Joseph D. Khoury

Ewing sarcoma family of tumors

Publisher Summary The terms ‘Ewings sarcoma’, ‘peripheral primitive neuroectodermal tumor (PNET)’, and ‘malignant small cell tumor of the thoracopulmonary region’ (Askin tumor) are currently regarded as manifestations of a single neoplastic entity with underlying common phenotypic and molecular features. These tumors are now grouped under the general eponym Ewings sarcoma family of tumors (ESFT) and are characterized by non-random translocations involving the EWS gene and one of several members of the ETS family of transcription factors. The Ewings sarcoma family of tumors is the second most common malignant neoplasm of bone arising in children and adolescents, with osteosarcoma being the most common. In the United States, the annual incidence rate of ESFT in the general population is three per million. Boys are more commonly affected than girls, and the disease exhibits marked predilection for whites and is particularly rare among black people. Most patients are between the ages of 5 and 20 years at the time of diagnosis (median, 14 years), and the disease is rare in individuals older than 40 and younger than 5 years. There is no evidence that ESFT is associated with any familial predisposition syndrome or environmental factors. Several studies have demonstrated an increased cumulative risk of secondary cancers following therapy for ESFT, with radiation-induced osteosarcoma and therapy-related acute myeloid leukemia being the most frequent. Conversely, the occurrence of ESFT as a second neoplasm after therapy for other tumors is rare.

Diffuse Large B-Cell Lymphoma, Not Otherwise Specified

Diffuse large B-cell lymphoma (DLBCL), not otherwise specified, is a neoplasm composed of large B-cells growing in a diffuse pattern. DLBCL is the most frequent type of non-Hodgkin lymphoma worldwide, and it encompasses a heterogeneous group of diseases that can be subdivided according to clinical, morphologic, phenotypic, or molecular criteria. Some cases of DLBCL arise in distinct clinicopathologic settings and may be better classified as unique entities, such as primary mediastinal (thymic) large B-cell lymphoma or as subtypes, such as DLBCL arising in patients with immunodeficiency or EBV + DLBCL of the elderly. In this Atlas, we focus on only those cases of DLBCL that present as nodal disease.

B-Cell Lymphoma, Unclassifiable, with Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma

This is a provisional category in the 2008 World Health Organization classification that includes aggressive lymphomas with histologic, biologic, and genetic features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Affected patients are mainly adults, presenting with nodal or extranodal disease, with frequent involvement of bone marrow, peripheral blood, and the central nervous system. The majority of cases are de novo, however some cases are the result of transformed follicular lymphoma. Most cases display a diffuse growth of intermediate- or occasional large-sized cells, high proliferation rate, admixed with few small reactive lymphocytes, and no stromal fibrosis. Frequent mitoses and a starry-sky pattern are common and reminiscent of BL. However, the cell variation is more distinct than usual BL and prominent nucleoli may occur. Rare cases composed of small cells with blastoid chromatin that mimics lymphoblastic lymphoma are also included in this category. In previous classifications, some cases that seemed like BL but with more nuclear variability were classified as atypical BL. However, gene profile studies of cases diagnosed with BL and atypical BL showed that they both share similar signatures, suggesting that they represent a spectrum of the same disease process. It became evident, therefore, that the category of atypical BL was unnecessary.

Cytogenetic findings in blastoid mantle cell lymphoma

A subset of mantle cell lymphoma (MCL) tumors has blastoid morphology, and a number of morphologic variants of blastoid MCL have been described in the literature. In this report, we document the cytogenetic findings in 27 cases of blastoid MCL. Conventional cytogenetic analyses were performed on bone marrow aspirates involved by MCL from 27 patients. There were 14 men and 13 women with a median age of 63 years (range, 40-79 years). Diagnostic tissue biopsy and bone marrow specimens were reviewed, and cases were divided into 2 morphologic groups: classic (12 cases) and pleomorphic (15 cases), as defined in the World Health Organization classification. All tumors had an immunophenotype compatible with MCL, were positive for cyclin D1, and carried the t(11;14). Twenty-four cases had complex karyotypes with 3 or more chromosomal abnormalities in addition to the t(11;14). In classic blastoid MCL, abnormalities of chromosomes 13, 18, and 8 were most common. In pleomorphic blastoid MCL, abnormalities of chromosomes 13, 17, and 3 were most frequent. Chromosome 22 abnormalities were detected exclusively in the pleomorphic group. Tumors in which the neoplastic cells showed prominent nucleoli had a significantly higher frequency of chromosome 17 abnormalities (P = 0.03). We conclude that blastoid MCL tumors often show complex cytogenetic aberrations. Some abnormalities correlate with morphologic features, suggesting that morphologic variants of blastoid MCL may arise via different molecular pathways.

Cytogenetic risk stratification of 417 patients with chronic myelomonocytic leukemia from a single institution

Approximately 30% of patients with chronic myelomonocytic leukemia (CMML) have karyotypic abnormalities and this low frequency has made using cytogenetic data for the prognostication of CMML patients challenging. Recently, a three‐tiered cytogenetic risk stratification system for CMML patients has been proposed by a Spanish study group. Here we assessed the prognostic impact of cytogenetic abnormalities on overall survival (OS) and leukemia‐free survival (LFS) in 417 CMML patients from our institution. Overall, the Spanish cytogenetic risk effectively stratified patients into different risk groups, with a median OS of 33 months in the low‐, 24 months in intermediate‐ and 14 months in the high‐risk groups. Within the proposed high risk group, however, marked differences in OS were observed. Patients with isolated trisomy 8 showed a median OS of 22 months, similar to the intermediate‐risk group (P = 0.132), but significantly better than other patients in the high‐risk group (P = 0.018). Furthermore, patients with more than three chromosomal abnormalities showed a significantly shorter OS compared with patients with three abnormalities (8 vs. 15 months, P = 0.004), suggesting possible a separate risk category. If we simply moved trisomy 8 to the intermediate risk category, the modified cytogenetic grouping would provide a better separation of OS and LFS; and its prognostic impact was independent of other risk parameters. Our study results strongly advocate for the incorporation of cytogenetic information in the risk model for CMML. Am. J. Hematol. 89:813–818, 2014.

Clinical features of De Novo acute myeloid leukemia with concurrent DNMT3A , FLT3 and NPM1 mutations

BackgroundDe novo acute myeloid leukemia (AML) with concurrent DNMT3A, FLT3 and NPM1 mutations (AMLDNMT3A/FLT3/NPM1) has been suggested to represent a unique AML subset on the basis of integrative genomic analysis, but the clinical features of such patients have not been characterized systematically.MethodsWe assessed the features of patients (n = 178) harboring mutations in DNMT3A, FLT3 and/or NPM1, including an index group of AMLDNMT3A/FLT3/NPM1 patients.ResultsPatients with AMLDNMT3A/FLT3/NPM1 (n = 35) were significantly younger (median, 56.0 vs. 62.0 years; p = 0.025), mostly women (65.7% vs. 46.9%; p = 0.045), and presented with a higher percentage of bone marrow blasts (p < 0.001) and normal cytogenetics (p = 0.024) in comparison to patients within other mutation groups in this study. Among patients <60 years old, those with AMLDNMT3A/FLT3/NPM1 had a shorter event-free survival (EFS) (p = 0.047). DNMT3A mutations and not FLT3 or NPM1 mutations were independently associated with overall survival (OS) (p = 0.026). Within mutation subgroups, patients with AMLDNMT3A/NPM1 had a significantly shorter OS compared to those with AMLFLT3-ITD/NPM1 (p = 0.047) suggesting that the adverse impact of DNMT3A mutations is more pronounced than that of FLT3- ITD among patients with NPM1 mutation.ConclusionsDNMT3A has a significant dominant effect on the clinical features and outcomes of de novo AML patients with concurrent DNMT3A, FLT3 and NPM1 mutations.

Epstein-Barr virus in lymphoproliferative processes: An update for the diagnostic pathologist

The Epstein-Barr virus is an orally transmitted herpesvirus that is widespread in human populations and exhibits marked B-cell tropism. It is associated with more human neoplasms than any other known virus, and its role in the pathogenesis of such neoplasms has been the subject of intense investigation. This review presents an overview and update of the biology of Epstein-Barr virus and the diagnostic features of lymphoproliferative disorders associated with this intriguing human pathogen.

Differential impact of minimal residual disease negativity according to the salvage status in patients with relapsed/refractory B‐cell acute lymphoblastic leukemia

Minimal residual disease (MRD) assessment predicts survival for patients with newly diagnosed acute lymphoblastic leukemia (ALL). Its significance in relapsed/refractory ALL is less clear.

Next-generation companion diagnostics: promises, challenges, and solutions.

Companion diagnostics are in vitro clinical laboratory assays designed to predict the efficacy of a targeted cancer therapy through assessment of 1 or more biomarkers whose status in a patient’s neoplasm assists in determining whether a drug may or may not be effective. Companion diagnostics can be developed after a drug has been marketed, or they may be codeveloped alongside a targeted cancer drug through clinical trials. Until recently, most companion diagnostics approved by the US Food and Drug Administration (FDA) have been designed along a linear paradigm of “one drug/one biomarker.” However, the limitations of this approach are becoming apparent as in vitro diagnostics are shifting to high-throughput assays, the scope of cancer heterogeneity at the molecular and proteomic levels is becoming increasingly known, and the armamentarium of targeted therapies continues to expand.1 Novel high-throughput testing platforms, namely next-generation sequencing (NGS) and mass spectrophotometry (MS) proteomics, are gradually disrupting traditional diagnostic assays and ushering in a new paradigm of companion diagnostics we refer to aptly as next-generation companion diagnostics.

Impact of trisomy 8 on treatment response and survival of patients with chronic myelogenous leukemia in the era of tyrosine kinase inhibitors

Impact of trisomy 8 on treatment response and survival of patients with chronic myelogenous leukemia in the era of tyrosine kinase inhibitors