Loh 03 Rar

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Loh 03 rar

Representative PCR analysis of promoter region CpG island sequence of MGMT and RAR-β2 from bisulfite-treated DNA obtained from melanoma cell lines. Fully methylated CpGs are indicated as solid black boxes and partially methylated CpGs are shown as shaded boxes. All CpGs contained in the MSP products are shown

In 2001, the World Health Organization (WHO), in collaboration with the Society for Hematopathology and the European Association of Haematopathology, published a Classification of Tumors of the Hematopoietic and Lymphoid Tissues as part of the 3rd edition of the series, WHO Classification of Tumors.1 That classification reflected a paradigm shift from previous schemes in that, for the first time, genetic information was incorporated with morphologic, cytochemical, immunophenotypic, and clinical information into diagnostic algorithms for the myeloid neoplasms. The 2001WHO classification was prefaced with a comment predicting that future revisions would be necessary because of rapidly emerging genetic and biologic information. Recently, a revised classification has been published as part of the 4th edition of the WHO monograph series.2 The aim of the revision was to incorporate new scientific and clinical information to refine diagnostic criteria for previously described neoplasms and to introduce newly recognized disease entities. Our purpose in this communication is to highlight major changes in the revised WHO classification of myeloid neoplasms and acute leukemia and to provide the rationale for those changes.

Although a BM core biopsy may not be required in every case, an adequate biopsy does provide the most accurate assessment of the marrow cellularity, topography, stromal changes, and maturation pattern of the hematopoietic lineages, and it can be invaluable in detecting residual disease following therapy. In addition, the biopsy provides material for immunohistochemical detection of antigens that can be diagnostically and prognostically useful, such as CD34, TdT, and Ki67, particularly if marrow aspirate smears are poorly cellular.6

or hemoglobin > 17 g/dL in men, 15 g/dL in women if associated with a documented and sustained increase of at least 2 g/dL from a person's baseline value that cannot be attributed to correction of iron deficiency

Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes. No significant increase or left-shift of neutrophil granulopoiesis or erythropoiesis.

Requires the failure of iron replacement therapy to increase hemoglobin level to the polycythemia vera range in the presence of decreased serum ferritin. Exclusion of polycythemia vera is based on hemoglobin and hematocrit levels, and red cell mass measurement is not required.

Causes of reactive thrombocytosis include iron deficiency, splenectomy, surgery, infection, inflammation, connective tissue disease, metastatic cancer, and lymphoproliferative disorders. However, the presence of a condition associated with reactive thrombocytosis does not exclude the possibility of ET if other criteria are met.

Presence of megakaryocyte proliferation and atypia,* usually accompanied by either reticulin or collagen fibrosis,or,in the absence of significant reticulin fibrosis, the megakaryocyte changes must be accompanied by an increased bone marrow cellularity characterized by granulocytic proliferation and often decreased erythropoiesis (ie, prefibrotic cellular-phase disease)

Requires the failure of iron replacement therapy to increase hemoglobin level to the polycythemia vera range in the presence of decreased serum ferritin. Exclusion of polycythemia vera is based on hemoglobin and hematocrit levels. Red cell mass measurement is not required.

It should be noted that patients with conditions associated with reactive myelofibrosis are not immune to primary myelofibrosis, and the diagnosis should be considered in such cases if other criteria are met.

The appreciation of the role abnormal PTKs play in the pathogenesis of the MPNs argued for the inclusion of other chronic myeloid proliferations related to constitutively activated PTKs under the MPN umbrella. Thus, systemic mastocytosis, which has many myeloproliferative features and is almost always associated with the KIT D816V mutation,45 has been added to the MPN category. Still, the pathogenesis of nearly one-half of cases of ET and PMF, all cases of chronic neutrophilic leukemia, and a number of cases of CEL remains unknown. For these, reliance on clinical, morphologic, and laboratory features is essential for diagnosis and classification.

Diagnostic algorithms for PV, ET, and PMF have substantially changed to include information regarding JAK2 V617F and similar activating mutations. Additional clinical, laboratory, and histologic parameters have been included to allow diagnosis and subclassification regardless of whether JAK2 V617F or a similar mutation is or is not present.

Recurring chromosomal abnormalities considered as presumptive evidence of MDS in the setting of persistent cytopenia of undetermined origin, but in the absence of definitive morphologic features of MDS

If the marrow myeloblast percentage is

Cases with Auer rods and

Some authors suggested that the previous WHO classification failed to emphasize the prognostic significance of increased blasts in the PB.69 To address this criticism, the revised classification redefines the criteria for refractory anemia with excess blasts (RAEB-1) to include patients with PB smears that consistently show 2% to 4% blasts in the blood, even if the blast percentage in the BM is less than 5%. Patients with 5% to 19% PB blasts or 10% to 19% blasts in the BM are classified in the highest WHO grade, RAEB-2.

The 3rd edition of the WHO classification was criticized by some pediatric hematologists for failing to recognize differences between the clinical and pathologic features of MDS in children and MDS in adults.75 At the CAC meeting it was the consensus of the pediatric hematologists and hematopathologists that children with MDS and 2% to 19% blasts in the PB and/or 5% to 19% blasts in the BM may be categorized according to the same criteria as for adults with MDS. However, in contrast to adults, isolated refractory anemia is uncommon in childhood MDS, which more commonly is initially associated with thrombocytopenia and/or neutropenia, often accompanied by a hypocellular BM.75 In order to emphasize the unique features of these cases of childhood MDS, the 4th edition of the WHO devotes a section to childhood MDS, in which a provisional entity, refractory cytopenia of childhood (RCC), is introduced in the classification. The category of RCC is reserved for childhood cases with less than 2% blasts in the blood and less than 5% in the marrow and persistent cytopenias associated with dysplasia in at least 2 cell lineages. Often, BM specimens in RCC are hypocellular, and if no MDS-related cytogenetic abnormalities are present, the distinction between RCC and aplastic anemia or congenital bone marrow failure syndromes may be very difficult. Furthermore, the distinction, if any, between RCC and refractory cytopenia with multilineage dysplasia as defined in adults is not clear at this time. More study is needed to clarify these questions, thus RCC is considered as a provisional entity.

Patients with refractory cytopenia(s) suspected to have MDS, but who lack diagnostic morphologic features may be considered to have presumptive evidence of MDS if they have specific MDS-related cytogenetic abnormalities.

An over-arching category of MDS, refractory cytopenia with unilineage dysplasia, has been added to incorporate patients who exhibit unilineage dysplasia associated with refractory anemia (unilineage erythroid dysplasia), refractory neutropenia (unilineage dysgranulopoiesis), or refractory thrombocytopenia (unilineage dysmegakaryocytopoiesis), and who have fewer than 1% blasts in the blood and fewer than 5% in the bone marrow.

The category of refractory cytopenia with multilineage dysplasia is no longer subdivided according to whether 15% or more of the erythroid precursors are ring sideroblasts (RS), that is, the former category of RCMD-RS is now incorporated in RCMD.

Patients with 2% to 4% blasts in the blood and less than 5% blasts in the bone marrow should be diagnosed as having RAEB-1 if other clinical and laboratory findings of MDS are present.

A provisional entity, refractory cytopenia of childhood (RCC), has been added to include children with cytopenia(s) with less than 2% blasts in the peripheral blood and less than 5% in the bone marrow and evidence of dysplasia in 2 or more lineages. For children with 2% to 19% blasts in the blood and/or 5% to 19% in the bone marrow, the MDS subclassification should be made using the same criteria used for adults. 041b061a72