Whole Exome Sequencing Identifies PHF14 Mutations in Neurocytoma and Predicts Responsivity to the PDGFR Inhibitor Sunitinib.

Neurocytomas are rare low-grade brain tumors predominantly affecting young adults, but their cellular origin and molecular pathogenesis is largely unknown. We previously reported a sellar neurocytoma that secreted excess arginine vasopressin causing syndrome of inappropriate anti-diuretic hormone (SIADH). Whole exome sequencing in 21 neurocytoma tumor tissues identified somatic mutations in the plant homeodomain finger protein 14 (PHF14) in 3/21 (14%) tumors. Of these mutations, two were missense mutations and 4 caused splicing site losses, resulting in PHF14 dysfunction. Employing shRNA-mediated knockdown and CRISPR/Cas9-based knockout approaches, we demonstrated that loss of PHF14 increased proliferation and colony formation in five different human, mouse and rat mesenchymal and differentiated cell lines. Additionally, we demonstrated that PHF14 depletion resulted in upregulation of platelet derived growth factor receptor-alpha (PDGFRα) mRNA and protein in neuroblastoma SHSY-5Y cells and led to increased sensitivity to treatment with the PDGFR inhibitor Sunitinib. Furthermore, in a neurocytoma primary culture harboring splicing loss PHF14 mutations, overexpression of wild-type PHF14 and sunitinib treatment inhibited cell proliferation. Nude mice, inoculated with PHF14 knockout SHSY-5Y cells developed earlier and larger tumors than control cell-inoculated mice and Sunitinib administration caused greater tumor suppression in mice harboring PHF-14 knockout than control SHSY-5Y cells. Altogether our studies identified mutations of PHF14 in 14% of neurocytomas, demonstrate it can serve as an alternative pathway for certain cancerous behavior, and suggest a potential role for Sunitinib treatment in some patients with residual/recurrent neurocytoma.

Postmortem Diagnosis of the Proteus Syndrome by Next Generation Sequencing of Affected Brain Tissue.

We report a case of a somatic overgrowth syndrome diagnosed at forensic autopsy with the aid of next generation sequencing as Proteus syndrome. Somatic overgrowth syndromes result from spontaneous somatic mutations that arise early in development and display a mosaic pattern of expression in patient tissues. Due to the temporal and anatomic heterogeneity of these syndromes, phenotypes vary widely, resulting in clinical overlap. Furthermore, the variable ratio of mutated to nonmutated cells in patient tissue can result in low-level mutations that could be missed using Sanger sequencing. Due to these factors, recent literature points to next generation sequencing (NGS) as an adjunct to diagnosis of these rare entities. A male in his fourth decade of life presented to our forensic autopsy service with physical features suggestive of a somatic overgrowth syndrome. Due to the paucity of clinical information accompanying the individual, a definitive diagnosis based on physical characteristics, alone, was not possible. Next generation sequencing of affected formalin-fixed and paraffin-embedded brain tissue confirmed the presence of the variant in AKT1 (c.49G>A, p.Glu17Lys, in 14.13% of reads) found in Proteus syndrome. To our knowledge, this is the first report of the mosaic variant of AKT1 detected in brain tissue and the first reported case of a postmortem diagnosis of Proteus syndrome with the aid of NGS. We conclude that NGS can be used as an adjunctive method to support a specific diagnosis among the somatic overgrowth syndromes postmortem in the absence of sufficient clinical history.

Elsberg Syndrome, Lumbosacral Radiculopathy, and Myelitis Due to Herpes Zoster in a Patient With Smoldering Myeloma.

Herpes zoster (HZ) is a common illness caused by the reactivation of latent varicella zoster virus (VZV) due to waning immunity, often secondary to old age or an underlying immunocompromised state. Its complications can manifest in variety of ways, including persistent neuralgias, vasculopathies, and stroke. Here, we describe a case of a 45-year-old man with a history of cryptogenic stroke and smoldering myeloma who was admitted with sacral HZ complicated by right lumbosacral radiculopathy and myelitis, otherwise known as Elsberg syndrome (ES). He was found to have an enhancing lesion in the peripheral conus medullaris on magnetic resonance imaging (MRI) with nonspecific inflammation and necrosis on biopsy pathology and cerebrospinal fluid (CSF) polymerase chain reaction (PCR) positive for VZV. The patient was initially treated with intravenous acyclovir and dexamethasone and discharged with a steroid taper and indefinite valacyclovir therapy. Twelve months postdischarge, the patient's right lumbosacral radiculopathy and myelitis had almost completely resolved; however, he continued to require bladder self-catheterization. We believe that the patient's underlying smoldering myeloma lead to an immunocompromised state, allowing for reactivation of latent VZV, resulting in both the patient's cryptogenic stroke years earlier and recent ES.

Epithelioid Sarcoma Arising in a Long-Term Survivor of an Atypical Teratoid/Rhabdoid Tumor in a Patient With Rhabdoid Tumor Predisposition Syndrome.

Rhabdoid tumor predisposition syndrome (RTPS) is defined as the presence of a SMARCB1 or SMARCA4 genetic aberration in a patient with malignant rhabdoid tumor. Patients with RTPS are more likely to present with synchronous or metachronous rhabdoid tumors. Based on the current state of rhabdoid tumor taxonomy, these diagnoses are based largely on patient demographics, anatomic location of disease, and immunohistochemistry, despite their nearly identical histologic and immunohistochemical profiles. Thus, the true distinction between such tumors remains a diagnostic challenge. Central nervous system atypical teratoid/rhabdoid tumor (AT/RT) is a rare, aggressive, primarily pediatric malignancy with variable histologic features and a well documented association with loss of SMARCB1 expression. Epithelioid sarcoma (ES) is a rare soft tissue tumor arising in patients of all ages and characteristically staining for both mesenchymal and epithelial immunohistochemical markers while usually demonstrating loss of SMARCB1 expression. To our knowledge we herein present the first documented case of a patient with RTPS who presented with metachronous AT/RT and ES.

Juvenile xanthogranuloma of the subdural spaces mimicking chronic hematoma with positive FDG uptake on PET: case report.

The authors report an unusual presentation of juvenile xanthogranuloma (JXG), a non-Langerhans cell histiocytosis of infancy and early childhood. This entity typically presents as a cutaneous head or neck nodule but can manifest with more systemic involvement including in the central nervous system. However, currently there is limited information regarding specific imaging features differentiating JXG from other neuropathological entities, with diagnosis typically made only after tissue sampling. The authors reviewed the initial images of a young patient with shunt-treated hydrocephalus and enlarging, chronic, extraaxial processes presumed to reflect subdural collections from overshunting, and they examine the operative discovery of a mass lesion that was pathologically proven to be JXG. Their results incorporate the important associated histological and advanced imaging features, including previously unreported metabolic activity on FDG PET. Ultimately, the case underscores the need to consider JXG in differential diagnoses of pediatric intracranial masses and highlights the potential role of PET in the initial diagnosis and response to treatment.

Cystic angiomatosis skull lesion obliteration with neuroendovascular sclerotherapy as a unique treatment: case report.

Cystic angiomatosis is a rare bone condition with complex presentation and difficult treatment. Current management strategies have poorly tolerated side effects and a low likelihood of disease eradication. The control of calvarial lesions that are symptomatic usually involves surgical excision and subsequent cranioplasty. This paradigm can present with a risk of morbidity and mortality depending on the anatomy of the lesion. Here, the authors present a novel approach to a difficult-to-treat occipital calvarial lesion directly overlying the transverse sinus, performing a small, partial-thickness craniectomy and alcohol sclerotherapy in a combined neurosurgery-neuroendovascular approach. At 3 years after treatment, the authors noted a complete, encouraging radiographic and clinical outcome.

Near haploidization is a genomic hallmark which defines a molecular subgroup of giant cell glioblastoma.

BACKGROUND: Giant cell glioblastoma (gcGBM) is a rare histologic subtype of glioblastoma characterized by numerous bizarre multinucleate giant cells and increased reticulin deposition. Compared with conventional isocitrate dehydrogenase (IDH)-wildtype glioblastomas, gcGBMs typically occur in younger patients and are generally associated with an improved prognosis. Although prior studies of gcGBMs have shown enrichment of genetic events, such as TP53 alterations, no defining aberrations have been identified. The aim of this study was to evaluate the genomic profile of gcGBMs to facilitate more accurate diagnosis and prognostication for this entity. METHODS: Through a multi-institutional collaborative effort, we characterized 10 gcGBMs by chromosome studies, single nucleotide polymorphism microarray analysis, and targeted next-generation sequencing. These tumors were subsequently compared to the genomic and epigenomic profile of glioblastomas described in The Cancer Genome Atlas (TCGA) dataset. RESULTS: Our analysis identified a specific pattern of genome-wide massive loss of heterozygosity (LOH) driven by near haploidization in a subset of glioblastomas with giant cell histology. We compared the genomic signature of these tumors against that of all glioblastomas in the TCGA dataset (n = 367) and confirmed that our cohort of gcGBMs demonstrated a significantly different genomic profile. Integrated genomic and histologic review of the TCGA cohort identified 3 additional gcGBMs with a near haploid genomic profile. CONCLUSIONS: Massive LOH driven by haploidization represents a defining molecular hallmark of a subtype of gcGBM. This unusual mechanism of tumorigenesis provides a diagnostic genomic hallmark to evaluate in future cases, may explain reported differences in survival, and suggests new therapeutic vulnerabilities.

Complex Patterns of GABAergic Neuronal Deficiency and Type 2 Potassium-Chloride Cotransporter Immaturity in Human Focal Cortical Dysplasia.

Focal cortical dysplasia (FCD) is a common histopathologic finding in cortical specimens resected for refractory epilepsy. GABAergic neuronal abnormalities and K-Cl cotransporter type 2 (KCC2) immaturity may be contributing factors for FCD-related epilepsy. We examined surgical specimens from 12 cases diagnosed with FCD, and brain tissues without developmental abnormality obtained from 6 autopsy cases. We found that GABAergic neuronal density was abnormal in FCD with 2 distinct patterns. In 7 of 12 (58%) FCD subjects, the GABAergic neuron density in dysplastic regions and in neighboring nondysplastic regions was equally reduced, hence we call this a "broad pattern." In the remaining cases, GABAergic neuron density was decreased in dysplastic regions but not in the neighboring nondysplastic regions; we designate this "restricted pattern." The different patterns are not associated with pathologic subtypes of FCD. Intracytoplasmic retention of KCC2 is evident in dysmorphic neurons in the majority of FCD type II subjects (5/7) but not in FCD type I. Our study suggests that (1) "broad" GABAergic deficiency may reflect epileptic vulnerability outside the dysplastic area; and (2) abnormal distribution of KCC2 may contribute to seizure generation in patients with FCD type II but not in type I.

Somatostatin Receptor Ligand Therapy-A Potential Therapy for Neurocytoma.

CONTEXT: Neurocytoma (NC) is a rare, low-grade tumor of the central nervous system, with a 10-year survival rate of 90% and local control rate of 74%. However, 25% of NCs will be atypical, with an elevated Ki-67 labeling index >2%, and will exhibit a more aggressive course, with a high propensity for local recurrence and/or craniospinal dissemination. Although no standard treatment regimen exists for these atypical cases, adjuvant stereotactic or conventional radiotherapy and/or chemotherapy have been typically offered but have yielded inconsistent results. CASE DESCRIPTION: We have described the case of a patient with a vasopressin-secreting atypical NC of the sellar and cavernous sinus region. After subtotal resection via endoscopic transsphenoidal surgery, the residual tumor showed increased fluorodeoxyglucose uptake and high somatostatin receptor (SSTR) expression on a 68Ga-DOTA-TATE positron emission tomography/CT scan. Somatostatin receptor ligand (SRL) therapy with lanreotide (120 mg every 28 days) was initiated. Four years later, the residual tumor was stable with decreased fluorodeoxyglucose tumor uptake. Immunocytochemical SSTR2 and SSTR5 expression >80% was further confirmed in a series of NC tissues. CONCLUSIONS: To the best of our knowledge, we have described the first use of SRL therapy for an atypical NC. Our results support consideration of adjuvant SRL therapy for NC refractory to surgical removal. Our findings further raise the possibility of SSTR-directed peptide receptor radionuclide therapy as NC therapy.

Hamartomas and choristomas in the nervous system.

Hamartomas are an overgrowth of mature tissues that normally occur in an area of the body, but with disorganization and often with one element predominating. Choristomas on the other hand, are a mass of tissue histologically normal for a part of the body other than the one in which it is located (heterotopic/ectopic). Many reports use choristoma and heterotopia interchangeably. What is included in the definition of hamartoma or choristoma varies. Malformations may be sometimes considered to be hamartomas and many ectopias could be included in the definition of choristoma. Hamartomas and choristomas can occur anywhere in the body including the nervous system.

Small Bowel Mucosal Involvement and Mesenteric Mass Formation in a Young Female with Type 3 Gaucher Disease. A Case Report.

Gaucher Disease arises due to a deficiency in the enzyme glucocerebrosidase and is the most common lysosomal storage disease. This enzyme deficiency leads to the accumulation of glucocerebroside within macrophages (Gaucher cells) and the resulting infiltration of these cells into organs can cause clinical symptoms. There are three types of Gaucher Disease that differ based on the clinical course and the presence or absence of neurological involvement, but classically, Gaucher cell infiltrates impact a patient's spleen, liver, bone marrow and cortex. In this report, we present a case of Type 3 Gaucher Disease involving small bowel mucosa with a mesenteric mass formation. These unusual sites of Gaucher cell deposition likely led directly to uncommonly seen clinical symptoms, including small bowel obstruction and lower gastrointestinal hemorrhage.

Bevacizumab Therapy for Pilomyxoid Astrocytoma.

Pilomyxoid astrocytoma is a rare tumor of the central nervous system generally found in young children near the hypothalamus. Herein, we report a 19-month-old female infant with a pilomyxoid astrocytoma, who underwent surgery as well as carboplatin and vincristine chemotherapy in an attempt to delay radiation therapy to the brain. Magnetic resonance imaging revealed that the tumor had increased in tumor volume on therapy. Chemotherapy with carboplatin and vincristine was stopped and bevacizumab therapy (10 mg/kg every other week) was initiated. After 15 months of bevacizumab therapy, the patient's tumor was significantly smaller. Bevacizumab therapy was discontinued for 6 months due to stability in tumor size but was resumed after tumor growth was observed. Patient was again placed on bevacizumab therapy with subsequent magnetic resonance imagings revealing a decrease in tumor size.

Intracranial Angiomatoid Fibrous Histiocytoma: Case Report and Literature Review.

BACKGROUND: Angiomatoid fibrous histiocytoma (AFH) is a rare and low-grade soft tissue lesion that typically arises from subcutaneous and deep dermal tissue of extremities. The first case was reported in 1979 by Enzinger and has since become known as a distinct entity. AFH has been increasingly reported in different organ systems, with rare reports of primary intracranial AFH. To date there have been 3 reports of intracranial AFH and 1 report of metastasis to the brain, most of which were in young adults. CASE DESCRIPTION: In this paper, we present a case of an older patient with a large, petrous apex AFH that was clinically mistaken for a trigeminal nerve schwannoma. We discuss radiographic and histologic features initially found and the findings that ultimately led to the diagnosis of AFH. We also discuss the findings noted in all other reports of intracranial AFH. CONCLUSION: We present a rare case of intracranial AFH in a patient relatively old for onset of diagnosis. To date, only 3 prior cases of AFH have been reported. The radiographic findings were nonspecific and initially pointed toward a diagnosis of schwannoma, whereas histopathology seemed to initially suggest meningioma. Further pathologic consultation finally confirmed AFH as the diagnosis. We suspect there are more cases of intracranial AFH that are misdiagnosed due to variability of findings on pathology. The behavior of this tumor remains in question as 1 of the 3 reported cases demonstrated significant recurrence. As such, gross total resection of this lesion is preferable.

Subcortical DNET in a Patient With an Enzymatic Deficiency: A Rare Case and Review of the Literature.

PURPOSE: This case report describes a toddler with a medical history of biotinidase deficiency who presented with atypical seizures due to a brain tumor. METHODS: This is a case report. RESULTS: Electroencephalogram revealed a frontal lobe mass, with magnetic resonance imaging confirmation of a mass extending from the frontal lobe into the genu and anterior corpus callosum. She underwent a near-total resection, and pathology identified a dysembryoplastic neuroepithelial tumor. The patient is now seizure free and clinically doing well. CONCLUSIONS: Children with biotinidase deficiency and atypical seizures should receive a full electroencephalogram evaluation, as brain tumors continue to be on the differential for seizures in this patient population.

High Levels of Gadolinium Deposition in the Skin of a Patient With Normal Renal Function.

OBJECTIVE: The aim of this study was to assess gadolinium deposition in the skin of a patient with normal renal function, based on estimated glomerular filtration rate values greater than 59 mL/min/1.73 m(2) after exposure to large cumulative doses of gadolinium-based contrast agents (GBCAs). MATERIALS AND METHODS: The patient underwent 61 contrasted brain MRI scans over the course of 11 years. Skin biopsies from the forearm and lower extremity were analyzed with inductively coupled plasma mass spectrometry (ICP-MS), laser ablation ICP-MS, and hydrophilic interaction liquid chromatography ICP-MS. RESULTS: The ICP-MS demonstrated high levels of gadolinium deposition (14.5 ± 0.4 µg/g), similar to previously reported gadolinium levels within the skin of patients with nephrogenic systemic fibrosis. The laser ablation ICP-MS demonstrated deposition of gadolinium within the deep layers of skin. Speciation analysis using hydrophilic interaction liquid chromatography ICP-MS demonstrated the presence of intact gadolinium-chelate species, although most of the gadolinium present could not be further characterized. Light microscopy demonstrated increased CD34 immunoreactivity in the connective tissue septations of the subcutaneous adipose tissue. The patient had no history of skin disorders and did not have a history of nephrogenic systemic fibrosis but did have severe joint contractures of unknown etiology. CONCLUSIONS: Our results, in contradiction to published literature, suggest that in patients with normal renal function, exposure to GBCAs in extremely high cumulative doses can lead to significant gadolinium deposition in the skin. This finding is in line with more recent reports of gadolinium deposition in the brain of patients with normal renal function. Future studies are required to address possible clinical consequences of gadolinium deposition in the skin, brain, and potentially other organs in patients with normal renal function. We recommend, in addition to following current US Food and Drug Administration and American College of Radiology guidelines based on estimated glomerular filtration rate values, that caution be used when administering large cumulative doses of GBCAs and that total cumulative dose of each agent administered is recorded in the patient's medical record.

A case of isolated amyloid light-chain amyloidosis of the radial nerve.

Peripheral nerve involvement may be the first sign of systemic amyloid light-chain (AL) amyloidosis, a rare disease. Physical examination and electrodiagnostic testing are the mainstays of peripheral neuropathy evaluation at presentation. Sural nerve biopsy is performed in conjunction with serum and urine protein evaluation to differentiate between focal and systemic disease. Systemic disease is treated with a combination of chemotherapy, steroids, and stem cell transplantation. Isolated peripheral nerve disease is extremely rare. The authors here report the case of an 80-year-old woman who presented with progressive right upper-extremity weakness due to right radial neuropathy discovered upon electrodiagnostic testing. Magnetic resonance neurography (MRN) revealed a focal lesion within the right radial nerve. She underwent radial nerve exploration and excision of an intraneural mass consisting of amyloid on histopathology, with mass spectrometry analysis diagnostic for AL amyloidosis. Noninvasive testing and clinical history did not suggest systemic involvement. This unique case of isolated peripheral nerve AL amyloidosis in the absence of signs and symptoms of systemic disease is described, and the literature demonstrating peripheral nerve involvement in AL amyloidosis is reviewed.

Calcifying Pseudoneoplasm of the Cervicomedullary Junction: Case Report and a Literature Review.

BACKGROUND: Calcifying pseudoneoplasm of the neuroaxis (CAPNON) is a rare, slow-growing tumor of a fibro-osseous origin that may present anywhere in the neuroaxis. Although typically benign, symptoms of CAPNONs typically present secondary to compression and surrounding mass effect. Histologically, the tumor has the characteristics of a foreign body reaction with giant cells, ossification, and the formation of psammoma bodies. On imaging, they can easily be confused with malginant lesions such as chondrosarcoma or chondroblastoma or even more benign pathologies like meningioma. CASE DESCRIPTION: We present a case of a patient with an incidentally found calcifying pseudoneoplasm involving the cervicomedullary junction with further involvement of the vertebral artery and the hypoglossal nerve. We also review the literature on these tumors to date. CONCLUSION: Calcifying pseudoneoplasm of the neuroaxis is a slow-growing, benign, noninfiltrative lesion whose pathogensis and natural history remains unclear. It can appear anywhere in the neuroaxis and does not have a prevelant location. Because of the indolent course and relative rarity of this tumor, there are no current guidelines on the immediate and long-term management of CAPNONs. This entity, although quite rare, should be considered in the differential for calcified lesions at the cervicomedullary junction. The consensus for treatment of CAPNONs when symptomatic is surgical resection.

Pseudoneoplasms in the nervous system.

Pseudotumors are frequent in the nervous system and form a category of lesions that are fraught with peril for the pathologist unaware of the similarities and differences with neoplasms. The most common pseudoneoplasms in the nervous system are demyelinative, inflammatory and vascular. Even normal histology can be mistaken for neoplasm.

Intracranial atherosclerosis: correlation between in-vivo 3T high resolution MRI and pathology.

BACKGROUND: High-resolution MRI (HRMRI) is a promising tool for studying intracranial atherosclerotic disease (ICAD) in-vivo, but its use to understand the pathophysiology of ICAD has been limited by a lack of correlation between MRI signal characteristics and pathology in intracranial arteries. DESCRIPTION OF CASE: A patient with symptomatic left cavernous carotid stenosis underwent 3T HRMRI and died 4 days later. In-vivo HRMRI and postmortem histopathology images were compared. MRI signal characteristics consistent with atherosclerotic plaque composed of lipid and loose matrix, fibrous tissue, and calcium were correlated with pathology findings. Intraplaque hemorrhage was not present on HRMRI or pathology. CONCLUSIONS: This report demonstrates correlation between atherosclerotic plaque components visualized on 3T HRMRI images obtained in-vivo and pathological specimens of a symptomatic ICAD plaque, providing an important step in developing HRMRI as an in-vivo research tool to understand ICAD pathology.