High-grade B-cell lymphomas with MYC, BCL2, and/or BCL6 rearrangements, “double-hit” or “triple-hit” lymphomas (DTHL), are aggressive neoplasms associated with a poor prognosis. A t(3;8)(q27;q24) ...rarely occurs in B-cell lymphomas that results in a unique “pseudo–double-hit” BCL6-MYC fusion, indistinguishable by interphase fluorescence in situ hybridization (FISH) from more conventional DTHL with independent MYC and BCL6 translocations. Reports of t(3;8)(q27;q24) lymphomas are sparse, and to better characterize their pathologic, cytogenetic, and clinical features, 6 new cases from 2 institutions and 19 previously published cases were reviewed. All new cases displayed aggressive morphologic features, and most previously published cases were classified as aggressive lymphomas. Collectively, all t(3;8)(q27;q24) cases had a germinal center (GC) phenotype, and most had complex karyotypes (22/24, 92%), including frequent concomitant BCL2 rearrangements (17/24, 71%). When compared to two large published DTHL cohorts, t(3;8)(q27;q24) lymphomas less often expressed BCL2 (P < .01), had a greater likelihood of extranodal involvement (P < .01), and more frequently appeared triple-hit by FISH analysis (P < .01). Despite presenting with aggressive clinicopathologic features, 100% (6/6) of t(3;8;)(q27;q24) patients achieved complete remission after intensive induction regimens, and 2- and 3-year overall survival rates were 63% (10/16) and 57% (8/14), respectively. These findings suggest that lymphomas with t(3;8)(q27;q24) may represent a subset of GC B-cell lymphomas distinct from conventional DTHL. Our results further highlight the value of routine karyotype assessment in aggressive B-cell lymphomas, and the importance of recognizing the t(3;8)(q27;q24) so that its clinical significance can be more fully explored.
•Reciprocal BCL6-MYC translocation occurs in a subset of aggressive B-cell lymphomas.•Lymphomas with BCL6-MYC are not easily distinguished from true double-hit lymphomas.•These lymphomas have a germinal center origin and frequent BCL2 translocations.•Lymphomas with BCL6-MYC may have better outcomes than true double-hit lymphomas.
The incidence of lymphoproliferative disorders (LPDs) is increasing in sub-Saharan Africa (SSA) due to population growth, aging, and human immunodeficiency virus (HIV). Despite significant burden, ...resources for diagnosis and treatment of LPDs are limited, with little infrastructure to deliver modern pathology services. Diagnostic and therapeutic decisions are therefore frequently made without tissue confirmation, leading to high rates of misdiagnosis and inappropriate treatment.
We have established a laboratory in Malawi to support clinical and research efforts at a national teaching hospital. Consensus real-time diagnoses are rendered by local pathologists after weekly clinicopathologic teleconferences involving clinicians and pathologists from the United States and Malawi. Additional ancillary studies are then performed in the United States prior to final diagnosis.
We report our first 2 years' experience and demonstrate high concordance between real-time diagnoses in Malawi and final diagnoses in the United States (5% major discordance rate for formalin-fixed, paraffin-embedded samples). In addition, we describe characteristics of pathologically confirmed LPDs in Malawi, highlighting differences by HIV status.
Our multidisciplinary approach can be a model for strong pathology services that provide direct, real-time support to clinical care and research in SSA.
Epigenetic regulation is essential for temporal, tissue-specific and parent-of-origin-dependent gene expression. It has recently been found that the mouse Polycomb group (PcG) gene Eed (embryonic ...ectoderm development) acts to maintain repression of the imprinted X chromosome. Here, we investigated whether Eed is also required for regulation of autosomal imprinted loci. Expression analyses showed that transcripts from the silent alleles of a subset of paternally repressed genes were present in Eed−/− embryos. Parent-of-origin methylation was preserved in these embryos, but we observed changes in the methylation status of specific CpGs in differentially methylated regions (DMRs) at affected but not at unaffected loci. These data identify Eed as a member of a new class of trans-acting factors that regulate parent-of-origin expression at imprinted loci.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background
Contemporary descriptions of classical Hodgkin lymphoma (cHL) are lacking from sub‐Saharan Africa where human immunodeficiency virus (HIV) and Epstein–Barr virus (EBV) are prevalent.
...Methods
We describe a prospective cHL cohort in Malawi enrolled from 2013 to 2015. Patients received standardized treatment and evaluation, including HIV status and EBV testing of tumors and plasma.
Results
Among 31 patients with confirmed cHL, the median age was 19 years (range, 2–51 years) and 22 (71%) were male. Sixteen patients (52%) had stage III/IV, 25 (81%) B symptoms, and 16 (52%) performance status impairment. Twenty‐three patients (74%) had symptoms >6 months, and 11 of 29 (38%) had received empiric antituberculosis treatment. Anemia was common with median hemoglobin 8.2 g/dL (range, 3.1‐17.1 g/dL), which improved during treatment. No children and 5 of 15 adults (33%) were HIV+. All HIV+ patients were on antiretroviral therapy for a median 15 months (range, 2–137 months), with median CD4 count 138 cells/μL (range, 23–329 cells/μL) and four (80%) having undetectable HIV. EBV was present in 18 of 24 (75%) tumor specimens, including 14 of 20 (70%) HIV− and 4 of 4 (100%) HIV+. Baseline plasma EBV DNA was detected in 25 of 28 (89%) patients, with median viral load 4.7 (range, 2.0–6.7) log10copies/mL, and subsequently declined in most patients. At 12 months, overall survival was 75% (95% confidence interval CI, 55%–88%) and progression‐free survival 65% (95% CI, 42%–81%). Baseline plasma EBV DNA and persistent viremia during treatment were associated with poorer outcomes.
Conclusion
cHL in Malawi is characterized by delayed diagnosis and advanced disease. Most cases were EBV associated and one‐third of adults were HIV+. Despite resource limitations, 12‐month outcomes were good.
A large-scale genomic analysis of patients with
-mutated myeloid disease has not been performed to date. We reviewed comprehensive genomic profiling results from 6043 adults to characterize ...clinicopathologic features and co-mutation patterns by ASXL1 mutation status.
mutations occurred in 1414 patients (23%). Mutation co-occurrence testing revealed strong co-occurrence (
< 0.01) between mutations in
and nine genes (
). Further analysis of patients with these co-mutations yielded several novel findings. Co-mutation patterns supported that
co-mutation may be biologically distinct from
/non-
spliceosome co-mutation. In AML,
co-mutated patients frequently harbored
mutations (42%), which were dependent on the presence of both
and
mutation (
< 0.05).
and
mutations were also exclusive in
co-mutated patients and associated with divergent chronic myeloid phenotypes. Our findings support that certain multi-mutant genotypes may be biologically relevant in
-mutated myeloid disease.
Summary
Outcomes for diffuse large B‐cell lymphoma (DLBCL) in sub‐Saharan Africa (SSA) are poorly described. We report mature data from one of the first prospective SSA cohorts. Patients aged ...≥18 years with DLBCL were enrolled in Malawi 2013–2017. Participants were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy and concurrent antiretroviral therapy (ART) if positive for human immunodeficiency virus (HIV+). Eighty‐six participants (mean age 47 years, standard deviation 13) were enrolled: 54 (63%) were male and 51 (59%) were HIV+, of whom 34 (67%) were on ART at DLBCL diagnosis. Median CD4 count was 0·113 cells × 109/l (interquartile range IQR 0·062–0·227) and 25 (49%) had HIV viral load <400 copies/μl. Participants received median six cycles CHOP (IQR 4–6). No patients were lost to follow‐up and the 2‐year overall survival was 38% (95% confidence interval 28–49). In multivariable analyses, Eastern Cooperative Oncology Group performance status (PS) ≥2 and lactate dehydrogenase (LDH) >2× upper limit of normal (ULN) were associated with mortality. HIV status was not associated with mortality. A simplified prognostic model of LDH >2× ULN and PS ≥2 performed at least as well as the age‐adjusted International Prognostic Index. DLBCL can be successfully treated in SSA and outcomes did not differ by HIV status. A simplified prognostic model prognosticates well and may be easier to use in resource‐limited settings but requires validation.
Intermediate-to-large B-cell lymphomas represent a heterogeneous group of aggressive lesions frequently encountered in practice. The differential diagnosis includes the most common of all lymphomas, ...diffuse large B-cell lymphoma (DLBCL), as well as Burkitt lymphoma (BL), B-lymphoblastic lymphoma, and the blastoid variant of mantle cell lymphoma. In recent decades, gene expression profiling studies have clarified the biologic origins and features of these diseases. Moreover, clinically relevant subtypes of DLBCL have been identified, and a new category was defined: B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL. Herein, we review the salient diagnostic features of the various entities within this differential diagnosis and provide a stepwise diagnostic approach for dealing with challenging cases.
A case-based approach is used to highlight diagnostic dilemmas and clinical decision points within the differential diagnosis of intermediate-to-large B-cell lymphomas.
Based on the published literature and World Health Organization criteria, we suggest a diagnostic algorithm for appropriate classification of these lymphomas.
Correct classification of intermediate-to-large B-cell lymphomas is important, because prognosis and therapeutic approach vary for different tumors and tumor subclasses. Understanding both disease-specific criteria and pathologic features that influence clinical behavior within a category is imperative for evaluation of these lymphomas.
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