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Atlas of Bone Marrow Neoplasms in Pediatric Patients

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Atlas of Bone Marrow Neoplasms in Pediatric Patients

Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index

Atlas of Bone Marrow Neoplasms in Pediatric Patients


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Atlas of Bone Marrow Neoplasms in Pediatric Patients


Xiayuan Liang, MD
Hematopathologist Associate Professor of Pathology University of Colorado Denver, Health Science Center The Childrens Hospital, Colorado

Table of Contents
Bette Jamieson, MA, SH(ASCP)
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index
Education Coordinator Department of Pathology University of Colorado Denver, Health Science Center The Childrens Hospital, Colorado

Atlas of Bone Marrow Neoplasms in Pediatric Patients


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Introduction
Although there are overlaps in hematopoietic disorders between adults and children, there is substantial uniqueness with regard to hematopoietic neoplasms and non-hematopoietic neoplasms affecting the bone marrow in pediatric patients. This book focuses on hematopoietic neoplasms and non-hematopoietic neoplasms involving the bone marrow and requiring bone marrow examination in routine pediatric practice. In addition to the common morphology of hematopoietic neoplasms, this book also illustrates unusual morphologies of some hematopoietic neoplasms and some uncommon non-hematopoietic tumors with bone marrow metastasis that cannot be found in other textbooks. A detailed discussion of each neoplasm is beyond the scope of this book. The selected areas of the bone marrow neoplasms in children included in this book are (1) myeloproliferative neoplasms and myelodysplastic syndromes, (2) acute myeloid leukemia and related precursor neoplasms, (3) precursor lymphoblastic leukemia/ acute lymphoblastic leukemia, (4) Burkitt leukemia, and (5) metastatic neoplasms.

Table of Contents
Introduction Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index

Atlas of Bone Marrow Neoplasms in Pediatric Patients


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Myeloproliferative Neoplasms and Myelodysplastic Syndromes


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Introduction MyeloproliferativeNeoplasms Neoplasms Myeloproliferative and MyelodysplasticSyndromes Syndromes and Myelodysplastic Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index

Chronic Myelogenous Leukemia (CML) Essential Thrombocythemia (ET) Juvenile Myelomonocytic Leukemia (JMML) Myelodysplastic Syndromes (MDS)

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Myeloproliferative Neoplasms and Myelodysplastic Syndromes


Myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal diseases of the bone marrow (BM) stem cell. MPN is characterized by involvement of all cell lines, with the proliferation predominantly in one of the cell lines (erythrocytes, myelocytes, monocytes or platelets) that is reflected in the BM by hypercellularity, intact maturation and minimal dyspoiesis. MDS characteristically shows cytopenia(s), dysplasia in one or more of the major myeloid cell lines, ineffective hematopoiesis manifested by hypercellularity of the BM, and increased risk of development of acute myeloid leukemia. Although MPN and MDS in pediatric patients are similar to their counterparts in adults, due to their rarity in children, there are limited cases and varieties compared with adult patients. However, juvenile myelomonocytic leukemia is a genuine childhood disorder and should bring about special consideration for BM evaluation in pediatric patients.

Chronic Myelogenous Leukemia (CML)


CML is a subtype of MPN. It is characterized by overproduction of mainly granulocytes and is consistently associated with the t(9;22)(q34;q11.2)/ BCR-ABL1 fusion gene located in the Philadelphia chromosome in all cell lines (myeloid and lymphoid). The natural history of untreated CML is bi- or triphasic: An indolent chronic phase is followed by an accelerated phase, a blast phase or both. CML is the most common type of MPN in childhood. Most patients are aged 6 years or older and usually present with hepatosplenomegaly and a high white blood cell (WBC) count (~100 x 109/L). In chronic phase, the peripheral blood (PB) shows marked leukocytosis with absolute neutrophilia in different stages of maturation, eosinophilia and basophilia (Figure A). The LAP (leukocyte alkaline phosphatase) score is markedly decreased (normal range: 30-130 in our institution) (Figure B). The platelet count is normal or increased. The BM cellularity is increased due to granulocytic hyperplasia with a maturation pattern and cellular components similar to those seen in the PB. Blasts are usually less than 5% of the nucleated cell population. Erythroid precursors are usually reduced in number. The megakaryocytes are generally increased in number and are small, with hypolobulated nuclei (Figure C). Accelerated phase of CML is manifested by any of the following: (1) persistent or increasing WBC and/or persistent or increasing splenomegaly unresponsive to therapy, (2) persistent thrombocytosis (>1000 x 109/L) uncontrolled by therapy, (3) persistent thrombocytopenia (<100 x 109/L) unrelated to therapy, (4) clonal cytogenetic evolution, (5) 20% or more basophils in the PB, and (6) 10%-19% myeloblasts in the PB or the BM. The diagnosis of blast phase can be made (1) when blasts 20% of the PB WBC or of the nucleated cells of the BM (Figures D and E) or (2) when there is an extramedullary blast proliferation.

Table of Contents
Introduction MyeloproliferativeNeoplasms Neoplasms Myeloproliferative and MyelodysplasticSyndromes Syndromes and Myelodysplastic Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index

Atlas of Bone Marrow Neoplasms in Pediatric Patients


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Figure A. Chronic phase: Peripheral blood (PB) smear showing marked leukocytosis with a spectrum maturation of neutrophilic cells, eosinophilia and basophilia (Wright-Giemsa, x1000).

Figure D. Blastic phase: BM biopsy demonstrating sheets of blasts (H&E, x400).

Table of Contents
Introduction MyeloproliferativeNeoplasms Neoplasms Myeloproliferative and MyelodysplasticSyndromes Syndromes and Myelodysplastic Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index

Figure B. Chronic phase: Markedly decreased LAP score (leukocyte alkaline phosphatase, x1000).

Figure E. Blastic phase: CD99 reactivity is detected by immunohistochemical stain (CD99, x400). The lineage of the blasts in this case is undifferentiated.

Figure C. Chronic phase: Bone marrow (BM) biopsy showing hypercellularity with marked myeloid and megakaryocytic hyperplasia and eosinophilia. The megakaryocytes in CML are characteristically smaller than normal megakaryocytes (H&E, x200).

Essential Thrombocythemia (ET)

Atlas of Bone Marrow Neoplasms in Pediatric Patients


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ET is a rare subtype of MPN that involves primarily the megakaryocytic lineage. It is characterized by sustained PB thrombocytosis (>450 x 109/L) and pronounced BM megakaryocytic hyperplasia and, clinically, by episodes of thrombosis and/ or hemorrhage. Since there is no known genetic or biological marker specic for ET, the diagnosis is made by exclusion of other causes for thrombocytosis. The major abnormality seen in the PB is marked thrombocytosis. The platelets often are varied in size and shape, including large or giant platelets, pseudopods and agranulated platelets (Figure A). The WBC count usually is normal. The BM usually displays a marked megakaryocytic hyperplasia (Figure B). The megakaryocytes are predominantly large to giant forms and display abundant mature cytoplasm and deeply lobulated and hyperlobulated (stag horn-like) nuclei (Figure C). The BM biopsy shows normocellularity or moderate hypercellularity. The megakaryocytes are dispersed throughout the BM or form clusters (Figure D). ET generally is considered a benign condition in children. Two forms of ET have been described in pediatric patients: primary type and familial type (FT). Primary ET can occasionally transform into myelobrosis or leukemia. The FT form of ET is autosomal dominant in inheritance pattern and is characterized by a lower incidence of hepatosplenomegaly than primary ET, without thrombotic or hemorrhagic complications, and does not transform into myelobrosis or leukemia.

Figure A. PB smear showing thrombocytosis with rare giant platelets (Wright-Giemsa, x1000).

Table of Contents
Introduction MyeloproliferativeNeoplasms Neoplasms Myeloproliferative and MyelodysplasticSyndromes Syndromes and Myelodysplastic Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index

Figure B. BM aspirate smear showing an increase in number and size of the megakaryocytes (Wright-Giemsa, x100).

Figure C. Enlarged megakaryocytes with bizarre lobulated nuclei (Wright-Giemsa, x400).

Atlas of Bone Marrow Neoplasms in Pediatric Patients


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This is an Interactive PDF. To navigate, please click on the chapters in the table of contents below. Then use the arrows at the bottom of the page to navigate within each chapter. For more information, please visit http://www.abbottdiagnostics.com/. Figure D. Hypercellular BM displays megakaryocytic hyperplasia. The megakaryocytes show large, hyperlobated and hyperchromatic nuclei (H&E, x400). Figure A. PB smear showing increased number of abnormal monocytes with cytoplasmic vacuoles (Wright-Giemsa, x1000).

Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index

Juvenile Myelomonocytic Leukemia (JMML) JMML is a clonal hematopoietic disorder of childhood. Clinically, it is characterized by male predominance and usually presents before 2 years of age except in patients with neurobromatosis type 1 (NF-1) in whom the diagnosis is made more often after 5 years of age. The patients usually present with hepatosplenomegaly, facial skin rash and lymphadenopathy. Pathologically, JMML is characterized by proliferation principally of the granulocytic and monocytic lineages (Figures A and B). Blasts plus promonocytes account for <20% of cells in the PB and the BM. Erythroid lineage and megakaryocytes are usually normal. BCR-ABL1 is absent. Mutations on the N-ras and K-ras genes are frequent. The spontaneous generation of myelomonocytic colonies in in vitro BM cultures in the absence of GM-CSF is seen in JMML. In contrast, cultures from normal individuals and patients with CML are cytokine dependent.

Figure B. BM aspirate smear shows myeloid hyperplasia, but the monocytic component is difcult to appreciate (Wright-Giemsa, x1000).

Myelodysplastic Syndromes (MDS)

Atlas of Bone Marrow Neoplasms in Pediatric Patients


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Based on the percentage of blasts, the percentage of ring sideroblasts, and the number of lineages of cytopenia and dysplasia present in the PB and/or the BM, the 2008 World Health Organization (WHO) Classication characterized MDS into the following seven categories.

Table 1-1. The 2008 WHO Classication of Myelodysplastic Syndromes MDS Categories
Refractory cytopenias with unilineage dysplasia (RCUD): Refractory anemia (RA) Refractory neutropenia (RN) Refractory thrombocytopenia (RT) Refractory anemia with ring sideroblasts (RARS)

PB Findings
Unicytopenia or bicytopenia No or rare blasts (<1%)

BM Findings
Unilineage dysplasia: 10% of the cells in one myeloid lineage <5% blasts <15% of erythroid precursors are ring sideroblasts 15% of erythroid precursors are ring sideroblasts Erythroid dysplasia only <5% blasts Dysplasia in 10% of the cells in 2 myeloid lineages (neutrophils and/or erythroid precursors and/or megakaryocytes) <5% blasts No Auer rods 15% ring sideroblasts Unilineage or multilineage dysplasia 5%-9% blasts No Auer rods Unilineage or multilineage dysplasia 10%-19% blasts Auer rods Unequivocal dysplasia in <10% of cells in one or more myeloid cell lines when accompanied by a cytogenetic abnormality considered as presumptive evidence for a diagnosis of MDS <5% blasts Normal to increased megakaryocytes with hypolobated nuclei <5% blasts Isolated del(5q) cytogenetic abnormality No Auer rods

Anemia No blasts

Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index

Refractory cytopenia with multilineage dysplasia (RCMD)

Cytopenia(s) No or rare blasts (<1%) No Auer rods <1 x 109/L monocytes

Refractory anemia with excess blasts-1 (RAEB-1)

Cytopenia(s) 5% blasts No Auer rods <1 x 109/L monocytes Cytopenia(s) 5%-19% blasts Auer rods <1 x 109/L monocytes Cytopenias 1% blasts

Refractory anemia with excess blasts-2 (RAEB-2)

MDS-unclassied (MDS-U)

MDS associated with isolated del(5q)

Anemia Normal or increased platelet count No or rare blasts (<1%)

Atlas of Bone Marrow Neoplasms in Pediatric Patients


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Dyserythropoiesis is characterized by the presence of vacuolization, megaloblastoid changes (Figure A), binucleation, multinucleation (Figure B), nuclear budding, nuclear irregularity, nuclear and cytoplasmic dys-synchrony in erythroid precursors and the presence of ring sideroblasts (Figure C). Dysmyelopoiesis is characterized by the presence of pseudo-Pelger-Huet neutrophils (Figure D), hypogranulated neutrophilic cells (Figure E), hypersegmented neutrophils (>5 segments), hypersegmented eosinophils (>2 segments) (Figure F), basophilic granules in eosinophils (Figure G), and others. Dysplastic platelets show giant and hypogranular platelets. Megakaryocytic dysplasia is characterized by the presence of micromegakaryocytes, monolobulated form, deep lobulated and hyperlobulated forms, or large and bizarre megakaryocytes. Rare PB blasts (1%) can be seen in RCUD, RCMD, MDS-U or MDS associated with isolated del(5q). In patients with RAEB-1 and RAEB-2, blasts are increased in the PB (Figure H) and/or the BM (Figure I), but are <20%.

Figure A. Dyserythropoiesis: Megaloblastoid change in a normoblast, two blasts present (Wright-Giemsa, x1000).

Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index

Figure B. Dyserythropoiesis: Multinucleated red blood cells (Wright-Giemsa, x1000).

Figure C. Dyserythropoiesis: Ring sideroblast (iron stain, x1000).

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Atlas of Bone Marrow Neoplasms in Pediatric Patients


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Figure D. Dysmyelopoiesis: Pseudo-Pelger-Huet neutrophil (Wright-Giemsa, x1000).

Figure G. Dysmyelopoiesis: Dysplastic eosinophils with basophilic granules (Wright-Giemsa, x1000).

Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index
Figure E. Dysmyelopoiesis: Hypogranulated band (Wright-Giemsa, x1000). Figure H. Refractory anemia with excess blasts (RAEB-2): PB smear showing circulating blasts (Wright-Giemsa, x1000).

Figure F. Dysmyelopoiesis: Hypersegmented eosinophils (Wright-Giemsa, x1000).

Figure I. Refractory anemia with excess blasts (RAEB-2): BM biopsy showing hypercellularity and increase of blasts (H&E, x400).

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Acute Myeloid Leukemia and Related Precursor Neoplasms


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AML With t(8;21)(q22;q22); RUNX1-RUNX1T1 AML With inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11   Acute Promyelocytic Leukemia (APL) With t(15;17)(q22;q12)PML-RARA

Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid and Acute MyeloidLeukemia Leukemia and Related Precursor PrecursorNeoplasms Neoplasms Related Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index

AML With 11q23 (MLL) Abnormalities  AML (Megakaryoblastic) With t(1;22)(p13;q13); RBM15-MKL1 AML With Myelodysplasia-Related Changes Therapy-Related AML (t-AML) AML With Minimal Differentiation, NOS (FAB M0) AML Without Maturation, NOS (FAB M1) AML With Maturation (FAB M2) and Eosinophilia, NOS  Acute Myelomonocytic Leukemia, NOS (FAB M4) Acute Erythroid Leukemia, NOS (FAB M6) Transient Abnormal Myelopoiesis (TAM)  (Myeloid Proliferation Related to Down Syndrome)

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Atlas of Bone Marrow Neoplasms in Pediatric Patients


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Acute Myeloid Leukemia and Related Precursor Neoplasms


Acute myeloid leukemia (AML) comprises a group of hematopoietic malignancies derived from the clonal proliferation of myeloid progenitors. In the past few decades, expanding knowledge of AML has resulted in major advances in the understanding and classication of this group of diseases. In 1976, the French-American-British Cooperative Group (FAB) proposed a classication system for acute leukemia based on morphologic features of blasts and cytochemical study results, with later minor modications (Table 2-1). Although the FAB classication system provided the standardization for dening and diagnosing acute leukemias, its correlation with prognosis is limited. With an increased recognition of the signicance of cytogenetic changes, the presence of multilineage dysplasia and previous therapy in AML, the WHO proposed a new classication of AML (Table 2-2), which incorporated these features with some morphologic features of the FAB AML classication. Here, we illustrate cases based on the 2008 WHO classication of AML, in combination with morphology described by the FAB classication.

Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid and Acute MyeloidLeukemia Leukemia and Related Precursor PrecursorNeoplasms Neoplasms Related Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index

Table 2-1. The FAB Classication of Acute Myeloid Leukemia (BM Blasts 30%)

M0 M1 M2 M3 M3 v M4 M4 eos M5a M5b M6 M7

AML with minimal differentiation AML without maturation AML with maturation Acute promyelocytic leukemia Acute promyelocytic leukemia, microgranular variant Acute myelomonocytic leukemia Acute myelomonocytic leukemia with eosinophilia Acute monoblastic leukemia Acute monocytic leukemia Acute erythroid leukemia Acute megakaryoblastic leukemia

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Table 2-2. The 2008 WHO Classication of Acute Myeloid Leukemia and Related Precursor Neoplasms (BM Blasts 20%)
AML with recurrent genetic abnormalities AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 Acute promyelocytic leukemia with t(15;17)(q22;q12); PML-RARA AML with 11q23 (MLL) abnormalities AML with t(6;9)(p23;q34); DEK-NUP214 AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1 AML with mutated NPM1 AML with mutated CEBPA AML with myelodysplasia-related changes Therapy-related myeloid neoplasms

Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid and Acute MyeloidLeukemia Leukemia and Related Precursor PrecursorNeoplasms Neoplasms Related Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index

AML, not otherwise specied AML with minimal differentiation AML without maturation AML with maturation Acute myelomonocytic leukemia Acute monoblastic and monocytic leukemia Acute erythroid leukemia Acute megakaryoblastic leukemia Acute basophilic leukemia Acute panmyelosis with myelobrosis Myeloid sarcoma Myeloid proliferations related to Down syndrome Transient abnormal myelopoiesis Myeloid leukemia associated with Down syndrome Blastic plasmacytoid dendritic cell neoplasm

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AML With t(8;21)(q22;q22); RUNX1-RUNX1T1

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Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid and Acute MyeloidLeukemia Leukemia and Related Precursor PrecursorNeoplasms Neoplasms Related Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index

This type of AML accounts for about 5% of all AML cases and generally shows maturation in neutrophil lineage (FAB M2) (Figure A). The t(8;21) results in fusion of the RUNX1 gene (also known as AML1 or CBFA) on chromosome 21 with the RUNX1T1 gene (also known as ETO) on chromosome 8, resulting in RUNX1-RUNX1T1 chimeric protein, which disrupts normal function of the core-binding factor (a transcriptional factor complex regulates normal hematopoiesis). Morphologically, the blasts are usually large with abundant basophilic cytoplasm. Auer rods are frequently present (Figure B). Cytochemically, blasts are positive for myeloperoxidase (MPO) (Figure C). AML with t(8;21)(q22;q22) is usually associated with a good response to chemotherapy, a high complete remission rate, and long-term disease-free survival.

Figure A. BM aspirate smear showing myeloblasts and several maturing myeloid elements, including bands and neutrophils (Wright-Giemsa, x1000).

Figure B. Auer rod present in a blast (Wright-Giemsa, x1000).

Figure C. Myeloperoxidase (MPO) reaction showing peroxidase reactivity in the blasts (MPO, x1000).

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AML With inv(16)(p13.1q22) or t(16;16) (p13.1;q22); CBFB-MYH11

Acute Promyelocytic Leukemia (APL) With t(15;17)(q22;q12); PML-RARA


APL/AML with t(15;17)(q22;q12) is an AML with abnormal promyelocytic proliferation and accounts for 9%-12% of AMLs. Genetically, the retinoic acid receptor alpha (RARA) gene on 17q12 fuses with a nuclear regulatory factor gene on 15q22 (promyelocytic leukemia or PML gene), resulting in a PML-RARA fusion gene product and sensitivity of APL to treatment with all-trans-retinoic acid.The patients may present with disseminated intravascular coagulation (DIC) before or during the treatment. There are two morphologic types: hypergranular/typical APL and microgranular/ hypogranular APL. The abnormal promyelocytes of hypergranular APL usually show variable nuclear size and irregular shape, with large and numerous cytoplasmic granules (Figure A). Characteristic cells (faggot cells) contain bundles of Auer rods (Figure B). The MPO by cytochemical stain is always strongly positive in all leukemic cells (Figure C). The Sudan Black B (SBB) reaction is also strongly positive in leukemic cells (Figure D). Cases of hypogranular variant are characterized by bilobed nuclear conguration and paucity or absence of cytoplasmic granules. However, the MPO reaction is strongly positive in these leukemic cells. Increase of abnormal promyelocytes and positive MPO reactivity can also be appreciated in BM biopsy (Figures E and F). The prognosis of APL is favorable.

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This type of AML represents about 5%-10% of all AML cases and usually shows myelomonocytic differentiation and eosinophilia (FAB M4 eos) with abnormal eosinophils in the BM (Figures A and B). Both inv(16) (p13.1q22) and t(16;16)(p13.1;q22) result in a fusion of the CBFB and MYH11 genes on chromosome 16, which, similar to the t(8;21), disrupts the core-binding factor transcription factor complex. Patients with AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22) have longer complete remissions.

Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid and Acute MyeloidLeukemia Leukemia and Related Precursor PrecursorNeoplasms Neoplasms Related Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index
Figure B. Eosinophilia present in a BM biopsy (H&E, x1000).

Figure A. Increase of blasts and eosinophils. Abnormal eosinophils showing basophilic granules or hypersegmentation (Wright-Giemsa, x1000).

Figure A. BM aspirate smear showing malignant promyelocytes (Wright-Giemsa, x1000).

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Figure B. Faggot cell with numerous Auer rods (Wright-Giemsa, x1000).

Figure E. BM biopsy showing increase of promyelocytes (H&E, x1000).

Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid and Acute MyeloidLeukemia Leukemia and Related Precursor PrecursorNeoplasms Neoplasms Related Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index
Figure D. Leukemic cells positive for Sudan Black B (SBB) (SBB, x1000). Figure C. Leukemic cells MPO-positive by cytochemical stain (MPO, x1000). Figure F. Promyelocytes in a BM biopsy, immunoreactive for MPO (MPO, x1000).

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AML With 11q23 (MLL) Abnormalities

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Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid and Acute MyeloidLeukemia Leukemia and Related Precursor PrecursorNeoplasms Neoplasms Related Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index

This type of AML may occur at any age but is more common in children, especially in infants. It represents 9%-22% of pediatric AML cases. The patients may present with DIC and sometimes show tissue inltrate. Morphologically, this leukemia is usually associated with myelomonocytic (FAB M4) or monocytic (FAB M5) differentiation. Monoblasts (Figure A) and/or promonocytes (Figure B) are typically predominant. Scattered ne azurophilic granules are sometimes present. Monoblasts and promonocytes are strongly positive by nonspecic esterase (Figure C). The monoblasts often are negative for MPO (Figure D). Genetically, this disease category is heterogenous since more than 40 different translocation partners have been reported to fuse with MLL. Patients with AML with 11q23 (MLL) usually have an intermediate survival rate.

Figure B. BM aspirate smear showing predominantly promonocytes (Wright-Giemsa, x1000).

Figure C. Positive nonspecic esterase (NSE) in blasts (NSE, x1000).

Figure A. BM aspirate smear showing predominantly monoblasts (Wright-Giemsa, x1000).

Figure D. Negative MPO in blasts (MPO, x1000).

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AML (Megakaryoblastic) With t(1;22)(p13;q13); RBM15-MKL1 This type of AML is uncommon and represents <1% of all AML cases. It is a de novo AML, restricted to infants and young children (3 years or less) with most cases occurring in the rst 6 months. The t(1;22)(q13;q13) results in a fusion of RNA-binding motif protein 15 (RBM15) (also known as OTT) and megakaryocyte leukemia-1 (MKL1) (also known as MAL). The fusion gene may modulate chromatin organization, HOX-induced differentiation and extracellular signaling pathway. The PB and BM blasts of AML with t(1;22) are similar to those of acute megakaryoblastic leukemia, not otherwise specied (NOS). Megakaryoblasts often are medium to large with round or slightly indented nucleus and ne chromatin. The cytoplasm is basophilic and often shows blebs or pseudopod formation (Figures A and B). Cytochemical stain of MPO is negative in megakaryoblasts (Figure C). The BM biopsy shows an increase of blasts and abnormal megakaryocytes (Figure D) with CD61 reactivity (Figure E). Reticulin brosis (Figure F) is a common nding. Platelet peroxidase can be detected by electron microscopy (Figure G). The patients usually respond well to chemotherapy, with long disease-free survival.

Figure B. A small cluster of megakaryoblasts in a BM aspirate smear (Wright-Giemsa, x1000).

Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid and Acute MyeloidLeukemia Leukemia and Related Precursor PrecursorNeoplasms Neoplasms Related Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index

Figure C. Megakaryoblasts cytochemically negative for MPO (MPO, x1000).

Figure A. PB smear showing a megakaryoblast with cytoplasmic blebs (Wright-Giemsa, x1000).

Figure D. BM biopsy showing increase of blasts and abnormal megakaryocytes (H&E, x400).

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AML With Myelodysplasia-Related Changes

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Figure E. Abnormal megakaryocytes and some blasts positive for CD61 (CD61, x400).

This disease category is dened as an AML with 20% PB or BM blasts with morphological features of MDS (Figures A-D) or a prior history of a MDS or MDS/MPN, or MDS-related cytogenetic abnormalities and absence of the specic genetic abnormalities of AML with recurrent genetic abnormalities. This type of AML occurs mainly in elderly patients and is rare in children. Chromosome abnormalities are similar to those seen in MDS, with -7/del(7q), -5/del(5q) or complex karyotypes most common. Patients with AML with myelodysplasiarelated changes generally have a poor prognosis.

Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid and Acute MyeloidLeukemia Leukemia and Related Precursor PrecursorNeoplasms Neoplasms Related Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index
Figure F. Marked BM brosis present (reticulin stain, x400). Figure A. Dysplastic blasts showing lobulated nuclei (Wright-Giemsa, x1000).

Figure G. Electron microscopy (EM) showing a positive platelet peroxidase reaction (PPR) in the nuclear envelope and rough endoplasmic reticulum (EM PPR, x100,000).

Figure B. Blasts, pseudo-Pelger-Huet neutrophils and vacuolated monocytes present (Wright-Giemsa, x1000).

20

Therapy-Related AML (t-AML)

Atlas of Bone Marrow Neoplasms in Pediatric Patients


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Figure C. Blasts and a micromegakaryocyte shown (Wright-Giemsa, x1000).

Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid and Acute MyeloidLeukemia Leukemia and Related Precursor PrecursorNeoplasms Neoplasms Related Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index
Figure D. BM biopsy showing increase of blasts and dysplastic megakaryocytes (H&E, x400).

The t-AML develops as a consequence of previous treatment with chemotherapy and/or radiation therapy for other malignant disorders. The t-AML can be further subdivided into alkylating agent-related and topoisomerase II inhibitor-related types. The former usually occurs 5 to 7 years after therapy and shows morphologic and cytogenetic changes similar to AML with myelodysplasia-related changes. The latter often occurs 2 to 3 years after therapy, tends to have monocytic features in blasts, and is frequently associated with MLL rearrangement. The case we present here is a 14-year-old male who was treated for his Ewing sarcoma. Two years later, large blasts were identied in his PB. BM aspirate was performed and showed an increase of large monocytic blasts (Figure A). The blasts show myelomonocytic differentiation with positive MPO (Figure B) and NSE reactivity (Figure C). The prognosis of t-AML is usually poor.

Figure A. BM aspirate smears showing large blasts with monocytic features (Wright-Giemsa, x1000).

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Atlas of Bone Marrow Neoplasms in Pediatric Patients


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This is an Interactive PDF. To navigate, please click on the chapters in the table of contents below. Then use the arrows at the bottom of the page to navigate within each chapter. For more information, please visit http://www.abbottdiagnostics.com/. Figure B. Blasts cytochemically reactive for MPO (MPO, x1000).

AML With Minimal Differentiation, NOS (FAB M0) This type of AML is characterized by uniform blasts without cytoplasmic granules, with no Auer rods (Figure A), and with negative blast cytochemical reactions for MPO (Figure B), SBB and NSE. The myeloid lineage of blasts (CD13 and/ or CD33) is recognizable only by ow cytometric immunophenotyping.

Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid and Acute MyeloidLeukemia Leukemia and Related Precursor PrecursorNeoplasms Neoplasms Related Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index
Figure C. NSE-positive in blasts (NSE, x1000). Figure A. BM aspirate smear showing undifferentiated blasts (Wright-Giemsa, x1000).

Figure B. Blasts are MPO-negative by cytochemical stain (MPO, x1000).

22

AML Without Maturation, NOS (FAB M1)

Atlas of Bone Marrow Neoplasms in Pediatric Patients


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This type of AML is characterized by a predominance of myeloblasts and <10% promyelocytes or other mature granulocytes in the BM (Figure A). The myeloid nature of blasts is demonstrated by MPO (Figure B) or SBB (3% of blasts) positivity and/or Auer rods.

AML With Maturation (FAB M2) and Eosinophilia, NOS This type of AML is characterized by a proliferation of myeloblasts associated with >10% promyelocytes or other mature granulocytes in the BM (Figure A). In rare cases, eosinophilia with dysplastic changes is present (Figure A).

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Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid and Acute MyeloidLeukemia Leukemia and Related Precursor PrecursorNeoplasms Neoplasms Related Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index
Figure B. MPO reaction showing strong peroxidase reactivity in 40% of the blasts (MPO, x1000). Figure A. The BM components are predominantly myeloblasts (Wright-Giemsa, x1000). Figure A. BM aspirate smear showing increased eosinophils in a patient with AML with maturation. Some eosinophils are dysplastic with hypersegmentation (Wright-Giemsa, x1000).

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Acute Myelomonocytic Leukemia, NOS (FAB M4) This type of AML is composed of myeloblasts, monoblasts and promyelocytes (Figure A). The PB or BM has 20% blasts (including promonocytes); neutrophils and their precursors, monocytes and their precursors each comprise at least 20% of BM cells. Myeloblasts are cytochemically MPOpositive (Figure B), and monoblasts, including promonocytes, are NSE-positive (Figure C).
Figure B. Positive MPO reaction in blasts (MPO, x1000).

Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid and Acute MyeloidLeukemia Leukemia and Related Precursor PrecursorNeoplasms Neoplasms Related Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index
Figure A. BM aspirate smear showing myeloblasts, monoblasts and promonocytes (Wright-Giemsa, x1000). Figure C. Positive NSE reaction in blasts (NSE, x1000).

24

Acute Erythroid Leukemia, NOS (FAB M6)

Atlas of Bone Marrow Neoplasms in Pediatric Patients


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Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid and Acute MyeloidLeukemia Leukemia and Related Precursor PrecursorNeoplasms Neoplasms Related Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index

This AML category is characterized by a combined proliferation of myeloblasts and red-cell precursors. There are two subtypes: (1) Erythroleukemia (erythroid/myeloid) is dened by the presence in the BM of 50% erythroid precursors in the entire nucleated cell population and 20% myeloblasts in the non-erythroid cell population (Figures A and B); (2) pure erythroid leukemia is dened as a neoplastic proliferation of immature cells committed exclusively to the erythroid lineage (80% of BM cells) with no evidence of a signicant myeloblast elements. Dyserythropoiesis is common (Figure C). Acute erythroid leukemia is usually associated with an aggressive clinical course.

Figure A. BM aspirate smear showing myeloblasts and increase of erythroid precursors (Wright-Giemsa, x1000).

Figure B. BM biopsy showing increase of erythroid precursors (H&E, x1000).

Figure C. Dyserythropoietic changes (megaloblastoid changes and nuclear irregularity) are present (Wright-Giemsa, x1000).

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Atlas of Bone Marrow Neoplasms in Pediatric Patients


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Transient Abnormal Myelopoiesis (TAM) (Myeloid Proliferation Related to Down Syndrome) TAM (also known as transient myeloproliferative disorder, TMD) is a unique disease of Down syndrome (DS) newborns that presents with clinical and morphologic ndings indistinguishable from acute megakaryoblastic leukemia. These patients may present with leukocytosis, thrombocytosis and numerous PB blasts with cytoplasmic blebs suggesting megakaryoblasts (Figure A). Platelets usually show giant forms and hypogranulated forms (Figure A). The percentage of PB blasts may exceed the blast percentage in the BM. Megakaryoblasts are negative for MPO (Figure B) by cytochemical stain and sometimes show a punctate staining pattern by NSE (Figure C). Most of the cases have spontaneous remission. Nontransient AML, mostly acute megakaryoblastic leukemia, develops 1 to 3 years later in 20%-30% of these children.

Figure A. PB smear showing a myeloblast, megakaryoblasts, an undifferentiated blast, nucleated red blood cells, thrombocytosis, and dysplastic platelets (giant platelets and hypogranulated platelets) (Wright-Giemsa, x1000).

Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid and Acute MyeloidLeukemia Leukemia and Related Precursor PrecursorNeoplasms Neoplasms Related Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index

Figure B. Megakaryoblasts are cytochemically negative for MPO (MPO, x1000).

Figure C. NSE shows punctate staining pattern in megakaryoblasts (NSE, x1000).

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Atlas of Bone Marrow Neoplasms in Pediatric Patients


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Precursor/Acute Lymphoblastic Leukemia

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Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Precursor/Acute Lymphoblastic Leukemia Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index

27

Precursor/Acute Lymphoblastic Leukemia


Atlas of Bone Marrow Neoplasms in Pediatric Patients
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Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Precursor/Acute Lymphoblastic Leukemia Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index

The terms precursor lymphoblastic leukemia and acute lymphoblastic leukemia (ALL) are used as synonyms. ALL is primarily a disease of children and accounts for approximately 75% of leukemias in childhood. Eighty-ve to 90% of cases are B-ALL, and 10%-15% of cases are T-ALL. About 75% of cases occur in children under 6 years of age. The incidence is substantially higher in white children than black children and appears to be highest in Hispanic children. Clinically, most patients present with evidence and consequences of BM failure, manifested by thrombocytopenia and/or anemia and/or neutropenia. WBC count may be decreased, normal or markedly increased with circulating blasts. Lymphadenopathy and hepatosplenomegaly are frequently seen. Bone pain is also a common symptom. Patients with T-ALL are usually older, have a high WBC count, and often present with breathing difculty due to a large mediastinal mass. Morphologically, lymphoblasts in most cases are small with scant cytoplasm, condensed nuclear chromatin and indistinct nucleoli (L1 morphology, Figure A). In some cases, lymphoblasts are larger cells with a moderate amount of light-blue to gray cytoplasm, dispersed nuclear chromatin and prominent nucleoli (L2 morphology, Figure B). In rare cases of ALL, blasts show unusual morphologic features, including hand-mirror morphology (Figure C); cytoplasmic vacuolization (Figures D and E); cytoplasmic azurophilic granules (Figures F and G); giant, Chediak-Higashi-like cytoplasmic granules (Figures H-J); association with eosinophilia (Figure K); pleomorphic morphology (Figure L); aplastic bone marrow (Figures M-O); and forming clusters mimicking metastatic tumors (Figure P).

B-ALL has a better prognosis in children than in adults. Approximately 80% of pediatric patients with B-ALL appear to be cured using current therapeutic strategies. The age, WBC count and genetic abnormalities are important prognostic factors. Children younger than 1 year of age (infantile ALL) or older than 10 years of age, ones presenting with a WBC count greater than 10,000/mm3, and ones unresponsive to therapy have an unfavorable prognosis. In addition, genetic abnormalities have very important prognostic implications. B-ALL with t(9;22)(q34;q11.2)/BCR-ABL1, t(v;11q23)/ MLL gene rearrangement, t(1;19)(q23;p13.3)/ E2A-PBX1(TCF3-PBX1) and hypodiploidy have an unfavorable outcome. B-ALL with t(12;21)(p13;q22)/ TEL-AML1(ETV6-RUNX1) and hyperdiploidy have a favorable outcome. T-ALL in childhood is generally considered a higher-risk disease than B-ALL, due to the frequent presence of high-risk clinical features (older age, higher WBC count).

Figure A. L1 morphology: Blasts showing little cytoplasm (Wright-Giemsa, x1000).

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Figure B. L2 morphology: Blasts showing moderate to abundant cytoplasm, ne chromatin and prominent nucleoli (Wright-Giemsa, x1000).

Figure E. Vacuolated variant: PAS is negative in the cytoplasmic vacuoles (PAS, x1000).

Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Precursor/Acute Lymphoblastic Leukemia Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index
Figure C. Hand-mirror variant: Blasts showing morphology mimicking a hand mirror (Wright-Giemsa, x1000). Figure F. Granular variant: Blasts showing pink azurophilic cytoplasmic granules (Wright-Giemsa, x1000).

Figure D. Vacuolated variant: Blasts showing large cytoplasmic vacuoles (Wright-Giemsa, x1000).

Figure G. Granular variant: The cytoplasmic granules are PAS-positive (PAS, x1000).

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Atlas of Bone Marrow Neoplasms in Pediatric Patients


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Figure H. ALL with giant, Chediak-Higashi-like granules: Blasts showing giant, pink cytoplasmic granules (Wright-Giemsa, x1000).

Figure K. ALL with eosinophilia: Increase of eosinophils present in an ALL. Some eosinophils show dysplasia with hypersegmentation (Wright-Giemsa,x1000).

Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Precursor/Acute Lymphoblastic Leukemia Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index
Figure I. ALL with giant, Chediak-Higashi-like granules: Granules positive for PAS (PAS, x1000). Figure L. Pleomorphic variant: Some blasts show cytomegaly, orid nuclei or multinucleation (WrightGiemsa, x1000).

Figure J. ALL with giant, Chediak-Higashi-like granules: Granules positive for PAS-diastase (PAS-diastase, x1000).

Figure M. Aplastic variant: BM biopsy showing hypocellularity (25%) (H&E, x100).

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Figure N. Aplastic variant: BM biopsy demonstrates increase of blasts (H&E, x1000).

Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Precursor/Acute Lymphoblastic Leukemia Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index
Figure O. Aplastic variant: Blasts are TdT-positive (immunostain TdT, x1000). Cytogenetic analysis detects MLL gene rearrangement in this case.

Figure P. ALL mimicking metastatic tumor: Lymphoblasts forming clumps (Wright-Giemsa, x400).

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Burkitt Leukemia

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Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Burkitt Leukemia Metastatic Neoplasms Index

32

4. Burkitt Leukemia
Atlas of Bone Marrow Neoplasms in Pediatric Patients
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Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Burkitt Leukemia Metastatic Neoplasms Index

Burkitt leukemia (BL) is a mature B-cell neoplasm (CD34-, TdT+, sIg+), primarily occurring in children and young adults. It is a very aggressive tumor with an extremely high proliferation rate. Epidemiologically, three clinical variants are recognized: endemic (Epstein-Barr virus [EBV]- associated), sporadic and immunodeciency-associated. Pathologically, the typical features of BL are the proliferation of monotonous, intermediately sized lymphoid cells, which show round nuclei with nely clumped and dispersed chromatin and multiple para-centrally situated nucleoli (Figure A). The cytoplasm is moderate in amount and is deeply basophilic, containing a number of lipid vacuoles (Figure B). BM biopsy shows malignant lymphoid inltrate with starry-sky appearance (Figure C). Variant and atypical morphologies have been described. Some cases of BL show greater nuclear pleomorphism (Figures D and E), and the nucleoli may be more prominent and fewer in number. Cases with human immunodeciency virus may show plasmacytoid differentiation. Genetically, translocation of MYC oncogene (8q24) is present. Most cases have MYC translocation to the immunoglobulin heavy chain (IGH) region, 14q32, or less commonly at the light chain (IGK), 2p12, or the light chain (IGL), 22q11. Although the tumor of endemic and sporadic forms is highly aggressive, it is potentially curable. With high-intensity treatment, the prognosis is very favorable, with 80%-90% survival.

Figure A. Classical BL: The tumor cells are monotonous and are medium in size with deep basophilic cytoplasm and abundant cytoplasmic vacuoles (Wright-Giemsa, x1000).

Figure B. Classical BL: Cytoplasmic vacuoles are positive for lipid by Oil Red O stain (Oil Red O, x1000).

Figure C. Classical BL: BM biopsy showing BL cell inltrate with starry-sky pattern (H&E, x400).

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Atlas of Bone Marrow Neoplasms in Pediatric Patients


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This is an Interactive PDF. To navigate, please click on the chapters in the table of contents below. Then use the arrows at the bottom of the page to navigate within each chapter. For more information, please visit http://www.abbottdiagnostics.com/. Figure D. Atypical BL: The tumor cells are pleomorphic and varied in size. Nuclei show convolution and marked irregularity (Wright-Giemsa, x1000).

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Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Burkitt Leukemia Metastatic Neoplasms Index
Figure E. Atypical BL: Blue-gray cytoplasm with rare vacuoles in some tumor cells (Wright-Giemsa, x1000).

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Metastatic Neoplasms
Click on a topic below to jump to a specic section. Or use the arrows at the bottom of the page to navigate within this chapter. Alveolar Rhabdomyosarcoma Ewing Sarcoma

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Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Metastatic Neoplasms Index

Neuroblastoma Nasopharyngeal Carcinoma (NPC) Classical Hodgkin Lymphoma (cHL) Non-Hodgkin Lymphoma (NHL) Langerhans Cell Histiocytosis (LCH)

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Metastatic Neoplasms
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Non-hematopoietic neoplasms and lymphomas can involve the BM. Examination of the BM is a common procedure in the clinical evaluation of children with solid and soft-tissue tumors, as well as lymphomas. It is required for tumor staging, treatment monitoring and documentation of recurrent disease. Non-hematopoietic tumors involving the BM usually form cell clumps. The BM aspirate and biopsy, in combination with ow cytometric analysis and immunohistochemical stain, are complementary to one another and are necessary and important for the assessment of metastatic tumors in the BM.
Figure A. Myoblasts are small, lymphoblast-like with scanty cytoplasm, and have central or slightly eccentric nuclei (Wright-Giemsa, x400).

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Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Metastatic Neoplasms Index

Alveolar Rhabdomyosarcoma Rhabdomyosarcoma is the most common soft-tissue sarcoma of childhood, with skeletalmuscle differentiation. Alveolar rhabdomyosarcoma is an aggressive type of rhabdomyosarcoma and frequently metastasizes to the BM. This tumor is included in the differential diagnosis of small blue cell tumors. Most tumor cells in alveolar rhabdomyosarcoma are small, lymphoblast-like with scanty cytoplasm, and have central or slightly eccentric nuclei with or without nucleoli (Figure A). Tumor cells may be discohesive, mimicking leukemic blasts in the BM. More frequently, tumor cells form loose clumps (Figure B). In BM biopsy, tumor cells show pink cytoplasm and form clusters or form a loose cohesive sheet (Figure C).

Figure B. A small cluster of myoblasts, which are larger than hematopoietic elements, showing vacuolated cytoplasm (Wright-Giemsa, x400).

Figure C. Bone marrow biopsy shows tumor cell inltrate. The tumor cells show pink cytoplasm (H&E, x400).

36

Ewing Sarcoma

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Ewing sarcoma is a primary malignant tumor of the bone in children and is one of the small blue cell tumors. The BM metastasis is detected in about 10% of cases at initial diagnosis. BM aspirate usually shows clumps of small, blue, round cells. Tumor cells may have abundant blue-gray cytoplasm (Figure A). The nuclei are round with distinct, small nucleoli. In some cases, tumor cells arrange in a noncohesive fashion, mimicking leukemia (Figure B). Necrosis is occasionally seen (Figures C and D). BM biopsy may show focal (Figure E) or diffuse (Figure F) tumor inltrate. Immunohistochemical stain CD99 shows cytoplasmic membrane staining pattern (Figure G). The demonstration of EWS-FLI1 or EWS-ERG fusion transcripts by cytogenetic and molecular genetic studies conrms the diagnosis.

Figure C. BM aspirate smear showing tumor cell necrosis (Wright-Giemsa, x400).

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Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Metastatic Neoplasms Index
Figure E. A cluster of tumor cells (center) is identied in a BM biopsy (H&E, x400). Figure D. BM biopsy showing tumor necrosis (H&E, x200). Figure A. Clumps of tumor cells that show abundant light-gray cytoplasm and cytoplasmic vacuoles (Wright-Giemsa, x400).

Figure B. Tumor cells are discohesive, mimicking acute lymphoblastic leukemia (Wright-Giemsa, x400).

37

Neuroblastoma

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Figure F. BM biopsy showing replacement by tumor cells mimicking a leukemic pattern (H&E, x400).

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Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Metastatic Neoplasms Index

Neuroblastoma is the most common solid tumor in children and most commonly arises from the adrenal gland. Neuroblastoma is the most frequent metastatic tumor in the BM of children and is included in the differential diagnosis of small blue cell tumors. In BM aspirate, tumor cells usually form tight clusters (Figure A). In some cases, Homer Wright rosettes (Figure B) or neuropils (Figure C) are present. At high magnication, tumor cells show high N/C ratio, scanty or a small amount of light-blue cytoplasm, homogenous chromatin and indistinct nucleoli (Figure D). In BM biopsy, tumor inltrate may be focal or diffuse. In most cases, tumor cells show blastic appearance (Figures D and E). In some post-treatment cases, tumor cells show ganglionic differentiation (Figure F). Immunohistochemically, tumor cells are positive for neuron-specic enolase (Figure G).

Figure G. CD99 highlights tumor cells with cytoplasm membrane staining pattern (CD99, x400).

Figure A. Clusters of tumor cells in a BM aspirate smear (Wright-Giemsa, x400).

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Figure B. Tumor cells form a Homer Wright rosette (Wright-Giemsa, x400).

Figure E. BM biopsy showing neuroblast inltrate with pink neuropils (H&E, x200).

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Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Metastatic Neoplasms Index
Figure C. Neuropils (gray material) noted adjacent to the tumor cells (Wright-Giemsa, x400). Figure F. Tumor cells showing ganglionic differentiation (H&E, x400).

Figure D. Tumor cells showing scanty cytoplasm and homogenous chromatin (Wright-Giemsa, x 1000).

Figure G. Tumor cells immuno-positive for neuron-specic enolase (neuron-specic enolase, x400).

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Nasopharyngeal Carcinoma (NPC)

Classical Hodgkin Lymphoma (cHL)


Classical Hodgkin lymphoma is a monoclonal lymphoid neoplasm (in most cases derived from B cells) and is most commonly seen in the adolescent age group of pediatric patients. Patients often present with peripheral lymphadenopathy, fever, night sweats and weight loss. Mediastinal involvement is most frequently seen in the nodular sclerosis subtype. The BM involvement occurs more commonly in adult patients than in pediatric patients. Pathologically, cHL is characterized by the presence of large Reed-Sternberg (RS) cells or variants in a background of a mixed population of inammatory cells (Figure A). RS cells and variants are immunoreactive for CD15 (Figure B) and CD30 (Figure C). BM brosis is often present in the BM metastatic cases.

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NPC is a squamous cell carcinoma (keratinizing or nonkeratinizing) arising from the surface epithelium of the upper aerodigestive tract. It is more common in Asia and is rare in the United States. Pediatric NPC is most common in northern and central Africa. There is a strong association between NPC and the presence of EBV. The majority of tumors behave as locally aggressive lesions. Metastasis to the lymph node is more common, but distant metastasis including the BM is rare. The case presented here is BM metastasis of NPC from an adolescent male, occurring a few years after the initial diagnosis. Tumor cells are large and cohesive with oval nuclei, vesicular chromatin and prominent nucleoli (Figure A). Positive reaction of the cytokeratin stain conrms the epithelial nature of the tumor cells (Figure B).

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Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Metastatic Neoplasms Index
Figure A. BM biopsy showing tumor inltrate. The large tumor cells display oval nuclei, vesicular chromatin and distinct, large nucleoli (H&E, x400). Figure A. A multinucleated Reed Sternberg (RS) cell, a mononucleated Hodgkin cell and RS variants are present in a BM biopsy. The background shows mixed inammatory cells (H&E, x400).

Figure B. Cytokeratin positivity in tumor cells (cytokeratin, x400).

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Non-Hodgkin Lymphoma (NHL)

Atlas of Bone Marrow Neoplasms in Pediatric Patients


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Figure B. RS cells are positive for CD15 (CD15, x400).

NHL is a heterogeneous group of lymphoid neoplasms. Diffuse large B-cell lymphoma (DLBCL) is a subtype of NHL and is biologically aggressive. Although it is most commonly seen in adults, de novo DLBCL occasionally occurs in children. Morphologically, DLBCL is characterized by diffuse proliferation of large malignant B cells. The BM metastasis occurs more often in adult patients than in pediatric patients. In rare cases, large tumor cells (Figures A and B) show an anaplastic appearance with the morphologic features similar to RS cells (RS-like cells) (Figure C). Immunohistochemically, tumor cells of DLBCL are CD20-positive (Figure D).

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Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Metastatic Neoplasms Index
Figure C. RS cells are CD30-positive (CD30, x400). Figure A. Scattered large anaplastic tumor cells are identied in a BM aspirate smear and show abundant gray cytoplasm and prominent nucleoli in a patient with diffuse large B-cell lymphoma (DLBCL) (WrightGiemsa, x400).

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Langerhans Cell Histiocytosis (LCH)

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Figure B. The tumor cells are slightly smaller than megakaryocytes (Wright-Giemsa, x400).

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Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Metastatic Neoplasms Index
Figure C. BM biopsy showing diffuse inltrate by DLBCL. The tumor cells are large and pleomorphic. Some of them mimic RS cells (H&E, x400).

LCH is a clonal neoplastic proliferation of Langerhans-type cells. Synonyms include histiocytosis X, eosiniphilic granuloma (solitary lesion), Hand-Schller-Christian disease (multiple lesions), and Letterer-Siwe disease (disseminated or visceral involvement). LCH primarily occurs in childhood, with a predilection for male patients. The solitary form often involves bone (skull, femur, vertebra, pelvic bones and ribs) and adjacent soft tissue. The multifocal lesions are largely conned to bone and adjacent soft tissue. In multisystem disease, the skin, bone, liver, spleen and BM are common sites of involvement. The most important diagnostic clue is to identify Langerhans cells, which are characterized by a large size, abundant pink cytoplasm, and oval/coffee bean-shaped, indented, folded or grooved nuclei. Associated multinucleated cells and eosinophilia are common ndings. The BM involvement may be focal (Figure A) with collection of Langerhans cells (Figure B). Langerhans cells are typically and consistently CD1a-positive (Figure C). Unifocal lesions have a favorable outcome, but multisystem disease carries a poor prognosis.

Figure D. Tumor cells positive for CD20 (CD20, x400).

Figure A. BM biopsy showing focal inltrate by a cluster of pink cells (H&E, x200).

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Atlas of Bone Marrow Neoplasms in Pediatric Patients


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Figure B. The tumor cells are large with abundant pink cytoplasm, folded nuclei, vesicular chromatin and small nucleoli (H&E, x400).

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Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Metastatic Neoplasms Index

Figure C. Tumor cells immunoreactive for CD1a (CD1a, x400).

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Atlas of Bone Marrow Neoplasms in Pediatric Patients


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Index

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Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index Index

44

Atlas of Bone Marrow Neoplasms in Pediatric Patients


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Index
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Acute erythroid leukemia (M6). . . . . . . . . . . 13, 14, 25 Acute lymphoblastic leukemia (ALL). . . . . . 28, 30, 31 Acute megakaryoblastic leukemia (M7). . . . 13, 14, 19, 26 Acute monoblastic leukemia (M5a). . . . . . . 13, 14, 18 Acute monocytic leukemia (M5b) . . . . . . . . 13, 14, 18  , 13, 14, 15, Acute myeloid leukemia (AML) . . . . . . . . . . 5 16, 18-28 Acute myelomonocytic leukemia (M4). . . 13, 14, 16, 18, 24 Burkitt leukemia (BL). . . . . . . . . . . . . . . . . . 33, 34 Chronic myelogenous leukemia (CML. . . . . 5, 6, 8 Chronic phase . . . . . . . . . . . . . . . . . . . . . . 5, 6 Cytopenia. . . . . . . . . . . . . . . . . . . . . . . . . . 5, 9 Dyserythropoiesis. . . . . . . . . . . . . . . . . . . . 10, 25 Dysmyelopoiesis. . . . . . . . . . . . . . . . . . . . . 10, 11 Dysplasia. . . . . . . . . . . . . . . . . . . . . . . . . . 5, 9, 10, 30 Dysplastic platelets. . . . . . . . . . . . . . . . . . . 10, 26 Eosinophilia . . . . . . . . . . . . . . . . . . . . . . . . 5, 6, 13, 16, 23, 28, 30, 42 Epstein-Barr virus (EBV). . . . . . . . . . . . . . . 33, 40 Essential thrombocythemia (ET) . . . . . . . . . 7 Ewing sarcoma. . . . . . . . . . . . . . . . . . . . . . 21, 37 FAB classication. . . . . . . . . . . . . . . . . . . . 13, 15, 16, 18, 22-25 Faggot cells. . . . . . . . . . . . . . . . . . . . . . . . 16, 17 Hand-mirror variant. . . . . . . . . . . . . . . . . . . 28, 29 Hepatosplenomegaly. . . . . . . . . . . . . . . . . 5 Hodgkin lymphoma . . . . . . . . . . . . . . . . . . 40 Homer Wright rosette. . . . . . . . . . . . . . . . . 38, 39 Hypersegmented eosinophils. . . . . . . . . . . 10, 11 Hypersegmented neutrophils . . . . . . . . . . . 10 Hypogranulated neutrophilic cells. . . . . . . . 10 Juvenile myelomonocytic. . . . . . . . . . . . . . 8 leukemia (JMML)

Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index Index

Acute myelomonocytic leukemia. . . . . . . . . 13, 16 with eosinophilia (M4 eos) Acute promyelocytic leukemia . . . . . . . . . . 13, 14, 16 (APL) (M3) Acute promyelocytic leukemia,. . . . . . . . . . 13, 16 microgranular variant (M3 v) AML with maturation (M2). . . . . . . . . . . . . . 13, 14, 15, 23 AML with minimal differentiation (M0) . . . . . 13, 22 AML without maturation (M1). . . . . . . . . . . 13, 23 Auer rods. . . . . . . . . . . . . . . . . . . . . . . . . . 9,15, 16, 17, 22, 23 Basophilia. . . . . . . . . . . . . . . . . . . . . . . . . . 5, 6 BCR-ABL1. . . . . . . . . . . . . . . . . . . . . . . . . 5, 8, 28 Blastic phase. . . . . . . . . . . . . . . . . . . . . . . 5, 6 Blasts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5, 6, 8, 9-16, 10, 11, 15-31, 36

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Atlas of Bone Marrow Neoplasms in Pediatric Patients


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Index
Click on page numbers to jump to that page. Note: Bold numbers indicate photo pages.
L1 morphology. . . . . . . . . . . . . . . . . . . . . . 28 L2 morphology. . . . . . . . . . . . . . . . . . . . . . 28, 29 Langerhans cell histiocytosis (LCH). . . . . . . 42 Leukocyte alkaline phosphatase (LAP) . . . . 5, 6 M0 (AML with minimal differentiation) . . . . . 13, 22 M1 (AML without maturation). . . . . . . . . . . 13, 23 M2 (AML with maturation). . . . . . . . . . . . . . 13, 15, 23 M3 (acute promyelocytic. . . . . . . . . . . . . . . 13, 14, 16 leukemia) (APL) Nasopharyngeal carcinoma (NPC) . . . . . . . 40 Neuroblastoma. . . . . . . . . . . . . . . . . . . . . . 38 Neurobromatosis . . . . . . . . . . . . . . . . . . . 8 Non-Hodgkin lymphoma (NHL). . . . . . . . . . 41 Nonspecic esterase (NSE). . . . . . . . . . . . . 18, 21, 22, 24, 26 Oil Red O. . . . . . . . . . . . . . . . . . . . . . . . . . 33 Philadelphia chromosome. . . . . . . . . . . . . . 5 Pseudo-Pelger-Huet. . . . . . . . . . . . . . . . . . 10, 11, 20 Refractory anemia with excess. . . . . . . . . . 9, 10 blasts-1 (RAEB-1) Refractory anemia with excess. . . . . . . . . . 9, 10, 11 blasts-2 (RAEB-2) Refractory cytopenias with. . . . . . . . . . . . . 9, 10 unilineage dysplasia (RCUD) Reed-Sternberg (RS) cells . . . . . . . . . . . . . 40, 41, 42 Rhabdomyosarcoma . . . . . . . . . . . . . . . . . 36 Sideroblasts. . . . . . . . . . . . . . . . . . . . . . . . 9, 10 Sudan Black B (SBB). . . . . . . . . . . . . . . . . 16, 17 Therapy-related AML (t-AML) . . . . . . . . . . . 21 Thrombocytopenia. . . . . . . . . . . . . . . . . . . 5, 9, 28 Thrombocytosis. . . . . . . . . . . . . . . . . . . . . 5, 7, 26 Transient abnormal myelopoiesis . . . . . . . . 26 (TAM) Down syndrome World Health Organization (WHO). . . . . . . . 9 (Table 1-1), Classication 13, 14

Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index Index

M3 v (acute promyelocytic leukemia, . . . . . 13, 16 microgranular variant) M4 (acute myelomonocytic leukemia). . . . . 1  3, 14, 16, 18, 24 M4 eos (acute myelomonocytic . . . . . . . . . 13, 14, 16 leukemia with eosinophilia) M5a (acute monoblastic leukemia). . . . . . . 13, 14, 18 M5b (acute monocytic leukemia) . . . . . . . . 13, 14, 18 M6 (acute erythroid leukemia). . . . . . . . . . . 13, 14, 25  3, 14, 19, M7 (acute megakaryoblastic leukemia). . . . 1 26 Megakaryocytes. . . . . . . . . . . . . . . . . . . . . 5, 6-8, 9, 10, 19-21, 42 Micromegakaryocytes. . . . . . . . . . . . . . . . . 10 Myeloblasts . . . . . . . . . . . . . . . . . . . . . . . . 5, 15, 23-25 Myelodysplastic syndromes (MDS). . . . . . . 5, 9, 10, 20 Myeloperoxidase (MPO). . . . . . . . . . . . . . . 15, 19, 21-24, 26 Myeloproliferative neoplasms (MPN). . . . . . 5, 7, 20, 26

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Atlas of Bone Marrow Neoplasms in Pediatric Patients


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Table of Contents
Introduction Myeloproliferative Neoplasms and Myelodysplastic Syndromes Acute Myeloid Leukemia and Related Precursor Neoplasms Precursor/Acute Lymphoblastic Leukemia Burkitt Leukemia Metastatic Neoplasms Index

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