Recently the World Health Organization (WHO), in collaboration with the European Association for Haematopathology and the Society for Hematopathology, published a revised and updated edition of the ...WHO Classification of Tumors of the Hematopoietic and Lymphoid Tissues. The 4th edition of the WHO classification incorporates new information that has emerged from scientific and clinical studies in the interval since the publication of the 3rd edition in 2001, and includes new criteria for the recognition of some previously described neoplasms as well as clarification and refinement of the defining criteria for others. It also adds entities—some defined principally by genetic features—that have only recently been characterized. In this paper, the classification of myeloid neoplasms and acute leukemia is highlighted with the aim of familiarizing hematologists, clinical scientists, and hematopathologists not only with the major changes in the classification but also with the rationale for those changes.
In a study conducted at three institutions, ibrutinib was associated with major responses in 73% of patients with Waldenström's macroglobulinemia who had received at least one previous treatment. ...Toxic effects of grade 2 or higher included neutropenia in 22% of the patients.
Waldenström’s macroglobulinemia is a malignant B-cell lymphoma that is associated with an accumulation of clonal lymphoplasmacytic cells and monoclonal IgM secretion.
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Despite advances in treatment, the disease eventually progresses in most patients, and new treatment options are needed.
Whole-genome sequencing has revealed a single activating somatic mutation in
MYD88
(resulting in a predicted protein change from leucine to proline at amino acid position 265) and multiple activating mutations in the C-terminal domain of
CXCR4
in patients with Waldenström’s macroglobulinemia.
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,
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In tumor cells, MYD88L265P triggers activation of nuclear factor κB (NF-κB) through two divergent pathways involving Bruton’s tyrosine kinase (BTK) . . .
Pediatric follicular lymphoma (PFL) is a variant of follicular lymphoma (FL) presenting as localized lymphadenopathy in children. Unlike conventional adult FL, PFL typically does not recur or ...progress. Clear diagnostic criteria for PFL are lacking, and it is uncertain whether this indolent lymphoma is defined by age or may occur in adults. We analyzed 27 FL in patients < 40 years of age and found that all 21 cases that lacked a BCL2 gene abnormality (BCL2-N; P < .0001) and had > 30% Ki67 fraction (high proliferation index, HPI; P = .0007) were stage I and did not progress or recur; in comparison, all 6 cases with BCL2 rearrangement and/or PI < 30% were stage III/IV, and 5 of 6 recurred or progressed. In a separate cohort of 58 adult FL (≥ 18 years of age), all 13 BCL2-N/HPI cases were stage I, and none progressed or relapsed, whereas 11 of 15 stage I cases with BCL2 gene abnormality and/or LPI relapsed or progressed (P = .0001). The adult and pediatric BCL2-N/HPI FL cases had similar morphologic features. Our results confirm the highly indolent behavior of PFL and suggest that these are characterized by HPI and absence of BCL2 gene abnormality. PFL-like cases also occur in adults and are associated with indolent behavior in this patient population.
Although generally curable with intensive chemotherapy in resource-rich settings, Burkitt lymphoma (BL) remains a deadly disease in older patients and in sub-Saharan Africa. Epstein-Barr virus (EBV) ...positivity is a feature in more than 90% of cases in malaria-endemic regions, and up to 30% elsewhere. However, the molecular features of BL have not been comprehensively evaluated when taking into account tumor EBV status or geographic origin. Through an integrative analysis of whole-genome and transcriptome data, we show a striking genome-wide increase in aberrant somatic hypermutation in EBV-positive tumors, supporting a link between EBV and activation-induced cytidine deaminase (AICDA) activity. In addition to identifying novel candidate BL genes such as SIN3A, USP7, and CHD8, we demonstrate that EBV-positive tumors had significantly fewer driver mutations, especially among genes with roles in apoptosis. We also found immunoglobulin variable region genes that were disproportionally used to encode clonal B-cell receptors (BCRs) in the tumors. These include IGHV4-34, known to produce autoreactive antibodies, and IGKV3-20, a feature described in other B-cell malignancies but not yet in BL. Our results suggest that tumor EBV status defines a specific BL phenotype irrespective of geographic origin, with particular molecular properties and distinct pathogenic mechanisms. The novel mutation patterns identified here imply rational use of DNA-damaging chemotherapy in some patients with BL and targeted agents such as the CDK4/6 inhibitor palbociclib in others, whereas the importance of BCR signaling in BL strengthens the potential benefit of inhibitors for PI3K, Syk, and Src family kinases among these patients.
•Tumor EBV status is more strongly associated with distinct genetic and etiological mechanisms than geographic origin.•EBV-positive BL genomes feature fewer driver mutations despite their greater mutational load that is partly a result of increased AICDA activity.
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A World Health Organization (WHO) classification of hematopoietic and lymphoid neoplasms has recently been published. This classification was developed through the collaborative efforts of the ...Society for Hematopathology, the European Association of Hematopathologists, and more than 100 clinical hematologists and scientists who are internationally recognized for their expertise in hematopoietic neoplasms. For the lymphoid neoplasms, this classification provides a refinement of the entities described in the Revised European-American Lymphoma (REAL) Classification—a system that is now used worldwide. To date, however, there has been no published explanation or rationale given for the WHO classification of the myeloid neoplasms. The purpose of this communication is to outline briefly the WHO classification of malignant myeloid diseases, to draw attention to major differences between it and antecedent classification schemes, and to provide the rationale for those differences.
Mutations at codon 641 of EZH2 are recurrent in germinal center B cell lymphomas, and the most common variants lead to altered EZH2 enzymatic activity and enhanced tri-methylation of histone H3 at ...lysine 27, a repressive chromatin modification. As an initial step toward screening patients for cancer genotype-directed therapy, we developed a screening assay for EZH2 codon 641 mutations amenable for testing formalin-fixed clinical specimens, based on the sensitive SNaPshot single nucleotide extension technology. We detected EZH2 mutations in 12/55 (22%) follicular lymphomas (FL), 5/35 (14%) diffuse large B cell lymphomas with a germinal center immunophenotype (GCB-DLBCL), and 2/11 (18%) high grade B cell lymphomas with concurrent rearrangements of BCL2 and MYC. No EZH2 mutations were detected in cases of Burkitt lymphoma (0/23). EZH2 mutations were frequently associated with the presence of BCL2 rearrangement (BCL2-R) in both the FL (28% of BCL-R cases versus 0% of BCL2-WT cases, p<0.05) and GCB-DLBCL groups (33% of BCL2-R cases versus 4% of BCL2-WT cases, p<0.04), and across all lymphoma types excluding BL (27% of BCL2-R cases versus 3% of BCL2-WT cases, p<0.003). We confirmed gain-of-function activity for all previously reported EZH2 codon 641 mutation variants. Our findings suggest that EZH2 mutations constitute an additional genetic "hit" in many BCL2-rearranged germinal center B cell lymphomas. Our work may be helpful in the selection of lymphoma patients for future trials of pharmacologic agents targeting EZH2 and EZH2-regulated pathways.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
CNS Hodgkin lymphoma Gerstner, Elizabeth R; Abrey, Lauren E; Schiff, David ...
Blood,
09/2008, Letnik:
112, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Central nervous system (CNS) involvement by Hodgkin lymphoma (HL) is rare. As a result, there is limited guidance for clinicians on how to manage these patients. Detailed information was collected on ...16 patients, the largest number to date, with meningeal or parenchymal CNS-HL confirmed by histopathology (15) or CSF (1). Eight patients presented with CNS-HL at diagnosis, 2 of whom had isolated CNS disease, while 8 patients developed CNS-HL at relapse. Patients received a range of treatments including surgery or radiation alone, radiation with chemotherapy, or chemotherapy alone. Median overall survival for all 16 patients was 60.9 months from first diagnosis of HL (systemic or CNS) and 43.8 months from diagnosis of CNS-HL. Although a majority of patients have died, long-term survival is possible in patients who achieve a complete response to treatment, particularly those who present with CNS involvement or involvement of the CNS is the sole site of relapsed disease.
Although chronic inflammatory disorders of the ocular adnexa are relatively common, their pathogenesis is in many cases poorly understood. Recent investigation suggests that many cases of sclerosing ...orbital inflammation are a manifestation of IgG4-related disease; however, most patients reported have been Asian, and it is not clear whether the results of studies from the Far East can be reliably extrapolated to draw conclusions about Western patients. We evaluated 38 cases previously diagnosed as orbital inflammatory pseudotumor or chronic dacryoadenitis to determine whether our cases fulfill the criteria for IgG4-RD (IgG4-related dacryoadenitis when involving the lacrimal gland, and IgG4-related sclerosing orbital inflammation when involving orbital soft tissue). Fifteen patients had IgG4-related dacryoadenitis or orbital inflammation. These patients included 9 men and 6 women, aged 24 to 77 years (median, 64 y). Lesions involved orbital soft tissue (8 cases), lacrimal gland (6 cases), and canthus (1 case). In 1 case, focal in situ follicular neoplasia was seen in a background of IgG4-RD. In another case, a clonal IGH gene rearrangement was detected. Four patients with IgG4-RD had evidence of IgG4-RD in other anatomic sites. Five patients, 1 man and 4 women, aged 26 to 74 years (median 50 y) had orbital lesions (2 involving lacrimal gland, 3 involving soft tissue) suspicious for, but not diagnostic of, IgG4-RD. Of 16 patients with IgG4-RD or probable IgG4-RD with information available regarding the course of their disease, 11 patients experienced recurrent or persistent orbital disease. However, no patient developed lymphoma, and no patient died of complications of IgG4-RD. Eighteen patients had lesions not representing IgG4-RD. They included 6 male and 12 female individuals aged 6 to 77 years (median, 47 y). These patients had a variety of diseases, including granulomatosis with polyangiitis (3 cases), Rosai-Dorfman disease (1 case), nonspecific chronic inflammation and fibrosis involving lacrimal gland or soft tissue (12 cases), and others. Clinical and pathologic findings among our patients with IgG4-RD involving the orbit are similar to those previously described in Asian patients. Careful evaluation of histologic and immunophenotypic features and clinical correlation are required to distinguish orbital IgG4-RD from other sclerosing inflammatory lesions in the orbit.
The European Association of Hematopathologists and the Society for Hematopathology have developed a new World Health Organization (WHO) classification of hematologic malignancies, including lymphoid, ...myeloid, histiocytic, and mast cell neoplasms.
Ten committees of pathologists developed lists and definitions of disease entities. A clinical advisory committee (CAC) of international hematologists and oncologists was formed to ensure that the classification would be useful to clinicians. The CAC met in November 1997 to discuss clinical issues related to the classification.
The WHO uses the Revised European-American Lymphoma (REAL) classification, published in 1994 by the International Lymphoma Study Group, to categorize lymphoid neoplasms. The REAL classification is based on the principle that a classification is a list of "real" disease entities, which are defined by a combination of morphology, immunophenotype, genetic features, and clinical features. The relative importance of each of these features varies among diseases, and there is no one gold standard. The WHO Neoplasms recognizes distinct entities defined by a combination of morphology and cytogenetic abnormalities. At the CAC meeting, which was organized around a series of clinical questions, participants reached a consensus on most of the questions posed. They concluded that clinical groupings of lymphoid neoplasms were neither necessary nor desirable. Patient treatment is determined by the specific type of lymphoma, with the addition of grade within the tumor type, if applicable, and clinical prognostic factors, such as the International Prognostic Index.
The WHO classification has produced a new and exciting degree of cooperation and communication between oncologists and pathologists from around the world, which should facilitate progress in the understanding and treatment of hematologic malignancies.
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