Intracranial mesenchymal tumors with FET-CREB fusion are composed of at least two epigenetic subgroups distinct from meningioma and extracranial sarcomas.

'Intracranial mesenchymal tumor, FET-CREB fusion-positive' occurs primarily in children and young adults and has previously been termed intracranial angiomatoid fibrous histiocytoma (AFH) or intracranial myxoid mesenchymal tumor (IMMT). Here we performed genome-wide DNA methylation array profiling of 20 primary intracranial mesenchymal tumors with FET-CREB fusion to further study their ontology. These tumors resolved into two distinct epigenetic subgroups that were both divergent from all other analyzed intracranial neoplasms and soft tissue sarcomas, including meningioma, clear cell sarcoma of soft tissue (CCS), and AFH of extracranial soft tissue. The first subgroup (Group A, 16 tumors) clustered nearest to but independent of solitary fibrous tumor and AFH of extracranial soft tissue, whereas the second epigenetic subgroup (Group B, 4 tumors) clustered nearest to but independent of CCS and also lacked expression of melanocytic markers (HMB45, Melan A, or MITF) characteristic of CCS. Group A tumors most often occurred in adolescence or early adulthood, arose throughout the neuroaxis, and contained mostly EWSR1-ATF1 and EWSR1-CREB1 fusions. Group B tumors arose most often in early childhood, were located along the cerebral convexities or spinal cord, and demonstrated an enrichment for tumors with CREM as the fusion partner (either EWSR1-CREM or FUS-CREM). Group A tumors more often demonstrated stellate/spindle cell morphology and hemangioma-like vasculature, whereas Group B tumors more often demonstrated round cell or epithelioid/rhabdoid morphology without hemangioma-like vasculature, although robust comparison of these clinical and histologic features requires future study. Patients with Group B tumors had inferior progression-free survival relative to Group A tumors (median 4.5 vs. 49 months, p = 0.001). Together, these findings confirm that intracranial AFH-like neoplasms and IMMT represent histologic variants of a single tumor type ('intracranial mesenchymal tumor, FET-CREB fusion-positive') that is distinct from meningioma and extracranial sarcomas. Additionally, epigenomic evaluation may provide important prognostic subtyping for this unique tumor entity.

Intracranial mesenchymal tumor with FET-CREB fusion-A unifying diagnosis for the spectrum of intracranial myxoid mesenchymal tumors and angiomatoid fibrous histiocytoma-like neoplasms.

Intracranial mesenchymal tumors with FET-CREB fusions are a recently described group of neoplasms in children and young adults characterized by fusion of a FET family gene (usually EWSR1, but rarely FUS) to a CREB family transcription factor (ATF1, CREB1, or CREM), and have been variously termed intracranial angiomatoid fibrous histiocytoma or intracranial myxoid mesenchymal tumor. The clinical outcomes, histologic features, and genomic landscape are not well defined. Here, we studied 20 patients with intracranial mesenchymal tumors proven to harbor FET-CREB fusion by next-generation sequencing (NGS). The 16 female and four male patients had a median age of 14 years (range 4-70). Tumors were uniformly extra-axial or intraventricular and located at the cerebral convexities (n = 7), falx (2), lateral ventricles (4), tentorium (2), cerebellopontine angle (4), and spinal cord (1). NGS demonstrated that eight tumors harbored EWSR1-ATF1 fusion, seven had EWSR1-CREB1, four had EWSR1-CREM, and one had FUS-CREM. Tumors were uniformly well circumscribed and typically contrast enhancing with solid and cystic growth. Tumors with EWSR1-CREB1 fusions more often featured stellate/spindle cell morphology, mucin-rich stroma, and hemangioma-like vasculature compared to tumors with EWSR1-ATF1 fusions that most often featured sheets of epithelioid cells with mucin-poor collagenous stroma. These tumors demonstrated polyphenotypic immunoprofiles with frequent positivity for desmin, EMA, CD99, MUC4, and synaptophysin, but absence of SSTR2A, myogenin, and HMB45 expression. There was a propensity for local recurrence with a median progression-free survival of 12 months and a median overall survival of greater than 60 months, with three patients succumbing to disease (all with EWSR1-ATF1 fusions). In combination with prior case series, this study provides further insight into intracranial mesenchymal tumors with FET-CREB fusion, which represent a distinct group of CNS tumors encompassing both intracranial myxoid mesenchymal tumor and angiomatoid fibrous histiocytoma-like neoplasms.

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas.

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.

Ciliated columnar epithelium in the esophagus and gastroesophageal junction: A different perspective from study of a North American population.

An index case of ciliated columnar epithelium in a gastroesophageal (GE) junction biopsy identified in routine surgical pathology practice struck us as highly unusual. However, pathology literature, mainly from Asian populations, reports ciliated columnar epithelium in up to 40% of tissue samples from the upper GI tract. This was inconsistent with our pathology practice experience, so we initiated a local review of cases at our Canadian centre. 1048 consecutive tissue samples from the esophagus and GE junction were reviewed retrospectively and no ciliated epithelium was identified. This review included 1000× oil immersion microscopy of 22 cases with "multilayered epithelium". In 971 cases verified in prospective surgical pathology practice following identification of the index case, 3 additional cases of ciliated columnar epithelium were identified. The index case had ciliated pseudostratified columnar epithelium, resembling respiratory epithelium, and had strong, diffuse expression of TTF-1 by immunohistochemistry. In the other 3 cases, the cilia were located on the surface of a pseudostratified columnar epithelium, a multilayered epithelium, or a low columnar epithelium, all TTF-1 negative. Over a year later, the index case proved to have arisen from a bronchial-esophageal fistula. The other cases were not associated with a fistula. Our conclusion is that ciliated columnar epithelium is rare in Canadian adults (<0.5% of patients). Ciliated epithelium due to a bronchial-esophageal fistula is exceptional, but something to consider if there is a suspicious clinical picture and TTF-1 expression. Other cases might represent a rare metaplastic phenomenon or remnant from fetal development.

Intracranial myxoid mesenchymal tumors with EWSR1-CREB family gene fusions: myxoid variant of angiomatoid fibrous histiocytoma or novel entity?

Intracranial myxoid mesenchymal tumor harboring EWSR1 fusions with CREB family of genes was recently described, and it resembles the myxoid variant of angiomatoid fibrous histiocytoma. We present three pediatric patients with intracranial EWSR1-rearranged myxoid mesenchymal neoplasm and provide a molecular genetic characterization of these tumors. Clinical histories and imaging results were reviewed. Histology, immunohistochemistry, EWSR1, FUS, NR4A3 fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS) were performed. A 12-year-old male (case 1), 14-year-old female (case 2), and 18-year-old male (case 3), presented with headaches, emesis, and seizures, respectively. The magnetic resonance images demonstrated tumors abutting the dura (cases 1 and 3) and in the third ventricle (case 2). All tumors were vascular, with solid sheets of monomorphic oval cells in a prominent myxoid/microcystic matrix. A thin fibrous pseudocapsule was present in all lesions, but definitive lymphocytic cuffing was absent. Morphologically, they closely resembled myxoid variant of angiomatoid fibrous histiocytoma. Mitoses were rare, and necrosis was absent. All tumors expressed desmin and GLUT1, and focal EMA and CD99. The proliferation index was low. FISH and NGS showed EWSR1-CREB1 fusion (cases 1 and 2), and EWSR1-CREM fusion (case 3). There were no FUS (16p11.2) or NR4A3 (9q22.33) rearrangements in case 3. Gains of 5q (including KCNIP1) and 11q (including CCND1) were present in cases 1 and 2. There were no common pathogenic genomic changes other than EWSR1 rearrangements across cases. CNS myxoid mesenchymal neoplasms with histological and immunophenotypic similarities to myxoid variant of AFH are rare, diagnostically challenging, and harbor EWSR1-CREB1 and also a novel EWSR1-CREM fusion not yet described in AFH. Therefore, it is uncertain if these tumors represent variants of AFH or a new entity. The copy number and mutational changes presented here provide support for future studies to further clarify this issue.

Evolución Genética del Virus Influenza A(H1N1) pdm09 en Paraguay 2009-2016

RESUMEN Una cepa triple reasortante del virus Influenza A emergió en al año 2009 dando origen a una pandemia que alcanzó a Paraguay en junio del mismo año. Con el fin de investigar la evolución genética del virus influenza A (H1N1) pdm09 en Paraguay fueron analizadas las secuencias nucleotídicas del Gen de la Hemaglutinina de 20 cepas de Influenza A(H1N1)pdm09, aisladas en el Centro Nacional de Influenza de Paraguay entre los años 2009 y 2016, y secuenciadas en el Centro Colaborador de OPS/OMS en Atlanta USA. El análisis filogenético muestra la circulación de al menos 5 grupos genéticos bien diferenciados de Influenza A(H1N1)pdm09 en Paraguay desde el 2009. Solamente los virus aislados en el 2016 pertenecen al sub Grupo genético 6B.1 en el cual se encuentra la actual cepa vacunal A/Michigan/45/2015 recomendada para el hemisferio Sur desde el año 2017. Los virus circulantes en años anteriores pertenecen a grupos antigénicamente indistinguibles de la cepa vacunal previa A/California/7/2009. No se encontraron diferencias resaltantes en las secuencias de los virus, relacionadas a severidad clínica ni a distribución geográfica. Los resultados de este estudio reafirman la necesidad de una vigilancia virológica sistemática para orientar el establecimiento de estrategias adecuadas de prevención y control de la influenza.

ABSTRACT A triple reassortant strain of Influenza A virus emerged in 2009, leading to a pandemic that reached Paraguay by June the same year. In order to investigate the genetic evolution of influenza A (H1N1)pdm09 virus in Paraguay, we analized the nucleotide sequences of the Hemagglutinin gene of 20 Influenza A (H1N1)pdm09 strains, isolated at the Paraguayan National Influenza Centre between 2009 and 2016, and sequenced at the PAHO/WHO Collaborating Center in Atlanta, USA. Phylogenetic analysis shows the circulation of at least 5 well-differentiated genetic groups of Influenza A (H1N1) pdm09 in Paraguay since 2009. Only the viruses isolated in 2016 belong to genetic subgroup 6B.1, the same as the current vaccine strain A/Michigan/45/2015, recommended for the Southern hemisphere since 2017. The viruses circulated previous years belong to groups antigenically indistinguishable from the previous vaccine strain A/California/7/2009. No significant differences were found in sequences of the viruses, related to clinical severity or geographic distribution. The results of this study reaffirm the need for systematic virological surveillance to guide the establishment of adequate strategies for the prevention and control of influenza.

Case report and literature review of a rare diagnosis of ossifying renal tumour of infancy.

One must entertain a broad differential diagnosis for infants presenting with gross hematuria. Initial workup includes urine analysis, serum laboratory values and abdominal ultrasound. We describe an infant presenting with gross hematuria found to have a calcified renal mass upon initial ultrasound and subsequent computed tomography scan. We considered a differential diagnosis of, but not exclusive to, staghorn calculi, nephroblastoma, Wilms' tumour, mesoblastic nephroma and ossifying renal tumour of infancy (ORTI). A nephrectomy was performed, and the pathology report identified the calcified mass as an ORTI.

Gastric hamartoma of the pylorus in an infant.

Gastric hamartomata, alternatively called adenomyomata, are rare, benign lesions of the gastric wall. They can present with a wide spectrum of symptomatology. Pure pyloric adenomyomata are exceedingly rare. We are reporting a 13-day-old infant with a gastric hamartoma at the pylorus presenting with gastric outlet obstruction mimicking infantile hypertrophic pyloric stenosis.

Identification of t(1;19)(q12;p13) and ploidy changes in an ependymosarcoma: a cytogenetic evaluation.

Gliosarcoma, a recognized subtype of glioblastoma, is a biphasic tumor exhibiting distinct glial and sarcomatous components. Ependymosarcomas are rarer, biphasic ependymal tumors exhibiting sarcomatous change. Genetic abnormalities associated with this curious phenotype are not well understood. We are presenting the first karyotype of ependymosarcoma with identification of a clonal t(1;19)(q12;p13). Fluorescence in situ hybridization (FISH) was performed with a probe set targeting 1q23 and 19p13.3. Although the tumor did not show evidence of t(1;19)(q23;p13.3) by FISH, increased ploidy was a feature of the sarcomatous component. On clinical followup the patient is doing well without evidence of recurrence 55 months after initial resection, and postoperative treatment with irradiation and temozolomide. The significance of the genetic alterations we describe associated with sarcomatoid change in ependymal neoplasms, and ultimately their prognostic relevance, merits further study.

Novel use of F-DOPA PET/CT imaging in a child with paraganglioma/pheochromocytoma syndrome.

We report the use of F-DOPA PET/CT imaging in the evaluation of a teenager with marked hypertension and right pararenal, left adrenal and left para-aortic mass lesions. The use of the modality for this clinical application has not been described previously within the pediatric imaging literature. The value of this technique relative to conventional imaging modalities is discussed and warrants consideration of its use, if available, for evaluating children with suspected paragangliomas/pheochromocytomas.

Limited dorsal myeloschisis: a distinctive clinicopathological entity.

BACKGROUND: Limited dorsal myeloschisis (LDM) is a distinctive form of spinal dysraphism characterized by 2 constant features: a focal "closed" midline defect and a fibroneural stalk that links the skin lesion to the underlying cord. The embryogenesis is hypothesized to be incomplete disjunction between cutaneous and neural ectoderms, thus preventing complete midline skin closure and allowing persistence of a physical link (fibroneural stalk) between the disjunction site and the dorsal neural tube. OBJECTIVE: To illustrate these features in 51 LDM patients. METHODS: All patients were studied with magnetic resonance imaging or computed tomography myelography, operated on, and followed for a mean of 7.4 years. RESULTS: There were 10 cervical, 13 thoracic, 6 thoracolumbar and 22 lumbar lesions. Two main types of skin lesion were saccular (21 patients), consisting of a skin-base cerebrospinal fluid sac topped with a squamous epithelial dome, and nonsaccular (30 patients), with a flat or sunken squamous epithelial crater or pit. The internal structure of a saccular LDM could be a basal neural nodule, a stalk that inserts on the dome, or a segmental myelocystocele. In nonsaccular LDMs, the fibroneural stalk has variable thickness and complexity. In all LDMs, the fibroneural stalk was tethering the cord. Twenty-nine patients had neurological deficits. There was a positive correlation between neurological grade and age, suggesting progression with chronicity. Treatment consisted of detaching the stalk from the cord. Most patients improved or remained stable. CONCLUSION: LDM is a distinctive clinicopathological entity and a tethering lesion with characteristic external and internal features. We propose a new classification incorporating both saccular and flat lesions.

Long-term outcome of total and near-total resection of spinal cord lipomas and radical reconstruction of the neural placode, part II: outcome analysis and preoperative profiling.

OBJECTIVE: To show the long-term benefits of total and near-total resection of complex spinal cord lipomas and reconstruction of the neural placode. METHODS: We analyzed 238 patients with dorsal, transitional, and chaotic lipomas who had total resection as described in part I for overall progression-free survival probability (PFS, Kaplan-Meier analysis) over 16 years. We also analyzed subgroup proportional recurrence hazard (Cox analysis) of 6 outcome predictors of sex, lipoma type, age, preoperative symptoms, previous surgery, and postoperative cord-sac ratio. These results were compared with an age-matched, lesion-matched series of 116 patients followed for 11 years after partial lipoma resection and with the Parisian series of nonsurgical treatment. RESULTS: The immediate effects of surgery were similar between total and partial resection: both achieved greater than 95% symptom stabilization or improvement rate. The neuro-urologic complication rates for the groups were also similar, 4.2% and 5.2% for total and partial resection, respectively. The combined cerebrospinal fluid leakage and wound complication rate of total resection was much lower at 2.5% than the 6.9% for partial resection, but both were better than published rates. The overall PFS for total resection was 82.8% at 16 years, comparing much more favorably with 34.6% for partial resection at 10.5 years (P < .0001). Culling only the asymptomatic patients with virgin (previously unoperated) lipomas to match the patient profile of the Parisian series, the PFS for prophylactic total resection for this subgroup increased to 98.4% at 16 years, versus 67% at 9 years for no surgery and 43.3% at 10.5 years for our own partial resection series, with a remarkable statistical difference between total and partial resection (P = .00001). Subgroup analyses showed that sex and lipoma type did not affect outcome. For the other predictor variables, while univariate analyses showed that young age, absence of symptom, and virgin lipomas correlated with better statistical PFS than older age, symptoms, and redo lipomas, these effects vanished with multivariate analyses. Cord-sac ratio stood alone as the only influential outcome predictor in multivariate analysis, with a 96.6% PFS for a low ratio of <30% and an 80.6% progression-free probability for a high ratio of >50%, and a 3-fold increase in recurrence hazard for high ratios (P = .0009). This suggested that all the individual effects of the other predictor variables could be reduced to whether a low cord-sac ratio could be achieved with total lipoma resection and placode reconstruction. Cord-sac ratio was the obvious factor that differentiated the outcomes between total and partial resection, the latter associated with a >90% chance of having a high cord-sac ratio. CONCLUSION: Total and near-total resection of lipomas and complete reconstruction of the neural placode produced a much better long-term progression-free probability than partial resection and nonsurgical treatment. The perioperative complications for total resection were low and compared favorably with published results. A low postoperative cord-sac ratio and well-executed placode neurulation were strongly correlated with good outcome. The ideal preoperative patient profile with early disease stabilization and the best recurrence-free probability is an asymptomatic child less than 2 years without previous lipoma surgery. There are strong indications that partial resection in many cases produces worse scarring on the neural placode and worse prognosis than no surgery.

Long-term outcome of total and near-total resection of spinal cord lipomas and radical reconstruction of the neural placode: part I-surgical technique.

OBJECTIVE: Partial resection of complex spinal cord lipomas is associated with a high rate of symptomatic recurrence caused by retethering, presumably promoted by a tight content-container relationship between the spinal cord and the dural sac, and incomplete detachment of the terminal neural placode from residual lipoma. Since 1991, we have performed more than 250 total/near-total resections of complex lipomas with radical reconstruction of the neural placodes. Sixteen years of follow-up have proven the long-term benefits of this technique. Part I of this series introduces our technique of total resection and reports the immediate surgical results. Part II will analyze the long-term outcomes of both total and partial resection and identify the factors affecting outcome. METHODS: From 1991 to 2006, 238 patients (age range, 2 months-72 years) with dorsal, transitional, and chaotic lipomas underwent total or near-total lipoma resection and radical placode reconstruction. Eighty-four percent of the patients were children younger than 18 years and 16% were adults. The technique consisted of wide bony exposure, complete unhinging of the lateral adhesions of the lipoma-placode assembly from the inner dura, untethering of the terminal conus, radical resection of the fat off the neural plate along a white fibrous plane at the cord-lipoma interface, meticulous pia-to-pia neurulation of the supple neural placode with microsutures, and expansile duraplasty with a bovine pericardial graft. Elaborate electrophysiological monitoring was used. RESULTS: Three postoperative observations concern us. The first is that of the 238 patients, 138 (58%) had no residual fat on postoperative magnetic resonance imaging; 81 patients (36%) had less than 20 mm3 of residual fat, the majority of which were small bits enclosed by neurulation; and 19 patients (8%), mainly of the chaotic lipoma group, had more than 20 mm of fat. There are no significant differences in the amount of residual fat among lipoma types, but redo lipomas are more likely than virgin (previously unoperated on) lipomas to have residual fat by a factor of 2 (P = 0.0214). The second concern is that the state of the reconstructed placode is objectively measured by the cord-sac ratio, obtained by dividing the sagittal diameter of the reconstructed neural tube by the sagittal diameter of the thecal sac. A total of 162 patients (68%) had cord-sac ratios less than 30% (low), 61 (25.6%) had ratios between 30% and 50% (medium), and only 15 (6.3%) had high ratios of more than 50%. Seventy-four percent of patients with virgin lipomas had low cord-sac ratios compared with 56.3% in the redo lipoma patients. The overall distribution of cord-sac ratio is significantly different between redo and virgin lipomas (P = 0.00376) but not among lipoma types. Finally, the incidence of combined neurological and urological complications was 4.2%. The combined cerebrospinal fluid leak and wound infection/dehiscence incidence was 2.5%. Both sets of surgical morbidity compared favorably with the published rates reported for partial resection. CONCLUSION: Total/near-total resection of spinal cord lipomas and complete reconstruction of the neural placode can be achieved with low surgical morbidity and a high yield of agreeable postoperative cord-sac relationship. Some large rambling transitional lipomas and most chaotic lipomas are the most difficult lesions to resect and tend to have less favorable results on postresection magnetic resonance imaging.

Ependymal tumors with sarcomatous change ("ependymosarcoma"): a clinicopathologic and molecular cytogenetic study.

Gliosarcomas are uncommon primary tumors of the central nervous system defined as exhibiting both glial and sarcomatous components. Sarcomatous change occurring in ependymal tumors is rare. We identified 11 such examples. There were 6 female and 5 male patients (median age, 18 y; range, 2 to 63). The tumors were located in the parieto-occipital (n=2), temporal (n=1), parietal (n=1), frontal (n=1), and occipital lobes (n=1), as well as the lateral ventricles (n=2), insula (n=1), cerebellopontine angle (n=1), and fourth ventricle/cerebellopontine angle (n=1). At presentation, the sarcomatous component was noted in 6 (of 10) cases and the ependymal element was grade III in 7 and grade II in 3 tumors, respectively. The sarcomatous component consisted of a reticulin rich, glial fibrillary acidic protein-negative fibrosarcoma (n=5) or pleomorphic spindle cell sarcoma (n=3), and 2 examples with heterologous elements: osseous and cartilaginous (n=1) and osseous only (n=1). The single case involving the fourth ventricle/left cerebellopontine angle consisted of subependymoma and fibrosarcoma components in roughly equal proportions at presentation. Fluorescence in situ hybridization studies performed with probes targeting the NF2 gene and other members of the protein 4.1 gene family demonstrated similar alterations in the ependymal and sarcomatous components in the cases tested, including polysomies/polyploidy (n=3), gains of 1q (n=3), deletions of 22q (n=2) and 6q (n=1), and monosomy 18 (n=1). There was no evidence of MDM2 or CCND1 amplification in any of the cases tested. On follow-up, 5 patients expired 4 months to 18 years after initial resection and 4 to 11 months after development of the sarcomatous component (mean, 7.6 mo); 1 patient is alive at 5 years with recurrent disease, and 1 is alive without recurrence 12 years after initial gross total resection followed by radiation therapy. Although rare, ependymal neoplasms must be included among the gliomas prone to undergo sarcomatous change and we propose the term "ependymosarcoma" for these tumors.

Clear cell meningioma: case report and review of the literature.

Clear cell meningioma (CCM) is a rare variant of meningioma. Only 17 cases have been previously reported in children. Although it has bland cytologic features, it has a higher rate of recurrence than does conventional meningioma. This variant has been reported in sites such as spinal/intradural (lumbar and thoracic), cerebellopontine angle, and supratentorial. The differential diagnosis of CCM includes microcystic meningioma, hemangioblastoma, and clear cell ependymoma. The characteristic histology and immunohistochemistry leads to the diagnosis. We present a case of a 7-year-old boy with a CCM of the cauda equina and a review of pediatric CCM.

Congenital pulmonary capillary hemangiomatosis: Report of two cases and review of the literature.

Pulmonary capillary hemangiomatosis (PCH) is a rare disease characterized by pulmonary hypertension and excessive neovascularization within the pulmonary interstitium, vasculature, and airways. We describe two unusual cases of congenital PCH. Both cases had concurrent anomalies, including renal and urinary bladder agenesis and hypertropic cardiomyopathy. In one case, capillary proliferation caused significant impingement of the proximal bronchial airways. A review of the current literature is described.