Induction of Transcriptional Inhibitor HES1 and the Related Repression of Tumor-Suppressor TXNIP Are Important Components of Cell-Transformation Program Imposed by Oncogenic Kinase NPM-ALK.

This study reports that hairy and enhancer of split homolog-1 (HES1), known to repress gene transcription in progenitor cells of several cell lineages, was strongly expressed in cells and tissues of T-cell lymphoma expressing the oncogenic chimeric tyrosine kinase nucleophosmin (NPM)-anaplastic lymphoma kinase [ALK; ALK T-cell lymphoma (TCL)]. The structural analysis of the Orange domain of HES1 indicated that HES1 formed a highly stable homodimer. Of note, repression of HES1 expression led to inhibition of ALK TCL cell growth in vivo.

Brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as frontline treatment for patients with CD30-positive B-cell lymphomas.

We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities.

Deletion 20q12 is associated with histological transformation of nodal marginal zone lymphoma to diffuse large B-cell lymphoma.

The genetic and molecular abnormalities underlying histological transformation (HT) of nodal marginal zone lymphoma (NMZL) to diffuse large B-cell lymphoma (DLBCL) are not well known. While del(20q12) is commonly deleted in myelodysplastic syndrome it has not previously been associated with DLBCL. We recently described a case of DLBCL harboring del(20q12) in a patient with a history of MZL involving lymph nodes and skin.

Correction: Transient stabilization, rather than inhibition, of MYC amplifies extrinsic apoptosis and therapeutic responses in refractory B-cell lymphoma.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cyclin D1 expression and novel mutational findings in Rosai-Dorfman disease.

Rosai-Dorfman disease (RDD) is an enigmatic histiocytic disorder classically diagnosed by a distinctive combination of pathological features: emperipolesis, or migration of intact haematological cells through the voluminous cytoplasm of lesional histiocytes, and expression of S100 by these histiocytes. The pathogenesis has long been elusive until the recent detection of recurrent and mutually exclusive mutations in several oncogenes in the mitogen-activated protein kinase (MAPK) pathway. Based on these findings, we investigated a cohort of 21 RDD patients and found that the lesional histiocytes in 86% (18/21) of patients exhibited strong and diffuse nuclear Cyclin D1 expression, which not only may provide a diagnostic marker for this sometimes pathologically challenging disease, but also probably reflects constitutive MAPK pathway activation because we additionally identified phosphorylated-ERK expression in 90% (19/21) of cases.

Transient stabilization, rather than inhibition, of MYC amplifies extrinsic apoptosis and therapeutic responses in refractory B-cell lymphoma.

Therapeutic targeting of initiating oncogenes is the mainstay of precision medicine. Considerable efforts have been expended toward silencing MYC, which drives many human cancers including Burkitt lymphomas (BL). Yet, the effects of MYC silencing on standard-of-care therapies are poorly understood.

Outcomes of patients with relapsed/refractory double-expressor B-cell lymphoma treated with ibrutinib monotherapy.

The B-cell receptor signaling pathway is active in diffuse large B-cell lymphomas, with increased expression of MYC and BCL2 protein. The overall response rate was 60% for relapsed/refractory non–germinal center double-expressor lymphoma patients treated with ibrutinib.

Rare case of low-grade extranodal NK/T-cell lymphoma, nasal type, arising in the setting of chronic rhinosinusitis and harboring a novel N-terminal KIT mutation.

Background: Extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT), is a rare aggressive subtype of non-Hodgkin lymphoma characterized by angioinvasion, angiodestruction, necrosis and strong association with Epstein-Barr virus (EBV). ENKTCL-NT occurs worldwide and is more prevalent in Asian and the Native American populations of Mexico, Central and South America. It represents approximately 10% of all peripheral T-cell lymphomas worldwide.

EBV-Negative Monomorphic B-Cell Posttransplant Lymphoproliferative Disorder with Marked Morphologic Pleomorphism and Pathogenic Mutations in , , , , and .

Posttransplant lymphoproliferative disorders (PTLDs) are a diverse group of lymphoid or plasmacytic proliferations frequently driven by Epstein-Barr virus (EBV). EBV-negative PTLDs appear to represent a distinct entity. This report describes an unusual case of a 33-year-old woman that developed a monomorphic EBV-negative PTLD consistent with diffuse large B-cell lymphoma (DLBCL) 13 years after heart-lung transplant.

Diffuse large B-cell lymphoma with concurrent high MYC and BCL2 expression shows evidence of active B-cell receptor signaling by quantitative immunofluorescence.

B-cell receptor (BCR)-mediated signaling plays an important role in the pathogenesis of a subset of diffuse large B-cell lymphoma (DLBCL), and novel agents targeting this pathway are now in clinical use. We have previously identified a signature of active BCR signaling on formalin-fixed paraffin-embedded specimens using quantitative immunofluorescence, allowing for identification of patients who might benefit from anti-BCR therapies. We sought to characterize the clinicopathologic significance of active BCR signaling in DLBCL by correlating measures of signaling intensity with clinical features and various tumor cell characteristics.

Marginal zone lymphoma-derived interfollicular diffuse large B-cell lymphoma harboring 20q12 chromosomal deletion and missense mutation of BIRC3 gene: a case report.

Background: Diffuse large B-cell lymphoma (DLBCL) typically leads to effacement of the nodal architecture by an infiltrate of malignant cells. Rarely (<1%), DLBCL can present with an interfollicular pattern (DLBCL-IF) preserving the lymphoid follicles. It has been postulated that DLBCL-IF is derived from marginal zone B cells and may represent a large-cell transformation of marginal zone lymphoma (MZL), however no direct evidence has been provided to date.

An Unusual Case of Extranodal Diffuse Large B-Cell Lymphoma Infiltrating Skeletal Muscle: A Case Report and Review of the Literature.

Diffuse large B-cell lymphoma is extranodal in approximately 40% of cases, arising in nearly any organ system. DLBCL involvement of soft tissue and in particular skeletal muscle is extremely rare, comprising less than 1% of all extranodal non-Hodgkin lymphomas (NHL). We report a case of a 79-year-old man that presented with a DLBCL of the left triceps.

Genetic aberrations in small B-cell lymphomas and leukemias: molecular pathology, clinical relevance and therapeutic targets.

Small B-cell lymphomas and leukemias (SBCLs) are a clinically, morphologically, immunophenotypically and genetically heterogeneous group of clonal lymphoid neoplasms, including entities such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), lymphoplasmacytic lymphoma (LPL), marginal zone lymphoma (MZL) and hairy cell leukemia (HCL). The pathogenesis of some of these lymphoid malignancies is characterized by distinct translocations, for example t(11;14) in the majority of cases of MCL and t(14;18) in most cases of FL, whereas other entities are associated with a variety of recurrent but nonspecific numeric chromosomal abnormalities, as exemplified by del(13q14), del(11q22), and +12 in CLL, and yet others such as LPL and HCL that lack recurrent or specific cytogenetic aberrations. The recent surge in next generation sequencing (NGS) technology has shed more light on the genetic landscape of SBCLs through characterization of numerous driver mutations including SF3B1 and NOTCH1 in CLL, ATM and CCND1 in MCL, KMT2D and EPHA7 in FL, MYD88 (L265P) in LPL, KLF2 and NOTCH2 in splenic MZL (SMZL) and BRAF (V600E) in HCL.

An unusual case of Philadelphia chromosome-positive chronic myelogenous leukemia with trisomy 19 presenting with megakaryoblastosis and myelofibrosis.

Initial identification of chronic myelogenous leukemia is very important since targeted therapy leads to life-saving remission. Rarely, chronic myelogenous leukemia presents with an unusual picture, making the diagnosis challenging. We describe such a case of chronic myelogenous leukemia in blast crisis in a previously healthy 61-year-old woman.

SYK inhibition modulates distinct PI3K/AKT- dependent survival pathways and cholesterol biosynthesis in diffuse large B cell lymphomas.

B cell receptor (BCR) signaling pathway components represent promising treatment targets in diffuse large B cell lymphoma (DLBCL) and additional B cell tumors. BCR signaling activates spleen tyrosine kinase (SYK) and downstream pathways including PI3K/AKT and NF-κB. In previous studies, chemical SYK blockade selectively decreased BCR signaling and induced apoptosis of BCR-dependent DLBCLs.

Extreme signet ring cell change in a large B-cell lymphoma of follicular origin.

We report a large B-cell lymphoma of follicular origin with extreme signet ring cell differentiation. Initially classified as follicular lymphoma on a fine needle core biopsy, the presence of cohesive sheets of extrafollicular signet ring cells triggered an excisional biopsy for further characterization. The excised lymph node revealed focal follicular hyperplasia, follicular lymphoma, and a neoplasm composed of vague nodules and sheets of large atypical cells, all of which virtually exhibited large clear intracytoplasmic vacuoles with peripheral displacement of nuclei.

Recurrent histiocytic necrotizing lymphadenitis with a long latency in a patient with autoimmunity: a case report and review of literature.

Kikuchi-Fujimoto disease (KFD), a histiocytic necrotizing lymphadenitis (HNL), characteristically presents as cervical lymphadenopathy in young Asian women. Most resolve spontaneously with rare recurrences described. We report a patient with biopsy-proven recurrence of KFD-like HNL after almost 8 years and analyze 65 additional published cases with recurrences.

Quantitative immunofluorescence reveals the signature of active B-cell receptor signaling in diffuse large B-cell lymphoma.

Purpose: B-cell receptor (BCR)-mediated signaling is important in the pathogenesis of a subset of diffuse large B-cell lymphomas (DLBCL) and the BCR-associated kinases SYK and BTK have recently emerged as potential therapeutic targets. We sought to identify a signature of activated BCR signaling in DLBCL to aid the identification of tumors that may be most likely to respond to BCR-pathway inhibition.

Experimental Design: We applied quantitative immunofluorescence (qIF) using antibodies to phosphorylated forms of proximal BCR signaling kinases LYN, SYK, and BTK and antibody to BCR-associated transcription factor FOXO1 on BCR-cross-linked formalin-fixed paraffin-embedded (FFPE) DLBCL cell lines as a model system and on two clinical cohorts of FFPE DLBCL specimens (n = 154).

Plasmablastic lymphomas with MYC/IgH rearrangement: report of three cases and review of the literature.

We report detailed clinicopathologic features of 3 cases of plasmablastic lymphoma (PBL) with MYC/IgH rearrangement, representing one third of PBL cases diagnosed at our institution. This study brings the total number of reported cases in the literature to 6. All patients were HIV+ with very low CD4 counts at diagnosis.

Massive localized lymphedema with unusual presentations: report of 2 cases and review of the literature.

Massive localized lymphedema is a benign soft tissue lesion that usually presents as a large mass in morbidly obese adults. The diagnosis may be challenging as it can mimic other lesions, including well-differentiated liposarcoma. We report 2 cases of massive localized lymphedema with unusual presentation.