Astroblastomas exhibit radial glia stem cell lineages and differential expression of imprinted and X-inactivation escape genes.

Astroblastomas (ABs) are rare brain tumors of unknown origin. We performed an integrative genetic and epigenetic analysis of AB-like tumors. Here, we show that tumors traceable to neural stem/progenitor cells (radial glia) that emerge during early to later brain development occur in children and young adults, respectively. Tumors with MN1-BEND2 fusion appear to present exclusively in females and exhibit overexpression of genes expressed prior to 25 post-conception weeks (pcw), including genes enriched in early ventricular zone radial glia and ependymal tumors. Other, histologically classic ABs overexpress or harbor mutations of mitogen-activated protein kinase pathway genes, outer and truncated radial glia genes, and genes expressed after 25 pcw, including neuronal and astrocyte markers. Findings support that AB-like tumors arise in the context of epigenetic and genetic changes in neural progenitors. Selective gene fusion, variable imprinting and/or chromosome X-inactivation escape resulting in biallelic overexpression may contribute to female predominance of AB molecular subtypes.

A Conservative Approach to the Treatment of a Rare Case of Cervical Spine Double Expressor Diffuse Large B-cell Lymphoma: A Case Report.

Non-Hodgkin's lymphomas are a group of lymphoid neoplasms, with diffuse large B-cell lymphoma (DLBCL) being the most common subtype. Genetic alterations involving c-MYC, BCL-2, and BCL-6 have been implicated in the pathogenesis of subtypes of DLBCL with poor prognostic implications. This case report demonstrates a retropharyngeal mass with extension through the bilateral neuroforamina into the epidural space and posterior elements of the cervical spine (C2-C3), for which biopsy revealed diffuse large B-cell lymphoma. Here we present a unique case as it provides a solution for the dilemma on how to treat a patient with a known prior malignancy (gastrointestinal [GI] melanoma) with a retropharyngeal mass with epidural extension (dumbbell-shaped tumor) with an inconclusive initial CT-guided needle-core biopsy. A CT-guided biopsy only yielded that the mass was neoplasm; we had a choice between attempting gross total resection of the mass or open biopsy. Attempting gross total resection would have entailed an anterior approach (transoral with possible odontoidectomy or endoscopic endonasal with possible odontoidectomy) along with posterior instrumentation and fusion from occiput to C3, which is a rather morbid procedure that would subject the patient to a decreased quality of life as well as risks of vascular injury, dysphagia, and infection. We elected to perform an open biopsy of the epidural component of the mass through a decompressive laminectomy, which allowed for decompression of the spinal cord as well as a sampling of the mass. This provided treatment for possible increasing epidural compression from the mass, as well as diagnostic tissue. A multidisciplinary team discussed the case and developed a treatment plan for the patient with systemic and intrathecal chemotherapy in combination with radiotherapy.

CNS Histoplasmosis as a Gliosarcoma mimicker: The diagnostic dilemma of solitary brain lesions.

Histoplasmosis is usually a benign, self-limited disease with lungs predilection. However, it might manifest as a disseminated disease in immunocompromised individuals. The involvement of the central nervous system (CNS) accounts for about 5-10% of cases with disseminated disease. Isolated histoplasmosis of the CNS is rare, and the literature shows only a few reported cases. By imaging studies, it usually presents as an isolated ring-enhancing lesion. Its spectrum of symptoms ranges from acute severe infection to progressive chronic meningitis, which delays the initial diagnosis, correct work-up and initiation of appropriate therapy. We present a case of a 57-year-old man from the Midwest of the United States who misdiagnosed with Gliosarcoma in 2019, for which he underwent appropriate management for Gliosarcoma. Presented for follow-up after new neurological symptoms; worsening in ring-enhancing brain lesions was found on magnetic resonance image MRI. After a re-examination of surgical pathological cases, histoplasmosis of the CNS was diagnosed. Failure of diagnosis CNS histoplasmosis early can lead to poor outcome and decrease chances of recovery.

Isolated Primary Sinonasal Adenocarcinoma of the Sphenoid Sinus.

Isolated lesions of the sphenoid sinus, particularly malignancies, are rarely reported and exist largely within the Otolaryngology literature. Delayed diagnosis may necessitate neurosurgical involvement; therefore, neurosurgeons must be aware of the range of pathologies in this region in order to provide adequate treatment. We present an unusual case of an 89-year-old female with several weeks of worsening headaches, vision loss, and cranial neuropathies. Work-up at an outside hospital was non-diagnostic. After referral, an expansive and erosive lesion within the left sphenoid sinus was identified. A transsphenoidal approach for resection of the lesion yielded a primary non-salivary non-intestinal type sinonasal adenocarcinoma, as well as bacterial sinusitis and probable allergic fungal sinusitis. The patient was treated with antimicrobial medications as well as stereotactic radiosurgery. Her neurological deficits did not improve with treatment, and she ultimately expired 3.5 months post-operatively after transition to hospice. Primary sinonasal adenocarcinoma is a very rare pathology in this location. Surgical intervention is necessary to obtain an accurate diagnosis and proceed with appropriate treatment. Delayed diagnosis likely portends a worse prognosis.

Digital karyotyping technology: exploring the cancer genome.

Identifying gene-specific alterations in cancer genomes has revealed molecules that are causal effectors of carcinogenesis and specific targets for cancer molecular diagnosis and molecular-based cancer therapies. Whole-genome analyses of many cancer genomes at the resolution of single genes is thus a desirable yet incompletely realized goal that could expedite progress in cancer diagnosis and treatment. Although methods for routine whole-genome sequencing or high-resolution epigenetic measurements are currently under development, high-resolution measurements of gene copy number, or 'gene dosage', are now underway in several laboratories. Digital karyotyping, array comparative genomic hybridization, and single nucleotide polymorphism arrays are techniques that have the potential to detect gene amplification, homozygous deletion and loss of heterozygosity at or below the average length of single genes. Recently, digital karyotyping of a small number (<20) of colon and brain cancer genomes has revealed tumor cases with significant genetic dosage alterations affecting few and, in some cases, only one complete gene. These experiments suggest that gene-specific gene dosage alterations may be sufficiently frequent to enable the identification of promising tumor gene candidates in small-scale experiments. The purpose of this review is to describe our understanding of cancer as a genetic disease, review the basic principles, methodologies and interpretational issues of traditional and high-resolution whole-genome screens, and describe the potential of our first detailed look at whole cancer genomes for progress in the understanding and treatment of cancer.

Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid.

Through digital karyotyping of permanent medulloblastoma cell lines, we found that the homeobox gene OTX2 was amplified more than 10-fold in three cell lines. Gene expression analyses showed that OTX2 transcripts were present at high levels in 14 of 15 (93%) medulloblastomas with anaplastic histopathologic features. Knockdown of OTX2 expression by siRNAs inhibited medulloblastoma cell growth in vitro, whereas pharmacologic doses of all-trans retinoic acid repressed OTX2 expression and induced apoptosis only in medulloblastoma cell lines that expressed OTX2. These observations suggest that OTX2 is essential for the pathogenesis of anaplastic medulloblastomas and that these tumors may be amenable to therapy with all-trans-retinoic acid.

Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas.

The phosphatidylinositol 3'-kinase pathway is activated in multiple advanced cancers, including glioblastomas, through inactivation of the PTEN tumor suppressor gene. Recently, mutations in PIK3CA, a member of the family of phosphatidylinositol 3'-kinase catalytic subunits, were identified in a significant fraction (25-30%) of colorectal cancers, gastric cancers, and glioblastomas and in a smaller fraction of breast and lung cancers. These mutations were found to cluster into two major "hot spots" located in the helical and catalytic domains. To determine whether PIK3CA is genetically altered in brain tumors, we performed a large-scale mutational analysis of the helical and catalytic domains. A total of 13 mutations of PIK3CA within these specific domains were identified in anaplastic oligodendrogliomas, anaplastic astrocytomas, glioblastoma multiforme, and medulloblastomas, whereas no mutations were identified in ependymomas or low-grade astrocytomas. These observations implicate PIK3CA as an oncogene in a wider spectrum of adult and pediatric brain tumors and suggest that PIK3CA may be a useful diagnostic marker or a therapeutic target in these cancers.

Neuropathology of primary restless leg syndrome: absence of specific tau- and alpha-synuclein pathology.

The neuroanatomical substrate for restless legs syndrome (RLS) is unknown. We identified 4 patients with idiopathic RLS who came to post-mortem examination, where brain and spinal cord tissue were available for neuropathological assessment. Lewy bodies were not identified and alpha-synuclein immunohistochemistry was uniformly negative. Neurofibrillary tangle pathology was variable and nonspecific. These findings suggest that tau- or alpha-synuclein brain pathology is not a component of primary RLS. Although chronic ischemic changes were found in all 4 cases, these were probably incidental. The absence of diagnostic microscopic brain or spinal cord pathology suggests that the pathologic substrate may be neurochemical or receptor based.