Acute Leukemias - Republican Scientific Medical Library

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114 Chapter 7 · <strong>Acute</strong> Lymphoblastic Leukemia: Clinical Presentation, Diagnosis, and Classification Table 7.1. Differential diagnosis of ALL Non-hematologic processes: Tuberculosis Heavy metals Human immunodeficiency virus (HIV) Infectious mononucleosis Autoimmune diseases Juvenile rheumatoid arthritis Osteomyelitis Hematologic processes: Differential diagnostic considerations from cytomorphology and histology In children Pertussis Hematogones Small round blue cell tumors In adults Chronic lymphocytic leukemia (CLL) Prolymphocytic leukemia (PLL) Lymphoma, especially blastic variant of mantle cell Plasmablastic myeloma In children and adults Reactive lymphocytosis (mononucleosis) Thymoma AML with minimal differentiation (M0) and without maturation (M1) <strong>Acute</strong> biphenotypic leukemia CML presenting in lymphoid blast phase surface and cytoplasmic markers evaluated by flow cytometry and immunohistochemistry. Immunophenotypic analysis is critical to confirm a morphologic diagnosis of ALL [27], to resolve a difficult differential diagnosis and to further subclassify cases into precursor-B and precursor-T lineage types. However, a specific immunophenotype identified at diagnosis might also be useful for evaluating residual disease by flow cytometry. Most immunophenotyping studies are performed from blood or marrow aspirates with surface and cytoplasmic markers by flow cytometry, but a growing number of markers are now available for immunophenotyping on tissue sections by Table 7.2. Immunophenotype A. Pertinent markers available for immunohistochemical studies General: TdT, CD34 B-cell: CD20, CD79A T-cell: CD3, CD4, CD8, CD5, CD45RO Myeloid: MPO, CD68, lysozyme, glycophorin A, Factor VIII, CD61 Other: keratin, NSE, myogenin, CD99 B. Commonly used markers for flow immunophenotyping in acute leukemia General: CD34, HLA-DR, TdT, CD45 B-cell markers: CD10, CD19, cCD22, CD20, cCD79A, CD24, cl, sIg T-cell markers: CD1a, CD2, cCD3, CD4, CD8, CD5, CD7 Myeloid: cMPO, CD117, CD13, CD33, CD11c, CD14, CD15 C. B-lineage ALL phenotypes: Pro-B: TdT+, CD19/22/79A+, CD10–, cl–, sIg– Common precursor-B: TdT+, CD19/22/79A+, CD10+, cl–, sIg– Pre-B: TdT+, CD19/22/79A+, CD10+, cl+, sIg– Burkitt: TdT–, CD19/22/79A+, CD10+, sIg+ D. T-lineage ALL phenotypes Pro/immature Thymocyte: TdT+, cCD3+, CD2/5/7+/– Common thymocyte: TdT+, cCD3+, CD2/5/7+, CD4+/CD8+, CD1a+ Mature thymocyte: TdT+/-, CD3+, CD2/5/7+, CD4+ or CD8+, CD1a– immunohistochemical techniques. This is of importance especially in cases which have low peripheral blast counts and in which bone marrow material is insufficient for flow analysis or in which a diagnosis is being made from an extramedullary site. Currently, there are many markers available for tissue immunophenotyping in acute leukemia [28], and a list of pertinent markers is given in Table 7.2 A. There are various recommendations concerning which antibodies to include in a routine flow cytometric panel for the work-up of an acute leukemia [29, 30], but there is no uniformly accepted panel. Commonly used markers are listed in Table 7.2 B.
a 7.3 · Diagnosis 115 The vast majority of cases of ALL (~ 85%) are of B lineage. These have been grouped into further subtypes, which may correspond to different levels of maturation in normal B-cell development. However, such differentiation schemes are not universally agreed upon and the terminology for the different subtypes is also not uniform. In fact, due to the lack of conformity, and the questionable significance of the further subclassification, the WHO classification scheme simply classifies cases as “precursor-B” and “precursor-T” ALL without additional categorization. The most common B-lineage ALL is the precursor-B phenotype with B-cell markers (CD19, CD22), TdT, cytoplasmic CD79A, CD34, CD10 (CALLA), and lack of cytoplasmic l (cl) and of surface immunoglobulin (sIg) expression. This type has variably been called “common precursor B” ALL, or “early precursor-B” ALL. A less common type lacks CALLA and may be at an earlier level of maturation that has been termed “pro-B” ALL. This type has a worse prognosis. A type with more maturation than common precursor-B ALL is characterized by the presence of cl, and is referred to as “Pre-B”ALL. Reports are conflicting, but this may be more commonly associated with t(1;19)(q23;p13). Burkitt leukemia has the immunophenotype of mature B cells with sIg expression. Whether rare cases of non-Burkitt ALL also exhibit a mature B phenotype (sIg+) is questionable, although such cases have been reported on [31]. B-lineage ALL phenotypes are listed in Table 7.2 C. T lineage ALL accounts for only 15–20% of cases and can also be separated into phenotypic groups which may correspond to different stages of thymic Tcell development [32]. As in B-lineage ALL, a type with intermediate differentiation is the most common. This “common thymocyte” type shows expression of the pan T-cell markers, CD2, cytoplasmic CD3 (cCD3), CD7, and CD5 and distinctively shows coexpression of CD4 and CD8, and expression of CD1a. A more primitive type called “prothymocyte” or “immature thymocyte” type has TdT, cCD3, and variable expression of CD5, CD2, and CD7, but lacks CD4, CD8, and CD1a. A more mature phenotype than the “common thymocyte” type has variable TdT, the pan T-cell markers, CD4 or CD8 but lacks CD1a. Again, because of lack of conformity and variability of marker expression, the WHO classification recognizes only the “precursor-T” group without further immunophenotypic categorization [12]. T-lineage ALL phenotypes are listed in Table 7.2 D. Table 7.3. Scoring system for biphenotypic leukemia Score Lineage B-lymphoid T-lymphoid Myeloid 2 cCD79A cCD3 MPO cl cCD22 anti-TCR 1 CD19 CD20 CD10 0.5 TdT CD24 CD2 CD5 CD8 CD10 TdT CD7 CD1a CD117 CD13 CD33 CD65 CD14 CD15 CD64 Greater than 2 points are needed to consider a lineage involved [36] Coexpression of other nonlymphoid markers is common on the lymphoblasts in both precursor-B and precursor-T ALL, and does not necessarily indicate bilineal potential. The myeloid markers, CD13 and CD33, are the most frequently expressed [33]. In the past, these have erroneously been interpreted as indicating a biphenotypic process and a worse prognosis, but more recently, this has not been found [34, 35]. Recently, more strict criteria with a uniform grading system have been instituted to help define the “biphenotypic” entity, illustrated in Table 7.3 [36]. Cytoplasmic expression of myeloperoxidase in ALL has also been reported by flow cytometric analysis. However, this does not correspond to the cytochemical detection of enzyme reactivity, and when identified with a polyclonal antibody, it is of only questionable significance [37]. Differential diagnostic considerations that have to be considered in immunophenotyping include hematogones, thymoma, biphenotypic leukemia, and CML presenting in lymphoid blast phase. Hematogones have the same immunophenotype as common precursor B ALL cells, but the hematogones exhibit a spectrum of maturation with a continuum of cells from immature to mature showing loss of CD34, and gain of CD20 and sIg [38, 39]. Thymoma cells have the phenotype of common thymocytes, and cannot be distinguished from common T ALL/lymphoblastic lymphoma by immunophenotype alone. Correlation with clinical presentation and histology are important for the correct interpretation. When
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E.H. Estey · S.H. Faderl · H. M.
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E. H. Estey Department of Leukemia
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VI Table of Contents 14 Philadelphi
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Therapy of AML Elihu Estey Contents
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Acute Myeloid Leukemia: Epidemiolog
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Relapsed and Refractory Acute Myelo
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a References 287 29. Hingorani AD,
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Subject Index A aberrant methylatio
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a Subject Index 291 CREB, see enhan
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