Ganglioglioma with anaplastic/high-grade transformation: Histopathologic, molecular, and epigenetic characterization of 3 cases.

Ganglioglioma (GG) with anaplasia (anaplastic ganglioglioma) is a rare and controversial diagnosis. When present, anaplasia involves the glial component of the tumor, either at presentation or at recurrence. To date, most published cases lack molecular characterization. We describe the histologic and molecular features of 3 patients presenting with BRAF p. V600E-mutant GG (CNS WHO grade 1) with high-grade glial transformation at recurrence. The tumors occurred in pediatric patients (age 9-16 years) with time to recurrence from 20 months to 7 years. At presentation, each tumor was low-grade, with a BRAFV600E-positive ganglion cell component and a glial component resembling pleomorphic xanthoastrocytoma (PXA) or fibrillary astrocytoma. At recurrence, tumors resembled anaplastic PXA or high-grade astrocytomas without neuronal differentiation. CDKN2A homozygous deletion (HD) was absent in all primary tumors. At recurrence, 2 cases acquired CDKN2A HD; the third case showed loss of p16 and MTAP immunoexpression, but no CDKN2A/B HD or mutation was identified. By DNA methylation profiling, all primary and recurrent tumors either grouped or definitely matched to different methylation classes. Our findings indicate that malignant progression of the glial component can occur in GG and suggest that CDKN2A/B inactivation plays a significant role in this process.

UHRF1 overexpression promotes osteosarcoma metastasis through altered exosome production and AMPK/SEMA3E suppression.

Loss-of-function mutations at the retinoblastoma (RB1) gene are associated with increased mortality, metastasis, and poor therapeutic outcome in several cancers, including osteosarcoma. However, the mechanism(s) through which RB1 loss worsens clinical outcome remains understudied. Ubiquitin-like with PHD and Ring Finger domains 1 (UHRF1) has been identified as a critical downstream effector of the RB/E2F signaling pathway that is overexpressed in various cancers. Here, we determined the role and regulatory mechanisms of UHRF1 in rendering osteosarcoma cells more aggressive. Higher UHRF1 expression correlated with malignancy in osteosarcoma cell lines, clinical samples, and genetically engineered mouse models. Gain- and loss-of-function assays revealed that UHRF1 has cell-intrinsic and extrinsic functions promoting cell proliferation, migration, invasion, angiogenesis, and metastasis. UHRF1 overexpression induced angiogenesis by suppressing AMPK activation and Semaphorin 3E (SEMA3E) expression. Further, UHRF1-mediated migration and metastasis resulted, at least in part, through altered expression of extracellular vesicles and their cargo, including urokinase-type plasminogen activator (uPA). Novel osteosarcoma genetically engineered mouse models confirmed that knocking out Uhrf1 considerably decreased metastasis and reversed the poorer survival associated with Rb1 loss. This presents a new mechanistic insight into RB1 loss-associated poor prognosis and novel oncogenic roles of UHRF1 in the regulation of angiogenesis and exosome secretion, both critical for osteosarcoma metastasis. This provides substantial support for targeting UHRF1 or its downstream effectors as novel therapeutic options to improve current treatment for osteosarcoma.

Embolization of a third ventricular choroid plexus papilloma: illustrative case.

BACKGROUND: Choroid plexus tumors are rare neoplasms that are typically found in the lateral ventricles. They have infrequently been reported in the third ventricle, and treatment strategies have varied. OBSERVATIONS: The authors described a 6-month-old patient who presented with irritability and hypotonia. The patient was found to have a large tumor in the third ventricle with obstructive hydrocephalus. Preoperative angiography revealed a feeding artery from the right medial posterior choroidal artery (MPChA). The feeding artery was effectively embolized, and the patient subsequently received open resection of the tumor. Pathology revealed features consistent with atypical choroid plexus papilloma (CPP). LESSONS: Choroid plexus tumors are often hypervascular, which can often make gross total resection (GTR) difficult. Preoperative angiography of tumors identifies feeding vessels, and embolization has the potential to decrease perioperative blood loss and allow for a higher GTR rate. Third ventricular CPPs appear to invariably receive vascular supply from the MPChA, arising from the right posterior cerebral artery. Embolization followed by resection of a choroid plexus tumor in the third ventricle is an effective treatment strategy.

Not All that Strictures Is IBD: Gastric Heterotopia Leading to Perforation and Small Bowel Obstruction Mimicking IBD.

A 14-year-old male presented with worsening chronic intermittent abdominal pain, mild anemia, positive fecal occult blood test, and elevated calprotectin. Computerized tomography and magnetic resonance imaging showed ileal dilation with mucosal enhancement and inflammatory changes suspicious for inflammatory bowel disease (IBD). Prominent mucosal folds were suggestive of gastric heterotopia, but Meckel's scan was negative. Upper endoscopy, colonoscopy, and double balloon enteroscopy were grossly and microscopically normal. Laparotomy revealed 17 cm of a dense, inflamed, stenotic segment of ileum. The strictured ileum had perforated and had been concealed by an adjacent loop of small bowel, ultimately producing an obstructive IBD-like picture, but was found to be histologically consistent with gastric oxyntic mucosa. This case illustrates the challenges of diagnosing and treating heterotopic gastric mucosa, and the importance of considering diagnoses other than IBD when evaluating stricturing disease of the small bowel.

A Liver Transplant for Local Control in a Pediatric Patient with Metastatic TFE3-Associated Perivascular Epithelioid Cell Tumor (PEComa) to the Liver.

Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors with widespread distribution throughout the body and unpredictable clinical behavior. Recently, a subset of these tumors has been reported to harbor Transcription Factor E3 (TFE3) gene rearrangement with distinct morphologic and immunophenotypic features. Although limited, these tumors may represent a separate entity from the conventional PEComas and may require different treatment approaches. Surgery is the main treatment option with no clear consensus on systemic therapy. Here, we present the first case of a malignant pediatric colonic TFE3-associated PEComa with isolated liver metastasis leading to liver transplantation for the local control.

A limited panel of INSM1 and LEF1 immunostains accurately distinguishes between pancreatic neuroendocrine tumor and solid pseudopapillary neoplasm.

Solid pseudopapillary neoplasm (SPN) and well differentiated pancreatic neuroendocrine tumor (PNET) can show significant cytomorphological overlap. In this study, we evaluated the role of INSM1 and LEF1 immunohistochemical stains in distinguishing between these two tumors. 22 SPN and 25 PNET surgically resected cases were stained for both INSM1 and LEF1. All the 22 cases of SPN showed strong and diffuse nuclear staining for LEF1 (in >95 % of tumor cells), while all 25 PNET were negative for LEF1. All 25 PNET cases were positive for INSM1 (moderate to strong intensity nuclear staining in >50 % of the tumor cells), while all 22 cases of SPN were negative for INSM1. The results of our study show that a limited panel comprising of INSM1 and LEF1 immunostains accurately distinguishes between SPN and PNET.

Automated leukocyte parameters are useful in the assessment of myelodysplastic syndromes.

BACKGROUND: Study utility of seven automated VCS parameters (V-volume, C-conductivity and S-scatter) in leukocytes as an objective read-out of dysplasia in Myelodysplastic Syndromes (MDS). METHODS: Peripheral blood was analyzed by Beckman-Coulter DxH800 hematology analyzer in 43 patients with low-grade, high-grade MDS and 21 control individuals. The differences in mean (MN) and standard deviation (SD) of each parameter were examined. The optimal sensitivity and specificity to predict MDS were determined by statistical analysis. RESULTS: In neutrophils, all means of the light scatters were significantly lower in high-grade MDS than in the control group. Mean median angle light scatter (MN-MALS-NE) and mean upper median angle light scatter (MN-UMALS-NE) were significantly different between low-grade MDS and control patients. MN-MALS-NE as a MDS predictor revealed 63% sensitivity and 67% specificity with a cutoff value of ≤133. SDs of each parameter in neutrophils differed significantly among three groups. SD of neutrophil upper median angle light scatter (SD-UMALS-NE) had 77% sensitivity and 82% specificity (cutoff value of ≥11.16) to predict MDS. CONCLUSIONS: MDS patients have a significant decrease with a linear trend in VCS parameters in neutrophils, indicating cell dysplasia. The degree of the heterogeneity measured by SD is the most predictive of MDS.

High-grade B-cell Lymphoma with MYC and BCL2 Rearrangement Arising from Follicular Lymphoma: Presentation as a Large Peripancreatic Mass.

Follicular lymphoma, the second most common non-Hodgkin lymphoma (NHL), primarily affects adults and shows an indolent clinical course. Rare cases of follicular lymphoma transform to a high-grade B-cell lymphoma with MYC and BCL2 rearrangements or "double-hit lymphoma". Transformation to a "double-hit lymphoma" portends a worse prognosis and requires aggressive treatment. We report a comprehensive clinical, pathologic and radiographic review of a patient with previously undiagnosed low-grade follicular lymphoma that transformed into a "double-hit lymphoma". The patient presented with a large heterogeneous mass 16 x 19 cm involving pancreatic head and neck and a mildly enlarged inguinal lymph node. Positron emission tomography (PET) study demonstrated Fluorodeoxyglucose (18F) (FDG)-avid peripancreatic mass. Tissue biopsy demonstrated a high-grade B-cell lymphoma with rearrangements t(14;18) and MYC, leading to the diagnosis of high-grade B-cell lymphoma with MYC and BCL2 rearrangements. Excisional biopsy of an inguinal lymph node demonstrated low-grade follicular lymphoma. Clonality studies demonstrated the same immunoglobulin clone V7-4 in inguinal lymph node and peripancreatic mass. Therefore, diagnosis of a high-grade B-cell lymphoma with MYC and BCL2 rearrangements that transformed from a low-grade follicular lymphoma was rendered. It is ultimately important to establish a tissue-based diagnosis at the different sites that are involved with lymphoma. Patient proceeded with the aggressive treatment with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (EPOCH-R) treatment.

Associations Between Placental Corticotropin-Releasing Hormone, Maternal Cortisol, and Birth Outcomes, Based on Placental Histopathology.

Preterm birth remains the leading cause of neonatal morbidity and mortality, with complex biochemical pathways requiring continued understanding and assessment. The objective of this study is to assess the associations between maternal cortisol and placental corticotropin-releasing hormone (placental CRH) concentrations with birth outcomes when stratified by placental histopathology. We conducted an analysis of 112 singleton pregnancies who received betamethasone between 23 and 34 weeks' gestation. Maternal blood and saliva were collected prior to betamethasone administration and samples assayed for plasma cortisol (pCort), salivary cortisol (sCort), and placental CRH levels. Placental findings were characterized as inflammatory, maternal vascular underperfusion (MVU), or no pathology, and compared for the outcomes of placental CRH, pCort, and sCort levels, gestational age at birth (GAB), and birthweight percentiles (BWP). Thirty-six subjects were characterized as inflammatory, 38 as MVU, and 38 without placental abnormalities. Histopathology groups differed significantly on placental CRH levels, GAB, and BWP. Post hoc tests suggested that the MVU group had higher placental CRH than the inflammatory or no pathology groups, and despite delivering earlier than the other two groups, the inflammatory group had infants with significantly higher BWP. No differences existed between groups in terms of mean plasma or sCort levels. Higher placental CRH and pCort levels were associated with earlier GAB in the overall sample, but when split by group, these associations remained significant only among the MVU group. Higher placental CRH was also associated with lower BWP in the overall sample but did not remain significant when split by group. Higher sCort was associated with lower BWP only in the MVU group. There is differentiation of placental CRH, cortisol, and birth outcomes when evaluated by placental histopathology. This highlights the importance of evaluating birth outcomes within the context of placental histopathology.

Epstein-Barr virus incidental expression in bone marrow cells: a study of 230 consecutive bone marrow biopsy samples.

Epstein-Barr virus (EBV) is associated with many neoplastic hematologic conditions, but scattered EBV-positive cells can be detected in lymph nodes of healthy individuals and they usually represent latently infected lymphocytes. The incidence of EBV detection in normal bone marrow samples has not been studied and is largely unknown. The lack of knowledge regarding the true incidence of encountering bystander latent EBV-positive cells in the bone marrow may potentially lead to a diagnostic dilemma when assessing a staging bone marrow for a patient with an EBV-positive B or T/NK-cell lymphoma. The aim of our study was to investigate the rate of detection of EBV expression in bone marrow samples and correlate any positive findings with various clinical parameters including patient's age, sex, clinical history, immune status, and any neoplastic transformation if follow-up data are available. We retrospectively studied 230 consecutive bone marrow biopsies performed in 2013 and found 5 cases (2.17%) with scattered EBV-positive cells by in situ hybridization. The observed scattered EBV-positive cells are largely small in size and likely represent bystander, latently infected cells. The rate of detection of EBV-positive cells in the bone marrow appears to be slightly higher in immunodeficient individuals (3%) than in immunocompetent patients (1%).

Congenital neuroglial choristoma of the foot.

Neuroglial choristomas are rare malformations of heterotopic neural tissue that have been previously reported predominantly in the head and neck. Competing theories of embryogenesis propose their origin as encephaloceles that have undergone resorption of their cranial connection or displaced neuroectodermal cells which have undergone ectopic proliferation. Most cases occur in midline or para-midline structures. There have been no prior published cases of a neuroglial choristoma in the extremities. We present a case of a 13-month-old otherwise healthy child who presented to our institution with a slowly growing foot mass who was found to have a neuroglial choristoma. This case suggests an early embryological migration defect as the etiology and offers a unique differential consideration for a benign extremity mass.

Gelatinous bone marrow transformation and emergence of clonal Philadelphia-negative cytogenetic abnormalities with excess blasts in a patient with chronic myeloid leukemia treated with dasatinib.

Gelatinous bone marrow transformation (GBMT) is a rare pathologic entity of unclear etiology characterized by adipose cell atrophy, focal hematopoietic tissue hypoplasia, and a distinct eosinophilic substance that stains with Alcian blue at pH 2.5. It is traditionally described in the context of malnutrition and cachexia from generalized disease and is important to identify because of its potential reversibility. Several recent case reports have described GBMT in patients with chronic myeloid leukemia (CML) on the first-generation tyrosine-kinase inhibitor (TKI) imatinib. Here, we describe a case of gelatinous transformation in a patient with CML receiving the second-generation TKI dasatinib who subsequently developed clonal cytogenetic abnormalities in Philadelphia chromosome negative cells with excess peripheral blasts consistent with advanced secondary myelodysplastic syndrome. While the development of clonal cytogenetic abnormalities in Philadelphia-negative cells has been frequently described in the setting of TKI, most abnormalities are transient and generally do not effect disease progression and/or transformation like in this case. Remarkably, after TKI discontinuation, repeat bone marrow biopsies had markedly diminished amounts of gelatinous transformation - supporting reversible GBMT with TKI removal. We review the relevant pathophysiology underlying our patient's possible therapeutic-mediated complications during CML therapy in an attempt to better understand the role of TKIs in the pathogenesis of these conditions.