Acute Leukemias (PDF)

Summary

This document is an excerpt from a clinical hematology textbook, and provides an overview of acute leukemias. It covers topics such as the classification, diagnosis, and clinical presentation of acute lymphoblastic and myeloid leukemias, including their subtypes and related precursor neoplasms. Cytochemical stains and their interpretation in distinguishing different types of leukemias are also discussed. The document contains multiple questions.

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31 Acute Leukemias Reeba A. Omman, Ameet R. Kini* OBJECTIVES After completion of this chapter, the reader will be able to: 1. Discuss the causes and development of acute leukemia. 4. Interpret the results of diagnostic tests for acute leukemias. 2. Characterize the diag...

31 Acute Leukemias Reeba A. Omman, Ameet R. Kini* OBJECTIVES After completion of this chapter, the reader will be able to: 1. Discuss the causes and development of acute leukemia. 4. Interpret the results of diagnostic tests for acute leukemias. 2. Characterize the diagnostic criteria used for acute myeloid 5. Discuss tumor lysis syndrome, including risk, cause, and and acute lymphoblastic leukemias. laboratory findings. 3. Compare and contrast acute lymphoblastic and myeloid 6. Discuss the cell staining patterns for the following tests: leukemias by morphology, presenting signs and symptoms, myeloperoxidase, Sudan black B, and esterases. laboratory findings, and prognosis. OUTLINE Introduction Subtypes of Acute Myeloid Leukemia and Related Classification Schemes for Acute Leukemias Precursor Neoplasms Acute Lymphoblastic Leukemia Acute Leukemias of Ambiguous Lineage World Health Organization Classification Cytochemical Stains and Interpretations Morphology Myeloperoxidase Prognosis Sudan Black B Immunophenotyping Esterases Genetic and Molecular Findings Acute Myeloid Leukemia Clinical Presentation CASE STUDY After studying the material in this chapter, the reader should be able to respond to the following case study: A 5-year-old child was seen by her family physician because of weakness and headaches. She had been in good health except for the usual communi- cable diseases of childhood. Physical examination revealed a pale, listless child with multiple bruises. The WBC count was 15 ! 109/L, the hemoglobin was 8 g/dL, and the platelet count was 90 ! 109/L. She had “abnormal cells” in her peripheral blood (Figure 31.1). Cytogenetic studies revealed hyperdiploidy. 1. What is the most likely diagnosis? 2. What characteristics of this disease indicate a positive prognosis? 3. What prognosis is associated with the hyperdiploidy? Figure 31.1 Peripheral Blood Film for the Patient in the Case Study. (Wright-Giemsa stain, !1000.) (From Rodak, B. F., & Carr, J. H.. Clinical Hematology Atlas. [5th ed.]. St. Louis: Elsevier.) * The authors extend appreciation to Bernadette F. Rodak, Woodlyne Roquiz, and Pranav Gandhi, whose work in prior editions provided the foundation for this chapter. 540 CHAPTER 31 Acute Leukemias 541 morphologic examination along with cytochemical stains INTRODUCTION to distinguish lymphoblasts from myeloblasts (Figure 31.2). The broad term leukemia is derived from the ancient Greek The use of cytochemical stains continues to be a useful ad- words leukos ("#$%óç), meaning “white,” and haima (&ἷ'&), junct for differentiation of hematopoietic diseases, especially meaning “blood.”1 As defined today, acute leukemia refers to acute leukemias. The details of the cytochemical stains are the rapid, clonal proliferation in the bone marrow of lym- addressed at the end of this chapter. In addition to morpho- phoid or myeloid progenitor cells known as lymphoblasts and logic and cytochemical stains, techniques commonly used to myeloblasts, respectively. When proliferation of blasts over- diagnose hematopoietic malignancies include flow cytometry whelms the bone marrow, blasts are seen in the peripheral and genetic/molecular studies. Findings of these techniques blood and the patient’s symptoms reflect suppression of are discussed throughout the chapter in relation to specific normal hematopoiesis. leukemias. For most cases of acute leukemia, the causes directly related Hematologists and pathologists are now moving toward to the development of the malignancy are unknown. The ex- more precise classification of many of the leukocyte neoplasms ceptions that exist are certain toxins that can induce genetic based on recurring chromosomal and genetic lesions found in changes leading to a malignant phenotype. Environmental ex- many patients. These lesions are related to disruptions of onco- posures known to lead to hematopoietic malignancies include genes, tumor suppressor genes, and other regulatory elements radiation and exposure to organic solvents, such as benzene. that control proliferation, maturation, apoptosis, and other vi- Rarely, leukemias can be seen in patients with known familial tal cell functions. In 2001 the World Health Organization cancer predisposition syndromes. Alkylating agents and other (WHO) published new classification schemes for nearly all of forms of chemotherapy used to treat various forms of cancer the tumors of hematopoietic and lymphoid tissues,5 and in can induce deoxyribonucleic acid (DNA) damage in hemato- some cases WHO melded the older morphologic schemes with poietic cells, leading to therapy-related leukemias. the newer schemes. For instance, in the WHO classification Regardless of the mechanism of initial genetic damage, the scheme for acute myeloid leukemias (AMLs), there are some development of leukemia is currently believed to be a stepwise remnants of the old FAB classification, but new classifications progression of mutations or “multiple hits” involving mutations were introduced for leukemias associated with consistently in genes that give cells a proliferative advantage, in addition to recurring chromosomal translocations. According to the WHO mutations that hinder differentiation.2,3 These mutations result classification, a finding of at least 20% blasts in the bone in transformation of normal hematopoietic stem cells or precur- marrow is required for diagnosis of the majority of acute leuke- sors into leukemic stem cells (LSCs). The LSCs then initiate, mias, and testing must be performed to detect the presence or proliferate, and sustain the leukemia.4 absence of genetic anomalies. The most recent (2017) WHO classification was released due to further insights into the mo- CLASSIFICATION SCHEMES FOR ACUTE lecular biology of the entities, with updates reflected in some of the classifications.6 In-depth discussion of each of the subclas- LEUKEMIAS sifications is beyond the scope of this book; only the most com- The French-American-British (FAB) classification of the mon subtypes of acute lymphoblastic leukemia and acute acute leukemias was devised in the 1970s and was based on myeloid leukemia are described. A B Figure 31.2 Lymphoblasts and Myeloblasts. (A), Lymphoblasts have a diameter two to three times the normal lymphocyte diameter, scant blue cytoplasm, coarse chromatin, deeper staining than myeloblasts, and inconspicuous nucleoli. (B), Myeloblasts have a diameter three to five times the lymphocyte diameter, moderate gray cytoplasm, uniform fine chromatin, two or more prominent nucleoli, and possibly Auer rods. (A and B, Bone marrow, Wright-Giemsa stain, !500.) 542 PART 5 Leukocyte Disorders also subcategorizes T-ALL into early T-cell precursor lympho- ACUTE LYMPHOBLASTIC LEUKEMIA blastic leukemia, which has limited early T cell differentiation.6 Acute lymphoblastic leukemia (ALL) is primarily a disease of childhood and adolescence, accounting for 25% of childhood Morphology cancers and up to 75% of childhood leukemia.7 The peak inci- Lymphoblasts vary in size but fall into two morphologic types. dence of ALL in children is between 2 and 5 years of age.8 Al- The most common type seen is a small lymphoblast (1.0 to though ALL is rare in adults, risk increases with age; most adult 2.5 times the size of a normal lymphocyte) with scant blue patients are older than 50 years of age. The subtype of ALL is an cytoplasm and indistinct nucleoli (Figure 31.2); the second important prognostic indicator for survival.6 Adults have a type of lymphoblast is larger (two to three times the size of a poorer outlook: 80% to 90% experience complete remission, lymphocyte) with prominent nucleoli and nuclear membrane but the cure rate is less than 40%.9,10 irregularities (Figure 31.3).13 These cells may be confused with Patients with B cell ALL typically present with fatigue the blasts of AML. (caused by anemia), fever (caused by neutropenia and infec- tion), and mucocutaneous bleeding (caused by thrombocyto- Prognosis penia). Lymphadenopathy, including enlargement, is often a Prognosis in ALL has improved dramatically over the past de- symptom.11 Enlargement of the spleen (splenomegaly) and of cades as a result of improvement in algorithms for treatment.13 the liver (hepatomegaly) may be seen. Bone pain often results The prognosis for ALL depends on age at the time of diagnosis, from intramedullary growth of leukemic cells.11 Eventual infil- lymphoblast load (tumor burden), immunophenotype, and tration of malignant cells into the meninges, testes, or ovaries genetic abnormalities. Children rather than infants or teens do occurs frequently, and lymphoblasts can be found in the cere- the best. Chromosomal translocations are the strongest predic- brospinal fluid.12 tor of adverse treatment outcomes for children and adults. Pe- In T cell ALL, there may be a large mass in the mediastinum ripheral blood lymphoblast counts greater than 20 to 30 ! leading to compromise of regional anatomic structures. Similar 109/L, hepatosplenomegaly, and lymphadenopathy all are asso- to B-ALL, T-ALL may present with anemia, thrombocytopenia, ciated with a worse outcome. The effects of other variables organomegaly, and bone pain, although the degree of leukope- previously associated with a poorer prognosis, such as sex and nia is often less severe.13 ethnic group, have been eliminated when patients have been given equal access to treatment in trials carried out at a single World Health Organization Classification institution.14 B-lymphoblastic leukemia/lymphoma (B-ALL) is subdivided into nine subtypes that are associated with recurrent cytoge- Immunophenotyping netic abnormalities.6 These entities are linked with unique Although morphology is the first tool used to distinguish ALL clinical, phenotypic, or prognostic features (Box 31.1). Cases of from AML, immunophenotyping and genetic analysis are the B cell ALL that do not exhibit the specific genetic abnormalities most reliable indicators of a cell’s origin. Because both B and are classified as B-lymphoblastic leukemia/lymphoma, not T cells are derived from lymphoid progenitors, both usually otherwise specified. Although 50% to 70% of patients with express CD34, terminal deoxynucleotidyl transferase (TdT), T-lymphoblastic leukemia/lymphoma have abnormal gene and human leukocyte antigen, DR subregion (HLA-DR). Four rearrangements, none of the abnormalities is clearly associated with specific biologic features. The 2017 WHO classification BOX 31.1 2017 WHO Classification of B-Lymphoblastic Leukemia/Lymphoma with Recurrent Genetic Abnormalities6 B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2);BCR-ABL1 B-lymphoblastic leukemia/lymphoma with t(v;11q23.3); KMT2A (MLL) rear- ranged B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1);TEL-AML1 (ETV6-RUNX1) B-lymphoblastic leukemia/lymphoma with hyperdiploidy B-lymphoblastic leukemia/lymphoma with hypodiploidy B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.1);IGH/IL3 B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); TCF3-PBX1 (E2A-PBX1) Figure 31.3 Peripheral Blood Film from a Patient with Acute Lym- B-lymphoblastic leukemia/lymphoma, BCR-ABL1-like phoblastic Leukemia. Note large lymphoblasts with prominent nucleoli B-lymphoblastic leukemia/lymphoma with iAMP21 and membrane irregularities. (Wright-Giemsa stain, !1000.) (From Rodak, B. F., & Carr, J. H.. Clinical Hematology Atlas. [5th ed.]. WHO, World Health Organization St. Louis: Elsevier.) CHAPTER 31 Acute Leukemias 543 TABLE 31.1 Immunophenotypic B-lymphoblastic leukemia/lymphoma with t(v;11q23); Characteristics of Acute Lymphoblastic KMT2A(MLL)-rearranged is more common in very young in- Leukemia (ALL) fants, and the translocation may even occur in utero.20 This leukemia has a very poor prognosis. About 25% of childhood ALL Subtype Immunophenotype ALL cases show a t(12;21)(p13.2;q22.1);ETV6-RUNX1 translo- Early (pro/pre-pre) B-ALL CD34, CD19, cytoplasmic CD22, TdT cation and appear to derive from a B cell progenitor rather than Intermediate (common) B-ALL CD34, CD19, CD10, cytoplasmic CD22, TdT the hematopoietic stem cell.21 This translocation is rare in Pre-B-ALL CD34, CD19, cytoplasmic CD22, adults. In children it carries an excellent prognosis, with a cure cytoplasmic ', TdT (variable) rate of over 90%. Hyperdiploidy in B-lymphoblastic leukemia/ T-ALL CD2, CD3, CD4, CD5, CD7, CD8, TdT lymphoma is common in childhood B-ALL, accounting for 25% of cases, but it is much less common in adults. This geno- type is associated with a very favorable prognosis in children. types of ALL have been identified by immunologic methods: Conversely, hypodiploidy (less than 46 chromosomes) conveys early B-ALL (pro-B, or pre-pre-B), intermediate (common) a poor prognosis in both children and adults. B-ALL, pre-B-ALL, and T-ALL (Table 31.1). B-ALL is charac- terized by specific B cell antigens that are expressed at different stages of B cell development. In general, B cells express CD19, ACUTE MYELOID LEUKEMIA CD20, CD22, CD24, C79a, CD10, cytoplasmic ', and PAX-5 AML is the most common type of leukemia in adults, and the (B cell specific activator protein). The degree of differentiation of incidence increases with age. AML is less common in children. B-lineage lymphoblasts often correlates with genetics and plays The FAB classification of AML was based on morphology and an important role in treatment decisions.6,13,15 In the earliest cytochemistry; the WHO classification relies heavily on molecu- stage of differentiation (pre-pre-B or pro-B), blasts express lar characterization and cytogenetics (Chapters 29 and 30).6 CD34, CD19, cytoplasmic CD22, and TdT. The incidence of pro-B-ALL is about 5% in children and 11% in adults. In inter- Clinical Presentation mediate, or common, B-ALL, CD10 is expressed. The most The clinical presentation of AML is nonspecific but reflects mature B-ALL is called pre-B-ALL, in which CD34 is typically decreased production of normal bone marrow elements. Most negative, but there is characteristic expression of cytoplasmic ' patients with AML have a total white blood cell (WBC) count heavy chain. Pre-B-ALL accounts for 15% of childhood cases between 5 and 30 ! 109/L, although the WBC count may range and 10% of adult B-ALL.16 from 1 to 200 ! 109/L. Myeloblasts are present in the peripheral T-ALL is seen most often in teenaged males with a mediasti- blood in 90% of patients. Anemia, thrombocytopenia, and neu- nal mass, elevated peripheral blast counts, meningeal involve- tropenia give rise to the clinical findings of pallor, fatigue, fever, ment, and infiltration of extra marrow sites.17,18 The common bruising, and bleeding. In addition, disseminated intravascular T cell markers CD2, CD3, CD4, CD5, CD7, and CD8 are usually coagulation and other bleeding abnormalities can be signifi- present. Most cases express TdT. A distinct subtype of T-ALL, cant.22 Infiltration of malignant cells into the gums and other ETP-ALL (early T cell precursor ALL) often shows expression of mucosal sites and skin also can be seen. myeloid makers and is thought to be derived from T cell pre- Splenomegaly is seen in half of AML patients, but lymph cursor cells that have the capacity for myeloid differentiation.6 node enlargement is rare. Cerebrospinal fluid involvement in Early studies showed poor response to therapy in ETP-ALL; AML is rare and does not seem to be as ominous a sign as in however, more recent studies have suggested that the prognosis ALL. Patients with AML tend to have few symptoms related to is the same as with other T-ALL with optimal therapy.6 the central nervous system, even when it is infiltrated by blasts. Common abnormalities in laboratory test results include Genetic and Molecular Findings hyperuricemia (caused by increased cellular turnover), hyper- Cytogenetic abnormalities are seen in the majority of B and phosphatemia (due to cell lysis), and hypocalcemia (the latter T cell ALL, which produce changes that affect normal B and two are also involved in progressive bone destruction). Hypoka- T cell development and underlie the pathogenesis of these neo- lemia is also common at presentation. During induction che- plasms. A majority of T-ALL have been shown to have gain-of- motherapy, especially when the WBC count is quite elevated, function mutations involving the NOTCH1 gene, which alters tumor lysis syndrome may occur. Tumor lysis syndrome is a the Notch receptor signaling pathway responsible for normal group of metabolic complications that can occur in patients T cell development.19 with malignancy, most notably lymphomas and leukemias, with In T-ALL, however, the cytogenetic alterations show less and without treatment of the malignancy. These complications specificity and less correlation with the prognosis and treat- are caused by the breakdown products of dying cancer cells, ment outcome than in B-ALL. B-lymphoblastic leukemia/ which in turn cause acute uric acid nephropathy and renal fail- lymphoma with the t(9;22)(q34;q11.2);BCR-ABL1 mutation ure. Tumor lysis syndrome is characterized by hyperkalemia, (Philadelphia chromosome–positive ALL) has the worst prog- hyperphosphatemia, hyperuricemia and hyperuricosuria, and nosis among ALLs. It is more common in adults than in chil- hypocalcemia.23 The hyperkalemia alone can be life-threatening. dren. Imatinib, which has shown success in treating chronic Aggressive prophylactic measures to prevent or reduce the myeloid leukemia, has improved survival (Chapter 32). clinical manifestations of tumor lysis syndrome are critical.24 544 PART 5 Leukocyte Disorders Subtypes of Acute Myeloid Leukemia and Related Precursor Neoplasms Laboratory diagnosis of AML begins with a complete blood count, peripheral blood film examination, and bone marrow aspirate and biopsy specimen examination. The total WBC count may be normal, increased, or decreased; anemia is usually present, along with significant thrombocytopenia. The bone marrow is usually hypercellular, and greater than 20% of cells typically are marrow blasts, although if certain genetic abnor- malities are present, the 20% blast threshold is not necessary for the diagnosis of AML.6 Each category is discussed, and a sum- mary of the classification is presented in Box 31.2. The 2017 WHO classification for myeloid malignancies has categorized AMLs with recurrent cytogenetic abnormalities Figure 31.4 Bone Marrow Aspirate from a Patient with Acute Myeloid into subgroups based on the primary cytogenetic aberrations Leukemia with t(8;21). Note myeloblasts with granular cytoplasm and along with a few new entities (Box 31.3).6 some maturation. (Wright-Giemsa stain, !500.) (From Rodak, B. F., & Carr, J. H.. Clinical Hematology Atlas. [5th ed.]. St. Louis: Elsevier.) AML with Recurrent Genetic Abnormalities Acute myeloid leukemia with t(8;21)(q22;q22.1);RUNX1/ RUNX1T1 The t(8;21)(q22;q22.1); RUNX1/RUNX1T1 mutation is found in about 5% of AML cases. Seen predominantly in myeloblasts with dysplastic granular cytoplasm, Auer rods, and children and young adults, AML with this translocation has some maturation (Figure 31.4), similar to the FAB M2 classifi- cation (discussed later in the chapter). Various anomalies, such as pseudo–Pelger-Huët cells and hypogranulation, can be seen. Eosinophilia is possible. Prognosis is generally favorable but BOX 31.2 2017 WHO Classification of may be negatively affected if unfavorable additional abnor- Myeloid Leukemia and Related Precursor malities, such as monosomy 7, occur.25 The diagnosis of this Neoplasms6 subtype is based on the genetic abnormality, regardless of blast count.6 Acute myeloid leukemia with recurrent genetic abnormalities Acute myeloid leukemia with myelodysplasia-related changes Acute myeloid leukemia with inv(16)(p13.1q22) or t(16;16) Therapy-related myeloid neoplasms (p13.1;q22);CBFB-MYH11. Accounting for approximately 5% to Acute myeloid leukemia, not otherwise specified 8% of all AML cases, core-binding factor (CBF) AML occurs at Myeloid sarcoma all ages, but it is found predominantly in younger patients.6 The Myeloid proliferations associated with Down syndrome genetic aberration is sufficient for diagnosis regardless of blast Blastic plasmacytoid dendritic cell neoplasm count.6,26 Myeloblasts, monoblasts, and promyelocytes are seen Acute leukemias of ambiguous lineage in the peripheral blood and bone marrow. In the bone marrow WHO, World Health Organization there may be eosinophilia with dysplastic changes (Figure 31.5). The incidence of extramedullary disease is higher than in most types of AML, and the central nervous system is a common site for relapse.6,26 The remission rate is good, but only one half of BOX 31.3 2017 WHO Classification of patients are cured.26 Acute Myeloid Leukemia with Recurrent Acute promyelocytic leukemia with PML-RARA. Acute pro- Genetic Abnormalities6 myelocytic leukemia comprises 5% to 10% of AML cases. It occurs in all age groups but is seen most commonly in young AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1 adults. This disorder is characterized by a differentiation block AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 APL with PML-RARA at the promyelocytic stage. The abnormal promyelocytes are AML with t(9;11)(p21.3;q23.3); KMT2A(MLL)-MLLT3 considered to be comparable to blasts for the purpose of AML with t(6;9)(p23;q34.1); DEK-NUP214 diagnosis. Detection of the 15;17 translocation is sufficient for AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM (RPN1-EVI1) diagnosis regardless of blast count.6,25 Characteristic of this AML with t(1;22)(p13.3;q13.3) RBM15-MKL1 presentation are the abnormal hypergranular promyelocytes, AML with BCR-ABL1 some with Auer rods (Figure 31.6). When promyelocytes release AML with gene mutations primary granule contents, their procoagulant activity initiates AML with mutated NPM1 disseminated intravascular coagulation; however, thromboem- AML with biallelic mutation of CEBPA bolic events may occur at presentation and during treatment.27 AML with mutated RUNX1 In one variant of APL, the granules are so small that because of WHO, World Health Organization the limits of light microscopy, the cells give the appearance of CHAPTER 31 Acute Leukemias 545 having no granules. This microgranular variant, accounting for 30% to 40% of APL cases, may be confused with other presen- tations of AML, but the presence of occasional Auer rods, the “butterfly” or “coin-on-coin” nucleus, and the clinical presenta- tion are clues. The treatment of APL is significantly different from all other types of acute myeloid leukemia, and it is there- fore important to arrive at an accurate diagnosis. Treatment includes all-trans-retinoic acid (ATRA) and arsenic trioxide.28 ATRA is a vitamin A analogue and induces differentiation of the malignant promyelocytes. In adults who achieve a complete remission, the prognosis is better than for any other type of AML.25 There are a few variantRARA translocations that confer a less favorable prognosis because the cells do not respond to ATRA therapy.6 Acute myeloid leukemia with t(9;11)(p22;q23);KMT2A (MLL)- Figure 31.5 Peripheral Blood Film from a Patient with Acute Myeloid MLLT3. AML with t(9;11)(p22;q23);KMT2A (MLL)-MLLT3 rep- Leukemia with inv(16). There is an increase in myeloid and monocytic resents a specific subgroup of the previous classification of AML lines. Eosinophilia may also be present. (Wright-Giemsa stain, !1000.) with 11q23 abnormalities, and AMLs with other KMT2A (MLL) (From Rodak, B. F., & Carr, J. H.. Clinical Hematology Atlas. [5th ed.]. abnormalities should not be placed in this group.29 AML with St. Louis: Elsevier.) t(9;11) is a rare leukemia (6% of AML cases) that presents with an increase in monoblasts and immature monocytes (Figure 31.7). The blasts are large with abundant cytoplasm and fine nuclear chromatin. The cells may have motility, with pseudopodia seen frequently. Granules and vacuoles can be observed in the blasts. Typically this disease occurs in children and may be associated with gingival and skin involvement and/or disseminated intravas- cular coagulation. Acute myeloid leukemia with t(6;9)(p23;q34);DEK-NUP214, acute myeloid leukemia with inv(3)(q21.3q26.2) or t(3;3)(q21.3; q26.2);GATA2, MECOM (RPN1-EVI1), acute myeloid leukemia (megakaryoblastic) with t(1;22)(p13.3;q13.1);RBM15-MKL1 and acute myeloid leukemia with BCR-ABL1. These are rare leuke- mias included in the 2017 WHO classification.6 Detailed de- scription of these entities is beyond the scope of this chapter. Acute myeloid leukemia with mutated NPM1, acute my- A eloid leukemia with biallelic mutations of CEBPA, and acute myeloid leukemia with mutated RUNX1. These three addi- tional entities with gene mutations were added in the 2017 WHO classification.6 B Figure 31.6 Peripheral Blood Films from a Patient with Acute My- eloid Leukemia with t(15;17) or Promyelocytic Leukemia. (A), Low- power view of the more common hypergranular variant. (Wright-Giemsa stain, !500.) (B), Oil immersion view of the microgranular variant show- ing bilobed nuclear features. (Wright-Giemsa stain, !1000.) (B from Figure 31.7 Bone Marrow Aspirate of a Patient with Acute Myeloid Rodak, B. F., & Carr, J. H.. Clinical Hematology Atlas. [5th ed.]. Leukemia with t(9;11) Abnormalities. Both monoblasts and immature St. Louis: Elsevier.) monocytes are increased. (Wright-Giemsa stain, !500.) 546 PART 5 Leukocyte Disorders Acute myeloid leukemia with mutated NPM1 (often leukemia TABLE 31.2 French-American-British (FAB) with monocytic features) and AML with biallelic mutations of Classification of the Acute Myeloid CEBPA are associated with a better prognosis.6,30 RUNX1 muta- Leukemias39,40 tions are associated with worse overall survival.31–34 Subtype Description Acute Myeloid Leukemia with Myelodysplasia-Related M0 Acute myeloid leukemia, minimally differentiated Changes M1 Acute myeloid leukemia without maturation M2 Acute myeloid leukemia with maturation AML with myelodysplasia affects primarily older adults and has M3 Acute promyelocytic leukemia a poor prognosis. This subcategory of AML with myelodysplasia- M4 Acute myelomonocytic leukemia related changes incorporates leukemias with at least 20% blasts, M4eo Acute myelomonocytic leukemia with eosinophilia multilineage dysplasia, a history of myelodysplastic syndrome M5a Acute monocytic leukemia, poorly differentiated (MDS) or MDS/myeloproliferative neoplasm (MPN), or a spe- M5b Acute monocytic leukemia, well differentiated cific MDS-associated cytogenetic abnormality except del(9q). M6 Acute erythroleukemia There must also be absence of AML with recurrent genetic ab- M7 Acute megakaryocytic leukemia normalities, NPM1 and biallelic mutation of CEBPA. There must be morphologic criteria for multilineage dysplasia, defined as greater than 50% dysplasia in at least two cell lineages.6 Significant dysplastic morphology includes pancytopenia with neutrophil hypogranulation or hypergranulation, pseudo– Pelger-Huët cells, and unusually segmented nuclei. Erythrocyte precursors have vacuoles, karyorrhexis, megaloblastoid features, and ring sideroblasts. There may be dysplastic micromegakaryo- cytes and dysplastic megakaryocytes. Genetic findings are simi- lar to those found in MDS, with complex karyotypes and (7/ del(7q) and (5/del(5q) being the most common.6,35 Therapy-Related Myeloid Neoplasms (t-MNs) t-MNs are further classified into therapy-related MDS (t-MDS), AML (t-AML) and myelodysplastic/myeloproliferative neo- plasms (t-MDS/MPN).6 Treatment with alkylating agents, radia- tion, or topoisomerase II inhibitors has been associated with the development of a secondary AML, MDS, or MDS/MPN.6,25,36,37 Figure 31.8 Bone Marrow Aspirate of a Patient with Acute Myeloid These therapy-related neoplasms account for 10% to 20% of Leukemia, Minimally Differentiated (French-American-British Clas- AMLs, MDSs, and MDSs/MPNs. Generally these disorders oc- sification M0). Blasts lack myeloid morphologic features and yield cur following treatment for a prior malignancy, but they have negative results with myeloperoxidase and Sudan black B staining. Auer also been associated with intensive treatment of patients rods are not seen. CD34 is frequently present. (Wright-Giemsa stain, !500.) (From Carr, J. H., & Rodak, B. F.. Clinical Hematology Atlas. with nonmalignant disorders requiring cytotoxic therapy.6,36,38 [4th ed.]. St. Louis: Elsevier.) Therapy-related myeloid neoplasms are similar in morphology to AML with myelodysplasia, monocytic/monoblastic leukemia, or AML with maturation, and the prognosis is generally poor, CD34), and CD117) (Figure 31.8).6,41 Auer rods typically are although therapy-related neoplasms with the t(15;17) and absent, and there is no clear evidence of cellular maturation. The inv(16) mutations behave more like the de novo counterparts.6,25 cells yield negative results with the cytochemical stains myeloper- oxidase and Sudan black B. These cases account for less than 5% Acute Myeloid Leukemia, Not Otherwise Specified of AML, and patients are generally either infants or older adults. Because the leukemias in the “not otherwise specified” category Acute myeloid leukemia without maturation. Closely aligned do not fit easily into the WHO subtypes described earlier, they with the blasts in minimally differentiated AML, the blasts in are grouped according to morphology, flow cytometric pheno- AML without maturation are also CD13), CD33), with CD117 typing (Chapter 28), and limited cytochemical reactions, as in and CD34 being positive in the majority of cases (Figure 31.9).6 the FAB classification. The FAB classification was based on the Blasts may comprise 90% of nonerythroid cells in the bone mar- cell of origin, degree of maturity, cytochemical reactions, and row, and fewer than 10% of the leukocytes show maturation to limited cytogenetic features (Table 31.2).39,40 A blast percentage the promyelocyte stage or beyond. At least 3% of blasts give of at least 20% in the peripheral blood or bone marrow is re- positive results with myeloperoxidase or Sudan black B stains.6,25 quired for diagnosis. This category accounts for about 25% of Acute myeloid leukemia with maturation. AML with matura- all AML, but as more genetic subgroups are recognized, the tion is a common variant that presents with greater than 20% blasts, number in this group will diminish.29 at least 10% maturing cells of neutrophil lineage (Figure 31.10), and Acute myeloid leukemia with minimal differentiation. The fewer than 20% precursors with monocytic lineage. Auer rods are blasts in AML with minimal differentiation are CD13), CD33), often present.6 CHAPTER 31 Acute Leukemias 547 Figure 31.9 Bone Marrow Aspirate from a Patient with Acute Myeloid Leukemia without Maturation (French-American-British Classification Figure 31.11 Peripheral Blood Film from a Patient with Acute M1). Blasts constitute 90% of the nonerythroid cells; there is less than Myelomonocytic Leukemia. Both myeloid and monocytic cells are 10% maturation of the granulocytic series beyond the promyelocyte present. Monocytic cells comprise at least 20% of all marrow cells, stage. (Wright-Giemsa stain, !500.) with monoblasts and promonocytes present. (Wright-Giemsa stain, !1000.) (From Rodak, B. F., & Carr, J. H.. Clinical Hematology Atlas. [5th ed.]. St. Louis: Elsevier.) in the marrow and peripheral blood, more than 80% of the marrow cells are of monocytic origin. These cells are CD14), CD4), CD11b), CD11c), )and CD64. Blasts are large with abundant, often agranular cytoplasm and large prominent nu- cleoli (Figure 31.12A). When some evidence of maturation is present, the cells are called promonocytes. Promonocytes in monocytic leukemias with differentiation are considered to be blast equivalents (Figure 31.12B). Nonspecific esterase testing usually yields positive results. Acute monoblastic/monocytic leukemia comprises fewer than 5% of cases of AML and is most common in younger individuals. Extramedullary involvement, including cutaneous and gingival infiltration, and bleeding dis- Figure 31.10 Bone Marrow Aspirate from a Patient with Acute orders are common. Nonspecific cytogenetic abnormalities are Myeloid Leukemia with Maturation. Blasts constitute 20% or more of seen in most cases.6,42 the nucleated cells of the bone marrow, and there is maturation beyond Pure erythroid leukemia. One of the major changes in the the promyelocyte stage in more than 10% of the nonerythroid cells. 2017 WHO classification is the removal of acute erythroleuke- (Wright-Giemsa stain, !1000.) mia (erythroid/myeloid type) – most of these cases will now be classified as MDS with excess blasts.6 Pure erythroid leukemia remains as M6, the only acute Acute myelomonocytic leukemia. Acute myelomonocytic erythroid leukemia.6 In this leukemia 80% or more of the leukemia is characterized by a significantly elevated WBC count bone marrow cells are erythroid, and greater than 30% are and the presence of myeloid and monocytoid cells in the pe- proerythroblasts.43–45 The myeloblast component is not sig- ripheral blood and bone marrow (Figure 31.11). Monocytic nificant. Complex rearrangements and hypodiploid chromo- cells (monoblasts and promonocytes) constitute at least 20% of some number are common. Chromosomes 5 and 7 are fre- all marrow cells, as do neutrophils and their precursors. The quently affected.6 monoblasts are large with abundant cytoplasm containing The red blood cell (RBC) precursors have significant small granules and pseudopodia. The nucleus is large and dysplastic features, such as multinucleation, megaloblastoid immature and may contain multiple nucleoli. Promonocytes asynchrony, and vacuolization. The nucleated RBCs in the pe- also are present and may have contorted nuclei. The cells are ripheral blood may account for more than 50% of the total positive for the myeloid antigens CD13 and CD33 and the number of nucleated cells. Ring sideroblasts, Howell-Jolly bod- monocytic antigens CD14, CD4, CD11b, CD11c, and CD64. ies, and other inclusions may be present (Figure 31.13). Abnor- Nonspecific cytogenetic changes are found in most cases.6 mal megakaryocytes may be seen. Pure erythroid leukemia has Acute monoblastic and monocytic leukemias. In these leu- an aggressive and rapid clinical course.6 kemias, which are divided into monoblastic and monocytic Acute megakaryoblastic leukemia. Patients with acute based on the degree of maturity of the monocytic cells present megakaryoblastic leukemia usually have cytopenias, although 548 PART 5 Leukocyte Disorders A Figure 31.13 Bone Marrow Aspirate from a Patient with Acute Ery- throid Leukemia. Erythroid precursors showing dysplastic features, in- cluding multinucleation and megaloblastic asynchrony. (Wright-Giemsa stain, !500.) (From Rodak, B. F., & Carr, J. H.. Clinical Hematology Atlas. [5th ed.]. St. Louis: Elsevier.) some may have thrombocytosis. Dysplastic features are often present in all cell lines. Diagnosis requires the presence of at least 20% blasts, of which at least 50% must be of mega- karyocyte origin. This category excludes AML with MDS-re- lated changes and Down syndrome–related cases, in addition to those with recurrent genetic abnormalities, as discussed B previously. Figure 31.12 Bone Marrow Aspirates from Patients with Acute Megakaryoblast diameters vary from that of a small lympho- Monoblastic Leukemia and Acute Monocytic Leukemia. (A), Acute cyte to three times their size. Chromatin is delicate with promi- monoblastic leukemia with more than 80% of the bone marrow cells of nent nucleoli. Immature megakaryocytes may have light blue monocytic origin. (Wright-Giemsa stain, !500.) (B), Acute monocytic leukemia with promonocytes. Promonocytes are considered blast cytoplasmic blebs (Figure 31.14A). Megakaryoblasts are identi- equivalents. (Wright Giemsa stain, !500.) (B from Carr, J. H., & Rodak, fied by immunostaining, using antibodies specific for cytoplas- B. F.. Clinical Hematology Atlas. [4th ed.]. St. Louis: Elsevier.) mic von Willebrand factor or platelet membrane antigens CD41 A B Figure 31.14 Peripheral Blood Film (A) and Bone Marrow Aspirate (B) from a Patient with Acute Mega- karyocytic Leukemia. (A), Note the heterogeneity of blasts, one small with scant cytoplasm, two with cytoplas- mic blebbing, and one quite large. (Wright-Giemsa stain, !1000.) (B), Positive reaction for CD42b. (Immunostain, !1000.) (B from Carr, J. H., & Rodak, B. F.. Clinical Hematology Atlas. [4th ed.]. St. Louis: Elsevier.) CHAPTER 31 Acute Leukemias 549 (glycoprotein IIb), CD42b (glycoprotein Ib) (Figure 31.14B), or CYTOCHEMICAL STAINS CD61 (glycoprotein IIIa).6 AND INTERPRETATIONS Myeloid Sarcoma Techniques such as flow cytometry, cytogenetic analysis, and Myeloid sarcoma refers to extramedullary proliferation of blasts molecular testing are now commonly used in the diagnosis of of one or more myeloid lineages that disrupts tissue architecture. acute leukemias. However, older techniques, such as cytochem- Tissue architecture must be effaced for the neoplasm to qualify ical stains, still retain their importance. An advantage of cyto- for this diagnosis. Tissues commonly affected include skin, gas- chemical stains is that they are relatively inexpensive and can be trointestinal tract and lymph nodes.6,25 performed by laboratories throughout the world, including in areas where resources and access to advanced techniques are Myeloid Proliferations Related to Down Syndrome limited. The cytochemical stains are summarized in Table 31.3. Unique patterns of malignancy occur in persons with trisomy 21 resulting in Down syndrome. Approximately 10% of Myeloperoxidase newborns with Down syndrome present with transient abnor- Myeloperoxidase (MPO) (Figures 31.15 and 31.16) is an en- mal myelopoiesis, which is morphologically indistinguishable zyme found in the primary granules of granulocytic cells (neu- from AML. Both conditions are associated with GATA1 muta- trophils, eosinophils, and, to a certain extent, monocytes). tions.46–48 Spontaneous remission generally occurs within a few Lymphocytes do not exhibit MPO activity. This stain is useful months. Among individuals with Down syndrome, there is a for differentiating the blasts of AML from those of ALL. fiftyfold increased incidence of AML during the first 5 years of life compared with individuals without Down syndrome. The leukemia is of megakaryocytic lineage, and young children re- TABLE 31.3 Acute Leukemia Cytochemical spond well to chemotherapy, although older children do not Reaction Chart fare as well.6,49 Condition MPO SBB NASDA ANBE ANAE ALL ( ( ( (/) (/) (focal) Blastic Plasmacytoid Dendritic Cell Neoplasm (focal) Blastic plasmacytoid cell neoplasm is a rare clinically aggressive AML ) ) ) ( ( tumor derived from precursors of plasmacytoid dendritic cells. AMML ) ) ) ) (diffuse) ) (diffuse) It presents with skin lesions and may ultimately progress to AMoL ( (/) ( ) (diffuse) ) (diffuse) involve peripheral blood and bone marrow.6,29 Megakaryocytic ( ( ( ( ) (localized) leukemia ), Positive reaction; (, negative reaction; (/), negative or positive ACUTE LEUKEMIAS OF AMBIGUOUS LINEAGE reaction; ALL, acute lymphoblastic leukemia; AML, acute myeloid leu- kemia; AMML, acute myelomonocytic leukemia; AMoL, acute mono- Acute leukemias of ambiguous lineage (ALALs) include leuke- cytic leukemia; ANAE, &-naphthyl acetate esterase; ANBE, &-naphthyl mia in which there is no clear evidence of differentiation along butyrate esterase; MPO, myeloperoxidase; NASDA, naphthol AS-D a single cell line; leukemias of this type are commonly referred chloroacetate esterase; SBB, Sudan black B. to as acute undifferentiated leukemias (AULs). Other cases of ALAL that demonstrate a multiplicity of antigens in which it is not possible to determine a specific lineage are called mixed phenotype acute leukemias (MPALs). The 2008 WHO classifica- tion significantly revised the criteria for this designation. This revision was maintained in the 2017 WHO classification and is shown in Box 31.4.6,50 BOX 31.4 WHO Classification of Acute Leukemia of Ambiguous Lineage (ALAL).6 Acute undifferentiated leukemia (AUL) – synonyms: ALAL without differentia- tion, primitive acute leukemia, stem cell leukemia Mixed phenotype acute leukemia (MPAL) – synonyms: biphenotypic acute leukemia, bilineal leukemia, mixed lineage acute leukemia, dual lineage acute leukemia, hybrid acute leukemia: MPAL with t(9;22)(q34.1;q11.2);BCR-ABL1 MPAL with t(v;11q23);KMT2A (MLL)-rearranged MPAL B/myeloid, not otherwise specified MPAL T/myeloid, not otherwise specified MPAL, not otherwise specified, rare types Figure 31.15 Positive Reaction to Myeloperoxidase Stain in Early Acute leukemias of ambiguous lineage, not otherwise specified Myeloid Cells. Note Auer rod at arrow. (Bone marrow, myeloperoxidase stain, !1000.) 550 PART 5 Leukocyte Disorders Figure 31.16 Strong Positive Reaction to Myeloperoxidase Stain in Figure 31.17 Sudan Black B Reaction. Positivity increases with the Leukemic Promyelocytes. From a patient with acute promyelocytic maturity of the granulocytic cell. (Bone marrow, Sudan black B stain, leukemia. (Bone marrow, myeloperoxidase stain, !1000.) !1000.) Interpretation MPO is present in the primary granules of most granulocytic cells, beginning at the promyelocyte stage and continuing throughout maturation. Leukemic myeloblasts are usually pos- itive for MPO. In many cases of the AMLs (without maturation, with maturation, and promyelocytic leukemia), it has been found that more than 80% of the blasts show MPO activity. Auer rods found in leukemic blasts and promyelocytes test strongly MPO positive. In contrast, lymphoblasts in ALL and lymphoid cells are MPO negative. It is important that the reaction only in the blast cells be used as the determining factor for the dif- ferentiation of acute leukemias. This is true for MPO and for Figure 31.18 Positive Reaction to AS-D Chloroacetate Esterase Stain. Two granulocytic cells with positive reaction. (Bone marrow, AS-C other cytochemical stains used in determining cell lineage chloroacetate esterase stain, !1000.) described in this chapter: maturing granulocytes are MPO positive; this is a normal finding and has little or no diagnos- tic significance. isoenzymes of esterases are present in leukocytes. Two substrate esters commonly used are &-naphthyl acetate and &-naphthyl Sudan Black B butyrate (both nonspecific). Naphthol AS-D chloroacetate Sudan black B (SBB) staining (Figure 31.17) is another useful (specific) also may be used. “Specific” refers to the fact that only technique for the differentiation of AML from ALL. SBB stains granulocytic cells show staining, whereas nonspecific stains also cellular lipids. The staining pattern is quite similar to that of may produce positive results in other cells. MPO; SBB staining is possibly a little more sensitive for the early myeloid cells. Interpretation Esterase stains can be used to distinguish acute leukemias that Interpretation are granulocytic from leukemias that are primarily of mono- Granulocytes (neutrophils) show a positive reaction to SBB cytic origin. When naphthol AS-D chloroacetate is used as a from the myeloblast through the maturation series. The stain- substrate, the reaction is positive in the granulocytic cells and ing becomes more intense as the cell matures as a result of the negative to weak in the monocytic cells (Figure 31.18). Chloro- increase in the numbers of primary and secondary granules. acetate esterase is present in the primary granules of neutro- Monocytic cells can demonstrate negative to weakly positive phils. Leukemic myeloblasts generally show a positive reaction. staining due to various changes that occur during differentia- Auer rods also show positivity. tion. Lymphoid cells generally do not stain. &-Naphthyl acetate, in contrast to naphthol AS-D chloroac- etate, reveals strong esterase activity in monocytes that can be Esterases inhibited with the addition of sodium fluoride.51,52 Granulo- Esterase reactions are used to differentiate myeloblasts and cytes and lymphoid cells generally show a negative result on neutrophilic granulocytes from cells of monocytic origin. Nine nonspecific esterase staining (Figure 31.19). CHAPTER 31 Acute Leukemias 551 A B Figure 31.19 !-Naphthyl Acetate Esterase Positivity in Cells of Monocytic Origin (A) and Inhibition of Reaction with Sodium Fluoride (B). (A), Positive reaction with &-naphthyl acetate esterase stain in imma- ture monocytic cells. (Bone marrow, &-naphthyl acetate esterase stain, !1000.) (B), Same specimen with addition of sodium fluoride to the stain. The esterase reaction in the immature monocytic cells is inhibited. (Bone marrow, &-naphthyl acetate esterase stain and sodium fluoride, !1000.) A diffuse positive &-naphthyl butyrate esterase reaction is seen in monocytes. &-Naphthyl butyrate is less sensitive than &-naphthyl acetate, but it is more specific. Granulocytes and lymphoid cells generally show a negative reaction (Figure 31.20), although a small positive dot may be seen in lymphocytes. In myelomonocytic leukemia, positive AS-D chloroacetate activity and positive &-naphthyl butyrate or &-naphthyl acetate activity should be seen because myeloid and monocytic cells are present. In myelomonocytic leukemia, at least 20% of the cells must show monocytic differentiation that is nonspecific esterase posi- Figure 31.20 !-Naphthyl Butyrate Esterase Positivity in Cells of tive and is inhibited by sodium fluoride. In the pure monocytic Monocytic Origin. From a patient with acute monoblastic/monocytic leukemias, 80% or more of the blasts are nonspecific esterase leukemia. Note the negative reaction of myeloid and erythroid precur- positive and specific esterase negative. sors. (Bone marrow, &-Naphthyl butyrate esterase stain, !1000.) SUMMARY The development of leukemia is currently believed to be a In children A is a disease in which the good prognosis stepwise progression of mutations, or “multiple hits,” involv- subtypes are associated with a 95% rate of complete remis- ing mutations that give leukemic stem cells a proliferative sion, but adults with ALL have a poorer outlook. advantage and also hinder differentiation. Infiltration of malignant cells into the meninges can occur, For most acute leukemias, causes directly related to the de- with lymphoblasts found in the cerebrospinal fluid, testes, velopment of the malignancy are unknown, but a few excep- and ovaries. tions exist. Some known causes include environmental tox- Prognosis in A depends primarily on age at the time of diag- ins, certain viruses, previous chemotherapy, and familial nosis, lymphoblast load (tumor burden), and immunopheno- predisposition. type. Chromosomal translocations seem to be the strongest There are several classification schemes for leukocyte predictor of adverse treatment outcomes for children and adults. neoplasia, including the FAB system, based primarily on The t( ) marker is found in a significant number of morphology and cytochemical staining, and the WHO sys- patients with childhood ALL. tem, which retains some elements of the FAB scheme but There are two main subtypes of A according to the emphasizes molecular and cytogenetic changes. classification system: B-lymphoblastic leukemia/lymphoma nly half of patients with A have leukocytosis, and many and T-lymphoblastic leukemia/lymphoma. do not have circulating lymphoblasts, but neutropenia, Tumor lysis syndrome is an increasingly common complication thrombocytopenia, and anemia are usually present. of treatment, especially in patients with a high tumor burden. 552 PART 5 Leukocyte Disorders Although morphology is the first tool in distinguishing A cytometry, cytogenetic analysis, and molecular biologic from AML, immunophenotyping is often the only reliable techniques in establishing a diagnosis. indicator of a cell’s origin. Cytochemical reactions may be enzymatic or nonenzymatic. The incidence of AM in adults increases with age. Fresh smears must be used to detect enzymatic activity, The clinical presentation of a patient with AM is nonspe- whereas nonenzymatic procedures may be performed on cific and reflects the decreased production of normal bone specimens that have been stored at room temperature. marrow elements, an elevated WBC count, and the presence MP stains primary granules and is useful in differentiating of myeloblasts. Anemia, thrombocytopenia, and neutrope- granulocytic from lymphoid cells. nia give rise to the clinical findings of pallor, fatigue, bruising S stains lipids and results parallel those with the MP and bleeding, and fever with infections. stain. The classification of AM is complicated by the presence or sterases help differentiate granulocytes and their precur- absence of multiple cell lines defined as “myeloid” in origin, sors from cells of monocytic origin. Butyrate esterase testing specific cells within these cell lines, and specific karyotype gives positive results in monocytes but not in granulocyte abnormalities. precursors, whereas naphthol AS-D chloroacetate esterase eukemias with ambiguous lineage include leukemias in which stains granulocyte precursors. there is no clear evidence of differentiation along a single cell line. Cytochemical techniques are often used in con unction with Now that you have completed this chapter, go back and read again the morphologic analysis, immunohistochemical methods, flow case study at the beginning and respond to the questions presented. REVIEW QUESTIONS Answers can be found in the Appendix. 6. Disseminated intravascular coagulation is more often seen 1. According to the WHO classification, except in leukemias in association with leukemia characterized by which of the with specific genetic anomalies, the minimal percentage of following mutations? blasts necessary for a diagnosis of acute leukemia is: a. t(12;21)(p13;q22) a. 10% b. t(9;22)(q34;q11.2) b. 20% c. inv(16)(p13;q22) c. 30% d. t(15;17)(q22;q12) d. 50% 7. Which of the following leukemias affects primarily children, 2. A 20-year-old patient has an elevated WBC count with 70% is characterized by an increase in monoblasts and monocytes, blasts, 4% neutrophils, 5% lymphocytes, and 21% mono- and often is associated with gingival and skin involvement? cytes in the peripheral blood. Eosinophils with dysplastic a. Pre-B-lymphoblastic leukemia changes are seen in the bone marrow. AML with which of b. Pure erythroid leukemia the following karyotypes would be most likely to be seen? c. AML with t(9;11)(p22;q23) a. AML with t(8;21)(q22;q22) d. APL with PML-RARA b. AML with t(16;16)(p13;q22) 8. A 20-year-old patient presents with fatigue, pallor, easy c. APL with PML-RARA bruising, and swollen gums. Bone marrow examination d. AML with t(9;11)(p22;q23) reveals 82% cells with delicate chromatin and prominent 3. Which of the following would be considered a sign of poten- nucleoli that are CD14), CD4), CD11b), and CD36). tially favorable prognosis in children with ALL? Which of the following acute leukemias is likely? a. Hyperdiploidy a. Minimally differentiated leukemia b. Presence of CD19 and CD20 b. Leukemia of ambiguous lineage c. Absence of trisomy 8 c. Acute monoblastic/monocytic leukemia d. Presence of BCR/ABL gene d. Acute megakaryoblastic leukemia 4. Signs and symptoms of cerebral infiltration with blasts are 9. Pure erythroid leukemia is a disorder involving: more commonly seen in: a. Pronormoblasts only a. AML with recurrent cytogenetic abnormalities b. Pronormoblasts and basophilic normoblasts b. Therapy-related myeloid neoplasms c. All forms of developing RBC precursors c. AML with myelodysplasia-related changes d. Equal numbers of pronormoblasts and myeloblasts d. ALL 10. A patient with normal chromosomes has a WBC count of 5. An oncology patient exhibiting signs of renal failure with 3.0 ! 109/L and dysplasia in all cell lines. There are 60% seizures after initial chemotherapy may potentially develop: blasts of varying sizes. The blasts stain positive for CD61. a. Hyperleukocytosis The most likely type of leukemia is: b. Tumor lysis syndrome a. Acute lymphoblastic c. Acute leukemia secondary to chemotherapy b. Acute megakaryoblastic d. Myelodysplasia c. Acute monoblastic d. APL with PML-RARA

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