoma/diagnosis , Adenoma/genetics , Cerebral Ventricle Neoplasms/genetics , Cerebral Ventricles/pathology , Child , Ependyma/pathology , Facial Neoplasms/diagnosis , Facial Neoplasms/genetics , Glioma, Subependymal/genetics , Humans , Male , Neoplasms, Multiple Primary/diagnosis , Neoplasms, Multiple Primary/genetics , Sebaceous Gland Neoplasms/diagnosis , Sebaceous Gland Neoplasms/genetics , Tuberous Sclerosis/geneticsABSTRACT
Subependymal giant cell astrocytomas are distinctive brain tumors that are seen only in tuberous sclerosis complex. Although histologically benign, they cause both moribidity and occasional mortality owing to progressive growth in some patients. Tuberous sclerosis complex is an autosomal dominant genetic disorder with a high sporadic case rate that is due to mutations in either of two genes, TSC1 and TSC2, encoding hamartin and tuberin, respectively. The pathogenesis of subependymal giant cell astrocytomas in tuberous sclerosis complex is uncertain. In this study, we examined the expression of tuberin and hamartin in subependymal giant cell astrocytomas from nine patients with tuberous sclerosis complex by immunohistochemistry with confocal microscopy. Loss of hamartin expression was seen in all subependymal giant cell astrocytomas, including five from patients with germline TSC2 mutations and two from patients with germline TSC1 mutations. The subependymal giant cell astrocytomas of six of nine patients had no expression of tuberin as well, whereas three patients retained some tuberin expression. Tuberin expression was seen in one patient with a TSC2 germline mutation and two patients whose mutational status was not determined. Overall, these data indicate a loss of both tuberin and hamartin expression in the subependymal giant cell astrocytomas of patients with both TSC1 and TSC2 mutations and are consistent with a two-hit disease pathogenesis model for the development of subependymal giant cell astrocytomas.
Subject(s)
Brain Neoplasms/complications , Brain Neoplasms/genetics , Glioma, Subependymal/complications , Glioma, Subependymal/genetics , Point Mutation/genetics , Proteins/genetics , Repressor Proteins/genetics , Tuberous Sclerosis/complications , Antibodies, Monoclonal/immunology , Antibodies, Neoplasm/immunology , Brain Neoplasms/immunology , Culture Techniques , DNA Mutational Analysis , Gene Deletion , Glioma, Subependymal/immunology , Humans , Immunohistochemistry , Mutation, Missense/genetics , Neoplasm Staging , Polymerase Chain Reaction , Proteins/immunology , Repressor Proteins/immunology , Tuberous Sclerosis Complex 1 Protein , Tuberous Sclerosis Complex 2 Protein , Tumor Suppressor ProteinsSubject(s)
Brain Neoplasms/genetics , Brain Neoplasms/pathology , Chromosome Aberrations , Chromosome Mapping , Glioma, Subependymal/genetics , Spinal Cord Neoplasms/genetics , Adult , Brain Neoplasms/surgery , Cerebral Ventricles , Female , Glioma, Subependymal/pathology , Glioma, Subependymal/surgery , Humans , Karyotyping , Male , Middle Aged , Spinal Cord Neoplasms/pathology , Spinal Cord Neoplasms/surgery , Tumor Cells, CulturedABSTRACT
Subependymomas are unusual tumors believed to arise from the bipotential subependymal cell. Previous reports of familial occurrence of subependymoma have involved monozygous twins and siblings. The authors describe the first reported occurrence of fourth ventricular subependymoma in a father and son, suggesting the possibility of direct inheritance.