Novel SOX10 indel mutations drive schwannomas through impaired transactivation of myelination gene programs.

BACKGROUND: Schwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas. METHODS: We performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a fetal glial cell model following transduction with wildtype and tumor-derived mutant isoforms of SOX10. RESULTS: We identified that nearly one-third of sporadic schwannomas lack alterations in known nerve sheath tumor genes and instead harbor novel recurrent in-frame insertion/deletion mutations in SOX10, which encodes a transcription factor responsible for controlling Schwann cell differentiation and myelination. SOX10 indel mutations were highly enriched in schwannomas arising from nonvestibular cranial nerves (eg facial, trigeminal, vagus) and were absent from vestibular nerve schwannomas driven by NF2 mutation. Functional studies revealed these SOX10 indel mutations have retained DNA binding capacity but impaired transactivation of glial differentiation and myelination gene programs. CONCLUSIONS: We thus speculate that SOX10 indel mutations drive a unique subtype of schwannomas by impeding proper differentiation of immature Schwann cells.

Spongiform leukoencephalopathy: A unique case of biopsy confirmed leukoencephalopathy secondary to toxic, non-inflammatory exposure.

Toxin-induced leukoencephalopathy is a rare neurological condition that has been previously associated with intracranial radiation, chemotherapy, drugs of abuse, and environmental exposures. Herein, we present a patient with brain-biopsy proven toxin-induced leukoencephalopathy, likely secondary to multiple environmental offenders including insecticides and non-Food and Drug Administration approved anabolic steroids, opioids, and benzodiazepines. A 60-year-old man presented to our service as a direct transfer from an outside facility for evaluation of a rapidly progressive neuropsychiatric decline. Extensive workup with blood work, cerebrospinal fluid analysis, paraneoplastic panel, serial magnetic resonance imaging brain with and without contrast, and electroencephalograms were unrevealing. Magnetic resonance imaging brain showed diffuse confluent white matter disease, which was non-specific. The patient was treated with high-dose methylprednisolone and trials of intravenous immunoglobulin without any significant improvement. Finally, a brain biopsy was performed, and pathology confirmed a spongiform leukoencephalopathy, favoring a toxin-related etiology. The diagnosis of toxin-induced leukoencephalopathy should be considered in patients with steep neuropsychiatric decline and associated diffuse white matter disease. Diagnosis relies heavily on history of exposure, clinical presentation, imaging findings, and ultimately, histopathology from brain biopsy. The recognition of the clinical presentation is important to pursue the appropriate diagnostic workup and treatment.

Facial Nerve Schwannoma Complicated by Acute Hemorrhage After Treatment with Stereotactic Radiosurgery.

BACKGROUND: Facial nerve schwannomas (FNSs) are rare benign tumors that arise from Schwann cells of the facial nerve. FNSs are similar to vestibular schwannomas in many aspects, yet their infiltrative nature into the facial nerve fascicles warrants a more conservative management approach. In the last decade, stereotactic radiosurgery (SRS) has shown promise in stabilizing or shrinking FNSs. CASE DESCRIPTION: A 71-year-old woman presented with mild facial paresis. Tumor growth after a period of watchful waiting warranted treatment with SRS, which was complicated by an acute posterior fossa hemorrhage and brainstem compression, necessitating microsurgical hematoma evacuation, tumor resection, and facial nerve substitution. CONCLUSIONS: SRS has led to better facial nerve function and outcomes and is currently considered a reasonable alternative to microsurgical resection in patients with FNSs. This is the first report to our knowledge of an acute, life-threatening hemorrhage after SRS in a patient with FNS.

Small lymphaticovenous malformation of the orbital apex clinicopathologic correlation.

PURPOSE: To familiarize clinicians with the clinical and magnetic resonance imaging (MRI) features of a small orbital apex lymphaticovenous malformation that resulted in blindness and evaded timely clinical diagnosis. OBSERVATIONS: A 68-year-old man presented with severe vision loss due to a 9 mm mass at the apex of the orbit above the optic nerve. When surgically removed 4 years later, the lesion was characterized by vascular spaces of varying size. Larger ones were filled with fibrin and organized thrombi. Stromal septa of endothelial-lined cavernous spaces were partially necrotic and there was evidence of remote hemorrhage. Some endothelial cells expressed D2-40, a marker of lymphatic channels. CONCLUSIONS AND IMPORTANCE: Unless a high index of suspicion is maintained for a lymphaticovenous malformation the clinical diagnosis of a small but vision-threatening lesion can be overlooked.

PIK3CA mutation in a mixed dysembryoplastic neuroepithelial tumor and rosette forming glioneuronal tumor, a case report and literature review.

BACKGROUND: Rosette forming glioneuronal tumors are rare, World Health Organization (WHO) grade I novel tumors frequently affecting the fourth ventricle or posterior fossa with typical neuronal pseudorosettes. RGNTs have been described as possessing additional histologic features of DNETs or pilocytic astrocytomas. Activating PIK3CA mutations have been identified as recurring genetic event in RGNTs. METHODS: We report a 35year old man who presented with binocular diplopia, headache, and was found to have a third ventricle tumor. Tumor pathology and oncogene evaluation were conducted. RESULTS: The tumor demonstrated histologic features consistent with mixed RGNT/DNET. Genetic studies revealed a PIK3CA mutation in exon 9 (E545K, C. 1633G>A) without IDH1, p53, 1p19q chromosomal co-deletion, or BRAF mutations. A literature search revealed six cases of PIK3CA mutations in RGNTs and seven cases of mixed RGNT/DNET. No cases of mixed RGNT/DNET with a PIK3CA mutation have been described. CONCLUSION: This is the first documented case of an RGNT/DNET with an activating PIK3CA mutation. The presence of a PIK3CA mutation aids histologic classification in the setting of mixed histology, and may have implications for targeting the PI3K/AKT/mTOR pathway in this tumor type.

Brown-Vialetto-Van Laere syndrome: clinical and neuropathologic findings with immunohistochemistry for C20orf54 in three affected patients.

Brown-Vialetto-Van Laere syndrome (BVVLS) is a rare degenerative neurological disorder characterized by pontobulbar palsy and sensorineural deafness. Since its initial description in 1894, fewer than 100 cases have been reported, and published neuropathological analyses of these cases are extremely rare. Recently, individuals with BVVLS have been found to carry mutations in the C20orf54 gene, which encodes the human homolog for a rat riboflavin transporter. We present the case of a male who presented at the age of 5 years with sensorineural deafness, as well as those of 2 infant sisters who presented at 11 and 13 months of age with weakness and ataxia, respectively. All cases were genetically confirmed. We include the 1st immunohistochemical characterization of C20orf54 expression in BVVLS and controls. Results showed punctate axonal staining in the control cases that was dramatically reduced in the 3 BVVLS cases compared to the 5 controls. This decreased staining was seen even in the neocortex, which was unaffected in the BVVLS cases by routine histology. While the implications of these results are far from definitive, and although the evaluation of more cases is needed, immunohistochemistry for the C20orf54 protein may eventually be useful, in the right clinical scenario, as a screening test when selecting cases for sequencing of the C20orf54 gene to diagnose BVVLS at autopsy.

Blind and confused.

A 62-year-old man developed confusion and was diagnosed as having encephalitis. The etiology was not identified. He continued to have cognitive impairment but remained clinically stable. Five months later, he woke with bilateral vision loss. On neurological examination, he had no light perception bilaterally. The remainder of the neurological examination results were normal. Magnetic resonance imaging of the brain revealed multiple brain lesions. He was treated with steroids and plasmapheresis, with mild improvement in vision. He was then transferred to a long-term care facility, where he developed increasing confusion and ultimately died. An autopsy was performed; the differential diagnosis, neuropathology, and final diagnosis are discussed here.

Lymph node melanosis in a patient with metastatic melanoma of unknown primary.

Tumoral or nodular melanosis in the skin is considered a variation of completely regressed melanoma, presenting clinically as a suspicious pigmented papule or nodule. Microscopically, the lesion consists of a nodular accumulation of heavily pigmented melanophages in the dermis, staining positive for immunohistochemical markers of histiocytic lineage (CD68) and negative for those of melanocytic lineage (S100, HMB-45, Melan-A). This process is rarely described in lymph nodes. We present a report of a patient with melanosis involving multiple lymph nodes of an axillary dissection, done for metastatic melanoma with an unknown primary, and discuss possible prognostic and treatment factors.