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Diffuse large B cell lymphoma, not otherwise specified (DLBCL, NOS) is the most common type of non-Hodgkin lymphoma (NHL). Significant efforts have been focused on utilizing advanced genomic technologies to further subclassify DLBCL, NOS into clinically relevant subtypes. These efforts have led to the implementation of novel algorithms to support optimal risk-oriented therapy and improvement in the overall survival of DLBCL patients. The pathogenesis of DLBCL at the molecular level indicates copy number variation (CNV) as one of the major forms of genetic alterations in the somatic mutational landscape. Random deregulation that results in complex breaks of chromosomes and restructuring of shattered chromosomal segments is called chromothripsis. Gene expression changes influenced by chromothripsis have been reported in cancer and congenital diseases. This chaotic phenomenon results in complex CNV, gene fusions, and amplification and loss of tumor suppressor genes. We present herein a summary of the most clinically relevant genomic aberrations, with particular focus on copy number aberrations in a case that highlights DLBCL, NOS arising from relapsed Hodgkin lymphoma. The focus of our study was to understand the relationship between the clinical, morphological, and genomic abnormalities in DLBCL, NOS through multiple techniques for therapeutic considerations. [ABSTRACT FROM AUTHOR]

dic(7;9) is a rare (<1%) and recurrent abnormality in both pediatric and adult B-ALL, resulting in partial monosomy of chromosomes 7p and 9p. Co-occurrence of dic(7;9) with PAX5 gene alterations including deletions, mutations and amplification have been reported. PAX5 encodes the B lymphoid transcription factor gene that is important in regulating B cell lineage differentiation, leading to B-cell development and may play a crucial role in B lymphoid leukemogenesis. Here, we present two cases of pediatric B-ALL with dic(7;9) with complex genomic aberrations. Case 1: is a four year old female who presented in 2024 with orbital and left sinus maxillary masses, anemia, fever and leukocytosis with peripheral blasts. Karyotype and fish were complex with 45,XX,der(7)dic(7;9)(p11.2;p13)del(7)(p13p11.2)t(7;20)(p13;q11.2),der(20)t(7;20)(p13;q11.2)[13]/46,XX[7]. SNP array revealed loss of 7p and 9p including IKAROS and PAX5 , respectively. Cerebral sinus fluid demonstrated a leukocytosis with leukemic blasts, resulting in a CNS3b classification. She had negative minimal residual disease at the end of induction on a very high-risk standard of care protocol and on consolidation therapy. Case 2: is a 10 year old male referred in 2022 for a month of fever and fatigue.. karyotype was complex with several rearrangements. 45,XY,dic(7)t(7;9)(p13;p13),-9,der(10)t(9;10)(q34.1;q22),der(12)t(7;12)(p13;p13),der(13)t(10;13)(q22;q34)[11]/46,XY[9]. The patient was treated on a standard risk standard of care protocol and had negative minimal residual disease at the end of induction. He remains in remission during maintenance therapy. Given the two dic (7;9) cases described here have complex karyotypes, it is possible that PAX5 and IKZF1 alterations may be contributing to this complex cytogenetic entity. [ABSTRACT FROM AUTHOR]

Copy number deletions at chromosomal region 3p14 are rare constitutional occurrences and the genes within this region are mainly unclassified. The small number of publications describing patients with 3p14 deletions list phenotypes of multiple congenital anomalies, movement disorders, feeding difficulties, developmental delay, and autism. Despite these recurring patient phenotypes, no potential candidate genes within this region have been identified. Here we describe two unrelated cases with overlapping 3p14.2 to 3p14.1 single-copy deletions. The first case is a 5-year-old male with childhood apraxia of speech, global developmental delay, autism spectrum disorder, and hyperkinesis. This patient's deletion is 3.1 Mb in size and contains 15 known genes and 8 OMIM genes. The second case is a 2-year-old female with prematurity, global developmental delay, failure to thrive, feeding difficulties, feeding tube dependency, short stature, microcephaly, PDA closure, autism spectrum disorder, and abnormalities on brain MRI. This patient's deletion is 3.5 Mb in size and contains 24 known genes and 10 OMIM genes. Taken together, 7 OMIM genes are deleted in both patients: PTPRG, FEZF2, CADPS, SNTN, THOC7, ATXN7, SCAANT1. We will explore how deletion of these potential candidate genes may impact the patients' shared phenotypes of autism and global developmental delay. Additionally, we will examine the three genes (PSMD6, PRICKLE2, ADAMTS9) that are deleted only in the second patient, who displays a more severe phenotype. This assessment may identify candidate genes for follow-up functional studies and will contribute to the literature by describing patients with rare copy number losses in this region. [ABSTRACT FROM AUTHOR]

Background: Plasma cell neoplasm and/or plasma cell myeloma (PCM) is a mature B-cell lymphoproliferative neoplasm of plasma cells that secrete a single homogeneous immunoglobulin called paraprotein or M-protein. Plasma cells accumulate in the bone marrow (BM) leading to bone destruction and BM failure. Diagnosis of PCM is based on clinical, radiologic, and pathological characteristics. The percent of plasma cells by manual differential (bone marrow morphology), the white blood cell (WBC) count, cytogenetics, fluorescence in situ hybridization (FISH), microarray, and next-generation sequencing of BM are used in the risk stratification of newly diagnosed PCM patients. The genetics of PCM is highly complex and heterogeneous with several genetic subtypes that have different clinical outcomes. National Comprehensive Cancer Network guidelines recommend targeted FISH analysis of plasma cells with specific DNA probes to detect genetic abnormalities for the staging of PCM (4.2021). Recognition of risk categories through training software for classification of high-risk PCM and a novel way of addressing the current approaches through bioinformatics will be a significant step toward automation of PCM analysis. Methods: A new artificial neural network (ANN) classification model was developed and tested in Python programming language with a first data set of 301 cases and a second data set of 176 cases for a total of 477 cases of PCM at diagnosis. Classification model was also developed with support vector machines (SVM) algorithm in R studio and interactive data visuals using Tableau. Results: The resulting ANN algorithm had 94% accuracy for the first and second data sets with a classification summary of precision (PPV): 0.97, recall (sensitivity): 0.76, f1 score: 0.83, and accuracy of logistic regression of 1.0. SVM of plasma cells versus TP53 revealed a 95% accuracy level. Conclusion: A novel classification model based only on specific morphological and genetic variables was developed using a machine learning algorithm, the ANN. ANN identified an association of WBC and BM plasma cell percentage with two of the high-risk genetic categories in the diagnostic cases of PCM. With further training and testing of additional data sets that include morphologic and additional genetic rearrangements, the newly developed ANN model has the potential to develop an accurate classification of high-risk categories of PCM. [ABSTRACT FROM AUTHOR]

Epstein Barr virus (EBV)-related hemophagocytic lymphohistiocytosis (EBV-HLH) is a form of acquired, infection-related HLH which typically represents a fulminant presentation of an acute EBV infection of CD8+ T cells with 30-50% mortality rate. Systemic EBV-positive lymphoproliferative disease of childhood (SE-LPD) is a rare T cell lymphoproliferative disorder predominantly arising in the setting of acute EBV infection, often presenting with HLH. Since both entities have been associated with clonal T cell populations, the discrimination between these diseases is often ambiguous. We report a unique case of a 21 years old female who presented with clinical and laboratory findings of florid HLH in the setting of markedly elevated EBV titers (>1 million) and an aberrant T cell population shown to be clonal by flow cytometry, karyotype, and molecular studies. This case raises the differential of EBV-HLH versus SE-LPD. Review of the literature identified 74 cases of reported EBV-HLH and 21 cases of SE-LPD with associated HLH in 25 studies. Of those cases with available outcome data, 62 of 92 cases (67%) were fatal. Of 60 cases in which molecular clonality was demonstrated, 37 (62%) were fatal, while all 14 cases (100%) demonstrating karyotypic abnormalities were fatal. Given the karyotypic findings in this sentinel case, a diagnosis of SE-LPD was rendered. The overlapping clinical and pathologic findings suggest that EBV-HLH and SE-LPD are a biologic continuum, rather than discrete entities. The most clinically useful marker of mortality was an abnormal karyotype rather than other standards of clonality assessment.