The immunohistochemical, DNA methylation, and chromosomal copy number profile of cauda equina paraganglioma is distinct from extra-spinal paraganglioma.

Paragangliomas are neuroendocrine tumors of the autonomic nervous system that are variably clinically functional and have a potential for metastasis. Up to 40% occur in the setting of a hereditary syndrome, most commonly due to germline mutations in succinate dehydrogenase (SDHx) genes. Immunohistochemically, paragangliomas are characteristically GATA3-positive and cytokeratin-negative, with loss of SDHB expression in most hereditary cases. In contrast, the rare paragangliomas arising in the cauda equina (CEP) or filum terminale region have been shown to be hormonally silent, clinically indolent, and have variable keratin expression, suggesting these tumors may represent a separate pathologic entity. We retrospectively evaluated 17 CEPs from 11 male and 6 female patients with a median age of 38 years (range 21-82), none with a family history of neuroendocrine neoplasia. Six of the 17 tumors demonstrated prominent gangliocytic or ganglioneuromatous differentiation. By immunohistochemistry, none of the CEPs showed GATA3 positivity or loss of SDHB staining; all 17 CEPs were cytokeratin positive. Genome-wide DNA methylation profiling was performed on 12 of the tumors and compared with publicly available genome-wide DNA methylation data. Clustering analysis showed that CEPs form a distinct epigenetic group, separate from paragangliomas of extraspinal sites, pheochromocytomas, and other neuroendocrine neoplasms. Copy number analysis revealed diploid genomes in the vast majority of CEPs, whereas extraspinal paragangliomas were mostly aneuploid with recurrent trisomy 1q and monosomies of 1p, 3, and 11, none of which were present in the cohort of CEP. Together, these findings indicate that CEPs likely represent a distinct entity. Future genomic studies are needed to further elucidate the molecular pathogenesis of these tumors.

Myocarditis and Raw Meat Consumption: Strange Bedfellows!

Trichinellosis is a parasitic infection that is associated with the consumption of raw meat. The specific genotype Trichinella nativa has been found in raw bear meat. The most common genotype that has been linked with myocarditis is T spiralis. We present a case of T nativa myocarditis secondary to consumption of raw bear meat. The clinical manifestations as well as therapy of this specific genotype is outlined.

The Concept of an Epilepsy Brain Bank.

Epilepsy comprises more than 40 clinical syndromes affecting millions of patients and families worldwide. To decode the molecular and pathological framework of epilepsy researchers, need reliable human epilepsy and control brain samples. Brain bank organizations collecting and supplying well-documented clinically and pathophysiologically tissue specimens are important for high-quality neurophysiology and neuropharmacology studies for epilepsy and other neurological diseases. New development in molecular mechanism and new treatment methods for neurological disorders have evoked increased demands for human brain tissue. An epilepsy brain bank is a storage source for both the frozen samples as well as the formaldehyde fixed paraffin embedded (FFPE) tissue from epilepsy surgery resections. In 2014, the University of Saskatchewan have started collecting human epilepsy brain tissues for the first time in Canada. This review highlights the necessity and importance of Epilepsy Brain bank that provides unique access for research to valuable source of brain tissue and blood samples from epilepsy patients.

Eosinophilic intracytoplasmic inclusions in Purkinje neurons of children.

Eosinophilic intracytoplasmic inclusions have been rarely described in Purkinje neurons of children with a variety of neurological conditions. Here we document these inclusions in five children from 3 to 14 years of age. One child had 7q deletion syndrome and a second had profound motor and cognitive delay ("cerebral palsy") of unknown origin, while three others were neurologically normal prior to death. These inclusions stain with the PAS method, are not strongly ubiquitinated, and are located in the lumen of endoplasmic reticulum. Their appearance in a wide range of disorders and in neurologically normal children suggests that they are a nonspecific protein trafficking anomaly, possibly aggravated under degenerative conditions.

IL-13 receptors as possible therapeutic targets in diffuse intrinsic pontine glioma.

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal childhood cancer of the brain. Despite the introduction of conventional chemotherapy and radiotherapy, improvements in survival have been marginal and long-term survivorship is uncommon. Thus, new targets for therapeutics are critically needed. Early phase clinical trials exploring molecularly-targeted therapies against the epidermal growth factor receptor (EGFR) and novel immunotherapies targeting interleukin receptor-13α2 (IL-13Rα2) have demonstrated activity in this disease. To identify additional therapeutic markers for cell surface receptors, we performed exome sequencing (16 new samples, 22 previously published samples, total 38 with 26 matched normal DNA samples), RNA deep sequencing (17 new samples, 11 previously published samples, total 28 with 18 matched normal RNA samples), and immunohistochemistry (17 DIPG tissue samples) to examine the expression of the interleukin-4 (IL-4) signaling axis components (IL-4, interleukin 13 (IL-13), and their respective receptors IL-4Rα, IL-13Rα1, and IL-13Rα2). In addition, we correlated cytokine and receptor expression with expression of the oncogenes EGFR and c-MET. In DIPG tissues, transcript-level analysis found significant expression of IL-4, IL-13, and IL-13Rα1/2, with strong differential expression of IL-13Rα1/2 in tumor versus normal brain. At the protein level, immunohistochemical studies revealed high content of IL-4 and IL-13Rα1/2 but notably low expression of IL-13. Additionally, a strong positive correlation was observed between c-Met and IL-4Rα. The genomic and transcriptional landscape across all samples was also summarized. These data create a foundation for the design of potential new immunotherapies targeting IL-13 cell surface receptors in DIPG.

Thoracic primary central nervous system melanoma and lumbar schwannoma of complex neurocristopathy: case report.

Complex neurocristopathy, a disorder resulting from the aberrant proliferation of tissues derived from neural crest cells, has been previously reported in 2 patients, both involving ophthalmic melanoma and other tumors. One patient had a periorbital neurofibroma, sphenoid wing meningioma, and choroid juxtapapillary meningioma. The other patient had a choroidal melanoma and an optic nerve sheath meningioma. The authors describe clinical and pathological findings in a patient who underwent resection of 2 distinct lesions: primary CNS melanoma at T-12 and an L-5 schwannoma. Clinical and histopathological findings of the case are reviewed. To the authors' knowledge, this is the first patient to present with complex neurocristopathy involving both a spinal melanoma and schwannoma.

Metastatic signet ring cell adenocarcinoma of the bladder: responsive to treatment?

Signet ring cell variant of mucinous adenocarcinoma of the urinary bladder is an exceptionally rare urologic malignancy, generally felt to be resistant to chemotherapy and radiotherapy. We describe a case of this malignancy with unusual sites of metastasis and an unexpectedly good response to treatment.

Extramedullary hematopoiesis involving the central nervous system and surrounding structures.

Extramedullary hematopoiesis in central nervous system is a rare condition that can present in association with hematologic conditions. In this single-center retrospective study from 1988 to 2010, we identified 8 cases of extramedullary hematopoiesis involving the central nervous system or meninges. Most were incidental autopsy findings, usually microscopic collections of cells in the meninges or around blood vessels in the brain of infants (4 cases; age, 10 days to 5 months), in 1 young child (age, 6.5 years with anemia), and 1 elderly adult (age, 81 years with end-stage idiopathic myelofibrosis). Two individuals (both with polycythemia rubra vera) presented with symptomatic intracranial or spinal canal lesions (age, 67 and 68 years). Mixed populations of immature hematopoietic cells were identified by characteristic morphology and appropriate immunohistochemistry. The precise pathogenesis of extramedullary hematopoiesis in central nervous system is unknown. In infants, extramedullary hematopoiesis is unlikely to be pathologic and most likely represents a resolving fetal state. The older children and adults with incidental or symptomatic extramedullary hematopoiesis usually have some underlying hematologic condition, which should be sought if not already recognized.

Diagnosis of ovarian carcinoma cell type is highly reproducible: a transcanadian study.

Reproducible diagnosis of ovarian carcinoma cell types is critical for cell type-specific treatment. The purpose of this study was to test the reproducibility of cell type diagnosis across Canada. Analysis of the interobserver reproducibility of histologic tumor type was performed among 6 pathologists after brief training in the use of modified World Health Organization criteria to classify ovarian carcinomas into 1 of 6 categories: high-grade serous, endometrioid, clear cell, mucinous, low-grade serous, and other. These 6 pathologists independently reviewed a test set of 40 ovarian carcinomas. A validation set of 88 consecutive ovarian carcinomas drawn from 5 centers was subject to local review by 1 of the 6 study pathologists, and central review by a single observer. Interobserver agreement was assessed through calculation of concordance and kappa values for pair-wise comparison. For the test set, the paired concordance between pathologists in cell type diagnosis ranged from 85.0% to 97.5% (average 92.3%), and the kappa values were 0.80 to 0.97 (average 0.89). Inclusion of immunostaining results did not significantly improve reproducibility (P=0.69). For the validation set, the concordance between original diagnosis and local review was 84% and between local review and central review was 94%. The kappa values were 0.73 and 0.89, respectively. With a brief training exercise and the use of defined criteria for ovarian carcinoma subtyping, there is excellent interobserver reproducibility in diagnosis of cell type. This has implications for clinical trials of subtype-specific ovarian carcinoma treatments.