Congenital undifferentiated sarcoma associated to BCOR-CCNB3 gene fusion

Small round cell sarcomas are aggressive bone and soft tissue tumors that predominantly affect children and young adults. A new group of sarcomas with a recurrent BCOR-CCNB3 gene fusion has been recently identified in previously unclassifiable small round cell sarcomas. BCOR-CCNB3 sarcomas share clinical and pathologic similarities with Ewing sarcoma, but show a stronger male predilection and less aggressiveness, as well as distinct gene expression profiling and pangenomic SNP array analyses. We report the unusual case of a congenital BCOR-CCNB3 retroperitoneal sarcoma in a female born at 34th gestational week, which was diagnosed in necropsy after 21hours of life. Immunohistochemical analy…

Carcinoma colorrectal serrado. Descripción histopatológica, inmunohistoquímica y molecular de un caso

Resumen El adenocarcinoma serrado es una variante del carcinoma colorrectal recientemente tipificada, y es el punto final de una via molecular denominada «via serrada». La lesion precursora en esta via es la mutacion del gen BRAF, que origina lesiones serradas con predisposicion a la metilacion genica y a la inestabilidad de microsatelites. En el presente estudio describimos un caso de adenocarcinoma de colon ascendente, con criterios histologicos compatibles con adenocarcinoma serrado: epitelio serrado, citoplasma amplio, nucleo vesicular y ausencia de necrosis. En el estudio inmunohistoquimico se observo perdida de la expresion del gen MLH1. El estudio molecular revelo altos niveles de in…

Epigenetic changes underlie the aggressiveness of histologically benign meningiomas that recur

Meningiomas are the most frequent primary brain tumor. Usually, they are curable by surgery, but even after seemingly complete resection, some low-grade lesions recur. Despite recent improvements, signatures having prognostic value in grade I tumors remain poorly characterized. The frequency and delicate location of these tumors suggest that the risk of recurrence might be more accurately predicted. Herein, we show an easy way to evaluate the methylation status of meningiomas and its correlation with the prognosis of the disease. A series of 120 meningiomas, including primary tumors and recurrences, were analyzed histopathologically, and 24 tumor suppressor genes (TSGs) were studied by meth…

Somatic copy number alterations are associated with EGFR amplification and shortened survival in patients with primary glioblastoma.

Glioblastoma (GBM) is the most common malignant primary tumor of the central nervous system. With no effective therapy, the prognosis for patients is terrible poor. It is highly heterogeneous and EGFR amplification is its most frequent molecular alteration. In this light, we aimed to examine the genetic heterogeneity of GBM and to correlate it with the clinical characteristics of the patients. For that purpose, we analyzed the status of EGFR and the somatic copy number alterations (CNAs) of a set of tumor suppressor genes and oncogenes. Thus, we found GBMs with high level of EGFR amplification, low level and with no EGFR amplification. Highly amplified tumors showed histological features of…

Assessing molecular subtypes of gastric cancer: microsatellite unstable and Epstein-Barr virus subtypes. Methods for detection and clinical and pathological implications.

Background The molecular classification of gastric cancer recognises two subtypes prone to immune checkpoint blockade: the microsatellite unstable and the Epstein-Barr virus (EBV)-related tumours. We aim to assess the concordance between immunohistochemistry and PCR for microsatellite status evaluation, and explore the value of microsatellite instability (MSI) and EBV as predictive survival factors. Material and methods We collected 246 consecutively diagnosed gastric cancer cases in all stages and evaluated the microsatellite status using immunohistochemistry for mismatched repair (MMR) proteins and PCR. EBV expression was studied through in situ hybridisation. Results Forty-five (18%) cas…

Identification of a Novel BRCA1 Alteration in Recurrent Melanocytoma Resulting in Increased Proliferation

Abstract Primary meningeal melanocytomas are rare tumors of the central nervous system. Although they are considered benign neoplasms, some reports describe recurrent rates up to 45%. Little is known about their genetic and epigenetic landscape because of their infrequency. Even less has been described about markers with prognostic value. Here we describe a patient who developed a primary meningeal melanocytoma, suffered 3 recurrences in a period of 6 years and died of the tumor. The genetic and epigenetic changes explored confirmed GNAQ mutation as an initiating event. We found an epigenetic alteration of GSTP1, a feature that has recently been described in meningiomas, from the beginning …

Transcriptomic identification of miR-205 target genes potentially involved in metastasis and survival of cutaneous malignant melanoma

AbstractCutaneous melanoma is an aggressive neoplasm and is responsible for the majority of skin cancer deaths. Several miRNAs are involved in melanoma tumor progression. One of them is miR-205, the loss of which contributes to the development of melanoma metastasis. We evaluated whole-genome mRNA expression profiling associated with different miR-205 expression levels in melanoma cells. Differential expression analysis identified 243 differentially expressed transcripts including inositol polyphosphate 5′-phosphatase-like protein-1 (INPPL1) and BTB/POZ Domain-Containing Protein 3 (BTBD3). INPPL1 and BTBD3 were downregulated when melanoma cells expressed miR-205, indicating that these genes…

The Amount of Melanin Influences p16 Loss in Spitzoid Melanocytic Lesions: Correlation With CDKN2A Status by FISH and MLPA.

AIMS The risk assessment of spitzoid lesions is one of the most difficult challenges in dermatopathology practice. In this regard, the loss of p16 expression and the homozygous deletion of CDKN2A, have been pointed in the literature as reliable indicators of high risk. However, these findings are poorly reproducible, and the molecular bases underlying the loss of p16 expression remain unclear. We aimed to identify the underlying events causing loss of CDKN2A/p16 in spitzoid tumors. MATERIALS AND METHODS We evaluated the immunohistochemical expression of p16, and the presence of CDKN2A genetic alterations detected through fluorescence in situ hybridization (FISH) and multiplex ligation-depen…

Molecular Progression in Unusual Recurrent Non-Pediatric Intracranial Clear Cell Meningioma

We report a case of a recurrent clear cell meningioma (CCM) in the frontal lobe of the brain of a 67-year-old man. The patient developed three recurrences: at 3, 10, and 12 years after his initial surgery. Histopathology observations revealed a grade 2 CCM with positivity for vimentin and epithelial membrane antigen. Expression of E-cadherin was positive only in the primary tumour and in the first available recurrence. Fluorescence in situ hybridization analyses demonstrated 1p and 14q deletions within the last recurrence. Multiplex ligation-dependent probe amplification studies revealed a heterozygous partial NF2 gene deletion, which progressed to total loss in the last recurrence. The las…

BRAF V600E Mutation in Two Distinct Meningeal Melanocytomas Associated With a Nevus of Ota

Defining Ewing and Ewing-like small round cell tumors (SRCT): The need for molecular techniques in their categorization and differential diagnosis. A study of 200 cases

Abstract Background Differentiation of Ewing sarcoma family of tumors (ESFT) and Ewing-like tumors remains problematic. Certain ESFT with morphological and immunohistochemical (IHC) profiles lack the EWSR1-ETS transcript. To improve diagnostic accuracy we investigated the presence of several specific transcripts in 200 small round cell tumors (SRCT) displaying ESFT morphology and immunophenotype in which EWSR1 FISH analysis was non-informative or negative. Design 200 tumors (formalin-fixed, paraffin-embedded) were analyzed by RT-PCR. All tumors were tested for EWSR1-ETS , EWSR1 / WT1 , PAX3 / 7-FOX01 or SYT / SSX transcripts, and the negative tumors were subsequently analyzed for CIC / DUX4…

Female New-Born with Undifferentiated Sarcoma Defined by Bcor-Ccnb3 Fusion Transcript

A female new-born presented with a sacrococcygeal mass with spinal cord compression. A preliminary histologic diagnosis determined a small round blue cell tumor and immunohistochemical results discarded neuroblastoma, rhabdomyosarcoma, rhabdoid tumor, Ewing or peripheral neuroectodermal tumor (PNET). The results obtained by SNPa showed a chromosome Xp11.4 deletion of 0.9 Mb, where the BCOR gene is located. RT-PCR did not detect the ETV6-NTRK3 or EWSR1-FLI1 fusion, but did reveal the presence of the BCOR-CCNB3 fusion transcript, recently reported in some undifferentiated sarcomas, establishing the diagnosis of “Ewing-like” sarcoma. Analysis of CCNB3 expression by immunohistochemistry showed …

Identification of New Genetic Clusters in Glioblastoma Multiforme: EGFR Status and ADD3 Losses Influence Prognosis

Glioblastoma multiforme (GB) is one of the most aggressive tumors. Despite continuous efforts to improve its clinical management, there is still no strategy to avoid a rapid and fatal outcome. EGFR amplification is the most characteristic alteration of these tumors. Although effective therapy against it has not yet been found in GB, it may be central to classifying patients. We investigated somatic-copy number alterations (SCNA) by multiplex ligation-dependent probe amplification in a series of 137 GB, together with the detection of EGFRvIII and FISH analysis for EGFR amplification. Publicly available data from 604 patients were used as a validation cohort. We found statistical associations…

Alteration of major vault protein in human glioblastoma and its relation with EGFR and PTEN status.

Glioblastoma (GBM) is the most frequent and malignant primary brain tumor. Conventional therapy of surgical removal, radiation and chemotherapy is largely palliative. Major vault protein (MVP), the main component of the vault organelle has been associated with multidrug resistance by reducing cellular accumulation of chemotherapeutic agents. With regard to cancer, MVP has been shown to be overexpressed in drug resistance development and malignant progression. The aim of the present study was to evaluate the MVP gene dosage levels in 113 archival samples from GBM and its correlation with patients' survival and epidermal growth factor receptor (EGFR) and phosphatase and tensin homolog (PTEN) …

Ewing-like sarcoma with CIC-DUX4 gene fusion in a patient with neurofibromatosis type 1. A hitherto unreported association.

Sarcoma with CIC-DUX4 gene fusion is emerging as the most prevalent subset of Ewing-like undifferentiated small round cell sarcomas with around 50 cases published. We report hereby the case of a 40-year-old male who presented a CIC-DUX4 sarcoma in deep soft tissues in his thigh. He had been diagnosed with neurofibromatosis type 1 at age 19 and over the years underwent resection of multiple neural neoplasms, including two malignant peripheral nerve sheath tumors with classical spindle-cell histopathology. The CIC-DUX4 sarcoma was treated with surgical resection, radiation and chemotherapy, but lung and brain metastases developed and the patient died from the disease 14 months after diagnosis…

Blattabacteria, the endosymbionts of cockroaches, have small genome sizes and high genome copy numbers.

Summary Blattabacteria are intracellular endosymbionts of cockroaches and primitive termites that belong to the class Flavobacteria and live only in specialized cells in the abdominal fat body of their hosts. In the present study we determined genome sizes as well as genome copy numbers for the endosymbionts of three cockroach species, Blattella germanica, Periplaneta americana and Blatta orientalis. The sole presence of blattabacteria in the fat body was demonstrated by rRNA-targeting techniques. The genome sizes of the three blattabacteria were determined by pulsed field gel electrophoresis. The resulting total genome sizes for the three symbionts were all approximately 650 15 kb. Compari…

Soft tissue myoepithelial carcinoma with rhabdoid-like features andEWSR1rearrangement: Fine needle aspiration cytology with histologic correlation

A new case of soft tissue myoepithelial carcinoma (MEC) with rhabdoid-like differentiation is presented including cytologic, histopathologic, immunohistochemical, and molecular biologic features. A 45-year-old woman was admitted to the Hospital with nodular mass involving the lower part of the abdominal wall. Fine-needle aspiration cytology showed a round cell tumor with abundant cytoplasm in the myxoid background. The nuclei were uniform, round to ovoid, with finely distributed chromatin, nucleoli, and pale, vacuolated, or eosinophilic cytoplasm with rhabdoid-like appearance resembling a soft tissue malignant rhabdoid tumor. The surgically removed tumor was poorly demarcated, yellow, soft,…

Primary paraesophageal Ewing’s sarcoma: an uncommon case report and literature review

Ewing’s sarcoma is a rare and highly aggressive cancer most frequently arising in people under 20 years of age. We report an uncommon case of primary paraesophageal Ewing’s sarcoma in a 25-year-old male harboring the infrequent EWSR1/ERG fusion transcript with multiple splice variants coexisting in the same tumor. The patient was totally refractory to chemotherapy and died 17 months after diagnosis. We underscore the need for better understanding of the molecular pathogenesis of the disease and improved systemic therapy options.

Primary paraesophageal Ewing’s sarcoma: an uncommon case report and literature review

Noelia Tarazona,1,* Lara Navarro,2,* Juan Miguel Cejalvo,3,* Valentina Gambardella,3,* J Alejandro Pérez-Fidalgo,3 Alejo Sempere,2 Samuel Navarro,2 Andrés Cervantes31Department of Medicine, GI and Lymphoma Unit, The Royal Marsden NHS Foundation Trust, London and Surrey, UK; 2Department of Pathology, 3Department of Hematology and Medical Oncology, Biomedical Research Institute, INCLIVA, University of Valencia, Valencia, Spain*These authors contributed equally to this workAbstract: Ewing’s sarcoma is a rare and highly aggressive cancer most frequently arising in people under 20 years of age. We report an uncommon case of primary paraesophageal Ewing’s…

Epigenetic changes in localized gastric cancer: the role of RUNX3 in tumor progression and the immune microenvironment

// Marta Jessica Llorca-Cardenosa 1, * , Tania Fleitas 1, * , Maider Ibarrola-Villava 1 , Maria Pena-Chilet 1 , Cristina Mongort 2 , Carolina Martinez-Ciarpaglini 2 , Lara Navarro 2 , Valentina Gambardella 1 , Josefa Castillo 1 , Susana Rosello 1 , Samuel Navarro 2 , Gloria Ribas 1 , Andres Cervantes 1 1 Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain 2 Department of Pathology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain * These authors contributed equally to this work Correspondence to: Gloria Ribas, email: gribas@incliva.es Andres Cervantes, email: andres.cervantes@uv.es Keywords: RUNX3, ARID1A, gastric ca…