Molecular characterization reveals NF1 deletions and FGFR1-activating mutations in a pediatric spinal oligodendroglioma.

Pediatric spinal oligodendrogliomas are rare and aggressive tumors. They do not share the same molecular features of adult oligodendroglioma, and no previous reports have examined the molecular features of pediatric spinal oligodendroglioma. We present the case of a child with a recurrent spinal anaplastic oligodendroglioma. We performed whole exome (paired tumor and germline DNA) and transcriptome (tumor RNA) sequencing, which revealed somatic mutations in NF1 and FGFR1. These data allowed us to explore potential personalized therapies for this patient and expose molecular drivers that may be involved in similar cases.

The loss of Nf1 transiently promotes self-renewal but not tumorigenesis by neural crest stem cells.

Neurofibromatosis is caused by the loss of neurofibromin (Nf1), leading to peripheral nervous system (PNS) tumors, including neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). A long-standing question has been whether these tumors arise from neural crest stem cells (NCSCs) or differentiated glia. Germline or conditional Nf1 deficiency caused a transient increase in NCSC frequency and self-renewal in most regions of the fetal PNS. However, Nf1-deficient NCSCs did not persist postnatally in regions of the PNS that developed tumors and could not form tumors upon transplantation into adult nerves. Adult P0a-Cre+Nf1(fl/-) mice developed neurofibromas, and Nf1(+/-)Ink4a/Arf(-/-) and Nf1/p53(+/-) mice developed MPNSTs, but NCSCs did not persist postnatally in affected locations in these mice. Tumors appeared to arise from differentiated glia, not NCSCs.

Skull fracture mimicking eosinophilic granuloma.

BACKGROUND: Delayed swelling after skull fractures is an uncommon complication following head trauma in children. Classically, growing skull fractures typically present in patients under 3 years of age with progressive subcutaneous fluid collections, or occasionally with neurologic symptoms. We present the case of a healthy 2-year-old boy with a lytic "punched-out" frontal skull lesion. The child presented 2 months after a minor forehead injury for which no medical attention was sought. METHODS: The skull defect had no associated leptomeningeal cyst or brain herniation. Imaging and presentation were thought to be consistent with eosinophilic granuloma. Histologic findings demonstrated a healing skull fracture. RESULTS: Cranioplasty was performed, and the patient had an uncomplicated postoperative course. CONCLUSIONS: In this report, we describe our experience with this atypical presentation of a healing skull fracture mimicking a typical eosinophilic granuloma.

Novel mutations in the Anoctamin 5 gene (ANO5) associated with limb-girdle muscular dystrophy 2L.

INTRODUCTION: We present a Jordanian man with the typical LGMD 2L phenotype of early, asymmetric quadriceps weakness and subsequent biceps brachii weakness. METHODS: Case report. RESULTS: Muscle biopsies document a progressive dystrophic pattern unrelated to known sarcolemmal defects associated with muscular dystrophy. Genetic testing revealed novel, heterozygote Anoctamin 5 gene mutations. CONCLUSIONS: This case report expands the known mutations resulting in LGMD 2L and supports the assertion that Anoctamin 5 mutations are more prevalent than previously recognized.

Spontaneous resolution of an infantile hemangioma in a dorsal root ganglion.

Infantile hemangiomas are tumors commonly seen in children. Few authors have reported infantile hemangiomas affecting the CNS, and there are no prior reports detailing spontaneous resolution of a histologically proven juvenile hemangioma within a dorsal root ganglion. The authors report the case of a newborn boy with a large cutaneous hemangioma in the midline of his back. Spinal MR images were obtained to rule out associated spinal cord tethering, and an intradural spinal lesion was unexpectedly discovered. Biopsy revealed an intradural infantile hemangioma within the dorsal root ganglion, and, based on this diagnosis, no resection was performed. Sixteen months following the biopsy, the cutaneous hemangioma had become involuted and the intradural hemangioma had completely resolved. The behavior of the intradural component in this case follows the natural history of many cutaneous infantile hemangiomas.

GNE Myopathy as a Myofibrillar Myopathy: Potential Important Disease Mechanism Implied by Muscle Biopsy.

We report a case of 2 sisters in their 20s with genetically confirmed UDP-N-acetylglucoasmine 2-epimerase/N-acetylmannosamine kinase myopathy along with muscle biopsy findings. Both patients described slowly progressive signs of distal-predominant weakness since adolescence that had been dismissed as "clumsiness." Exam and electrodiagnostic testing suggested a predominately distal myopathy. Muscle biopsy of the left tibialis anterior revealed rimmed vacuoles and, interestingly, also had characteristic features of a myofibrillar myopathy. Genetic testing confirmed a diagnosis of autosomal recessive GNE myopathy in both patients. GNE myopathy has not typically been considered a myofibrillar myopathy, but this case raises possibilities worthy of further exploration. It is possible that the unique combination of pathogenic alleles in GNE reported here has led to a novel form of GNE myopathy with muscle biopsy showing characteristic features of GNE myopathy and myofibrillar myopathy. The other possibility is that myofibrillar myopathy may be a more common feature of GNE myopathies than classically described.

Primary diffuse leptomeningeal melanomatosis: Description and recommendations.

Primary melanocytic disease of the central nervous system is a rarely encountered condition currently without consensus on treatment and lacking major guidelines for management. Understanding the nature of the disease and differentiating primary melanocytic disease from the much more commonly encountered secondary (metastatic) melanoma is important in identifying the condition and pursuing appropriate treatment.

Blood-brain barrier-adapted precision medicine therapy for pediatric brain tumors.

Targeted chemotherapeutics provide a promising new treatment option in neuro-oncology. The ability of these compounds to penetrate the blood-brain barrier is crucial for their successful incorporation into patient care. "CNS Targeted Agent Prediction" (CNS-TAP) is a multi-institutional and multidisciplinary translational program established at the University of Michigan for evaluating the central nervous system (CNS) activity of targeted therapies in neuro-oncology. In this report, we present the methodology of CNS-TAP in a series of pediatric and adolescent patients with high-risk brain tumors, for which molecular profiling (academic and commercial) was sought and targeted agents were incorporated. Four of five of the patients had potential clinical benefit (partial response or stable disease greater than 6 months on therapy). We further describe the specific drug properties of each agent chosen and discuss characteristics relevant in their evaluation for therapeutic suitability. Finally, we summarize both tumor and drug characteristics that impact the ability to successfully incorporate targeted therapies into CNS malignancy management.

Peripheral primitive neuroectodermal tumor/Ewing's sarcoma of the craniospinal vault: case reports and review.

The peripheral primitive neuroectodermal tumor/Ewing's sarcoma family tumor (pPNET/ESFT) group includes small round cell tumors of the bone, soft tissue, and nerve with morphological attributes of the germinal neuroepithelium. Peripheral PNETs/ESFTs also occur within the craniospinal vault, a region including the central nervous system, the meninges, and the cranial and spinal nerve roots. Gene rearrangements between the EWS gene on chromosome 22q12 and members of the ETS gene family are common in and specific to pPNETs/ESFTs. Another defining characteristic of pPNETs/ESFTs is their membranous expression of the MIC2 gene product. We describe 2 cases of pPNETs within the craniospinal vault. An intradural tumor arising from the nerve roots of the cauda equina was discovered in a 32-year-old man presenting with radiculopathic back pain and lower-extremity weakness. An intracranial pPNET that mimicked a meningioma was found in a 21-year-old man presenting with headache and visual disturbances. MIC2 gene product expression and EWS/ETS gene rearrangement were detected in both case patients. The literature with regard to pPNETs/ESFTs arising within the craniospinal vault is reviewed.

Differentiation of recurrent brain tumor versus radiation injury using diffusion tensor imaging in patients with new contrast-enhancing lesions.

BACKGROUND AND PURPOSE: The purpose of this study was to assess the use of diffusion tensor imaging (DTI) in the evaluation of new contrast-enhancing lesions and perilesional edema in patients previously treated for brain neoplasm in the differentiation of recurrent neoplasm from treatment-related injury. METHODS: Twenty-eight patients with new contrast-enhancing lesions and perilesional edema at the site of previously treated brain neoplasms were retrospectively reviewed. Nine directional echoplanar DTIs with b=1000 s/mm(2) were obtained using a single-shot spin-echo echoplanar imaging. Standardized regions of interest were manually drawn in several regions. Mean apparent diffusion coefficient (ADC), fractional anisotropy (FA) and eigenvalue indices (lambda( parallel) and lambda( perpendicular)) and their ratios relative to the contralateral side were compared in patients with recurrent neoplasm versus patients with radiation injury, as established by histological examination or by clinical course, including long-term imaging studies and magnetic resonance spectroscopy. RESULTS: The ADC values in the contrast-enhancing lesions were significantly higher (P=.01) for the recurrence group (range=1.01 x 10(-3) to 1.66 x 10(-3) mm(2)/s; mean+/-S.D.=1.27+/-0.15) than for the nonrecurrence group (range=0.9 x 10(-3) to 1.31 x 10(-3) mm(2)/s; mean+/-S.D.=1.12+/-0.14). The ADC ratios in the white matter tracts in perilesional edema trended higher (P=.09) in treatment-related injury than in recurrent neoplasm (mean+/-S.D.=1.85+/-0.30 vs. 1.60+/-0.27, respectively). FA ratios were significantly higher in normal-appearing white matter (NAWM) tracts adjacent to the edema in the nonrecurrence group (mean+/-S.D.=0.89+/-0.15) than in those in the recurrence group (mean+/-S.D.=0.74+/-0.14; P=.03). Both eigenvalue indices lambda( parallel) and lambda( perpendicular) were significantly higher in contrast-enhancing lesions in the recurrence group than in those in the nonrecurrence group (P=.02). As well, both eigenvalue indices lambda( parallel) and lambda( perpendicular) were significantly higher in perilesional edema than in normal white matter (P<.01 and P<.001, respectively) in both groups. CONCLUSION: The assessment of diffusion properties, especially ADC values and ADC ratios, in contrast-enhancing lesions, perilesional edema and NAWM adjacent to the edema in the follow-up of new contrast-enhancing lesions at the site of previously treated brain neoplasms may add to the information obtained by other imaging techniques in the differentiation of radiation injury from tumor recurrence.

Resolution of innumerable cerebral Nocardia paucivorans abscesses after medical management.

Nocardia species are an infrequent cause of brain abscesses. We report a 50-year-old man with Nocardia paucivorans cerebral abscesses. Brain MRI revealed innumerable small ring-enhancing lesions. The patient initially responded to treatment with antibiotics and steroids, but experienced worsening after discontinuation of steroids. Brain biopsy performed to exclude central nervous system lymphoma produced nodular tissue with branching filaments on silver stain. Steroids were re-initiated and tapered slowly. The patient completed 1year of antibiotic therapy, after which he had no neurological symptoms and complete resolution of all brain abscesses on MRI.

Hemangiomas of the geniculate ganglion.

OBJECTIVE: To describe the presentation, evaluation, and management of patients with geniculate ganglion hemangioma. STUDY DESIGN: Retrospective case review. SETTING: Tertiary-care academic medical center. PATIENTS: Six patients with hemangiomas of the geniculate ganglion, evaluated and managed at a single institution. INTERVENTION: All patients underwent imaging and follow-up, with five of the patients undergoing operative intervention. MAIN OUTCOME MEASURES: Tumor size and extent, facial nerve and hearing function, histopathologic findings, and complications are discussed as a function of observation versus microsurgical excision. RESULTS: Six patients with ossifying hemangiomas of the geniculate ganglion were evaluated at a single institution over a 10-year period. These patients underwent operative intervention when their facial nerve function began to decline. Hearing was preserved in five of the six cases. Resection and grafting of the facial nerve was required in five of six cases. Two of the six cases were found to have histologic evidence of facial nerve infiltration on pathologic examination. CONCLUSION: The majority of these tumors infiltrated the facial nerve and could not be completely removed without excision of the nerve itself. Based on this experience, it would seem reasonable to defer surgical excision until facial nerve function has declined to grade 3 or worse. Whether earlier subtotal excision would result in better outcomes or not remains unanswered. This study presents several complicated scenarios that illustrate the difficulty of clinical decision-making in this disease. Associated clinical dilemmas and controversies are discussed.

Angiotropic large cell lymphoma with imaging characteristics of CNS vasculitis.

This report documents a case of angiotropic large cell lymphoma (ALCL) with imaging characteristics of CNS vasculitis. A 47-year-old man was unresponsive after a 5-month progression of neurologic deterioration and intermittent fevers. MR imaging revealed multiple areas of abnormally increased T2 signal intensity in the cerebral cortex and subcortical white matter. Despite corticosteroid treatment for presumed CNS vasculitis, the patient died. Necropsy revealed a diffuse intravascular malignant mononuclear proliferation consistent with ALCL.

Differential expression of cytokeratins 8 and 20 distinguishes craniopharyngioma from rathke cleft cyst.

BACKGROUND: Craniopharyngiomas are epithelial neoplasms usually located in the sellar and suprasellar regions. Distinguishing craniopharyngioma from Rathke cleft cyst is sometimes difficult, and the distinction is clinically significant because Rathke cleft cysts have a better prognosis than craniopharyngiomas. DESIGN: We retrieved 10 cases with a primary diagnosis of craniopharyngioma and 5 cases with a diagnosis of Rathke cleft cyst for analysis. Five cases of normal pars intermedia of pituitary glands from autopsy served as controls. We evaluated the expression patterns of a broad range of low- to intermediate-molecular weight cytokeratins (CK7, CK8, CK10, CK17, CK18, CK19, and CK20) and high-molecular weight cytokeratins (K903: a combination of CK1, CK5, CK10, and CK14; and CK5/6) in these cases. RESULTS: Craniopharyngiomas had a cytokeratin expression pattern distinct from that of Rathke cleft cysts and pituitary gland pars intermedia: craniopharyngiomas did not express cytokeratins 8 and 20, whereas Rathke cleft cysts and pars intermedia of pituitary glands both expressed cytokeratins 8 and 20. CONCLUSION: The differential expression of cytokeratins distinguishes between craniopharyngioma and Rathke cleft cyst, and this difference could be useful for identifying craniopharyngioma in difficult cases in which only a small biopsy is available. The different cytokeratin profiles of craniopharyngioma and Rathke cleft cyst suggest that these lesions do not come from the same origin, or that they come from a different developmental stage of the pouch epithelium.

Radiation-induced intradural malignant peripheral nerve sheath tumor of the cauda equina with diffuse leptomeningeal metastasis.

Malignant peripheral nerve sheath tumors (MPNSTs) are rare, affecting only a small portion of the general population. In many cases, MPNSTs occur in association with neurofibromatosis Type 1 and at times arise secondary to previous radiation therapy (RT). These tumors can be found essentially anywhere a peripheral nerve is present, but they rarely originate primarily from the spinal nerve or cauda equina and cause leptomeningeal spread. This report describes the treatment course of a 43-year-old man with a history of testicular seminoma treated with RT a decade before, who was found to have a large sacral MPNST. The patient underwent complete sacrectomy for gross-total resection. Despite this effort, he was eventually found to have metastatic lesions throughout the spine and brain, ultimately resulting in acute hydrocephalus and death. Biopsy results of these metastatic lesions proved to be characteristic of his original MPNST. The literature is also reviewed and the diagnostic modalities, management strategies, and prognosis of MPNST are discussed.

Symptomatic calcified perineural cyst after use of bone morphogenetic protein in transforaminal lumbar interbody fusion: a case report.

BACKGROUND CONTEXT: Human recombinant bone morphogenetic protein-2 (BMP-2) is commonly used in spinal surgery to augment arthrodesis, and a number of potential complications have been documented. PURPOSE: To present the case of a delayed radiculopathy that occurred because of a calcified perineural cyst that formed after an L4-L5 transforaminal lumbar interbody fusion (TLIF) in which BMP-2 was used. STUDY DESIGN/SETTING: Case report of a 70-year-old man presented with back and right lower extremity pain. METHODS: A 70-year-old man who had previously undergone a right L4-L5 TLIF presented 20 months after surgery with progressively radiating right leg pain. Imaging revealed a right-sided L4-L5 cystic lesion posterior to the interbody cage. The patient underwent reexploration, and a calcified mass was discovered. RESULTS: Histopathology revealed fragments of organized collagenous connective tissue, new collagen, and partially calcified fragments of fibrocartilage, bone, and ligament. CONCLUSIONS: This is the first reported case of a symptomatic calcified perineural cyst developing after a fusion procedure in which BMP-2 was used. The presence of connective tissue with metaplastic bone formation and maturation within the lesion suggests that formation of the cyst was secondary to application of BMP-2, as it possesses both osteogenic and chondrogenic capabilities.

Pathologic basis of central nervous system infections.

Radiology provides valuable gross pathologic information about central nervous system (CNS) infections. Major categories of infectious lesions of the brain and spinal cord are recognized by imaging such as diffuse, focal, or multifocal. This article discusses the pathologic basis of these radiographic findings. It illustrates examples with gross and microscopic photographs of CNS infections, and the tissue reactions to these infections. Where the organism can spread within the CNS, and cellular responses to the organism underlie both the radiographic and pathologic findings.

External and internal influences on muscle pathology.

Three cases of different types of neuromuscular diseases demonstrate different muscle responses to external stress or intrinsic muscle abnormalities. The first muscle biopsy shows stenosis of its vessels causing acute muscle ischemia, stress from an external vascular disease. The muscle response is similar to the cellular necrosis seen in primary muscle diseases (myopathies), but the histologic pattern is more focal than most myopathies. The second muscle biopsy demonstrates the effects of external motor nerve injury or disease causing groups of muscle fibers to atrophy. If a nerve reinnervates the muscle, it changes the fiber types in distinct patterns. The third muscle biopsy shows an intrinsic muscle abnormality causes chronic failure of the muscle fibers to thrive and repeated attempts by the fibers to regenerate, stimulating other tissue repair processes, like fibrosis, to change the muscle. Depending on the etiologic factor, muscle will respond to internal and external influences in different manners.

Tumorigenic cells are common in mouse MPNSTs but their frequency depends upon tumor genotype and assay conditions.

Tumor-initiating cells have been suggested to be rare in many cancers. We tested this in mouse malignant peripheral nerve sheath tumors (MPNSTs) and found that 18% of primary and 49% of passaged MPNST cells from Nf1(+/-); Ink4a/Arf(-/-) mice formed tumors upon transplantation, whereas only 1.8% to 2.6% of MPNST cells from Nf1(+/-); p53(+/-) mice did. MPNST cells of both genotypes require laminin binding to ß1-integrin for clonogenic growth. Most MPNST cells from Nf1(+/-); Ink4a/Arf(-/-) mice expressed laminin, whereas most MPNST cells from Nf1(+/-); p53(+/-) mice did not. Exogenous laminin increased the percentage of MPNST cells from Nf1(+/-); p53(+/-) but not Nf1(+/-); Ink4a/Arf(-/-) mice that formed tumorigenic colonies. Tumor-forming potential is common among MPNST cells, but the assay conditions required to detect it vary with tumor genotype.

Langerhans cell histiocytosis of the optic chiasm: case report.

BACKGROUND AND IMPORTANCE: Langerhans cell histiocytosis (LCH) is an uncommon disease, usually affecting the cranium and peripheral bones. We present a rare case of isolated optic chiasm involvement by LCH to highlight the importance of considering LCH in the differential diagnosis of optic chiasm lesions. CLINICAL PRESENTATION: A 71-year-old woman presented with a 6-week history of worsening peripheral vision, headaches, weakness, cold sensitivity, and fatigue. She was found to have dense bitemporal hemianopsia. Magnetic resonance imaging revealed a 2-cm lesion, contrast enhancing on T1 and bright on T2 signal, involving the optic chiasm but not the pituitary gland. Preoperative considerations included optic nerve glioma, choristoma of the stalk, sarcoid, hypothalamic glioma, and Langerhans cell histiocytosis. The patient underwent a right subfrontal craniotomy for biopsy of the lesion. The optic chiasm was grossly enlarged with no tissue external to the chiasm. A midline incision was made in the lamina terminalis, and multiple biopsies were taken of firm fibrous material. Histologically, the tumor was characteristic for LCH and included a mixture of histiocytes with features of Langerhans cells, eosinophils, small lymphocytes, macrophages, neutrophils, and plasma cells. CONCLUSION: LCH is a rare disease, generally affecting bone, skin, lymph nodes, and in more severe cases, visceral organs. LCH involving the optic pathways is a rare condition that should be included in the differential for adults with mass lesions involving the orbit, eye, optic nerve, or chiasm. Future clinical and basic science research is needed to better understand LCH, its molecular origin, and its growth pattern.