atlas neoplams abbott

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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

Atlas of Bone Marrow Neoplasms in Pediatric Patients INterActIve PDF

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Atlas of Bone Marrow Neoplasms in Pediatric Patients

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visit http://www.abbottdiagnostics.com/. Xiayuan Liang, MDHematopathologist Associate Professor of Pathology University of Colorado Denver, Health Science Center The Childrens Hospital, Colorado

Bette Jamieson, MA, SH(ASCP)Education Coordinator Department of Pathology University of Colorado Denver, Health Science CenterThe Childrens Hospital, Colorado

Atlas of Bone Marrow Neoplasms in Pediatric Patients

http://www.abbottdiagnostics.com/http://www.abbottdiagnostics.com/

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Introduction

IntroductionAlthough 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.


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Click on a topic below to jump to a specific section. Or use the arrows at the bottom of the page to navigate within this chapter.

Chronic Myelogenous Leukemia (CML)

Essential Thrombocythemia (ET)

Juvenile Myelomonocytic Leukemia (JMML)

Myelodysplastic Syndromes (MDS)


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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 (

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

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).

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

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


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Essential Thrombocythemia (ET)

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 specific 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 myelofibrosis 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 myelofibrosis or leukemia.

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

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

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


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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 neurofibromatosis

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

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Myelodysplastic Syndromes (MDS)

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)

Classification characterized MDS into the following seven categories.

Table 1-1. The 2008 WHO Classification of Myelodysplastic Syndromes

MDS Categories PB Findings BM Findings

Refractory cytopenias with unilineage dysplasia (RCUD): Refractory anemia (RA) Refractory neutropenia (RN) Refractory thrombocytopenia (RT)

Unicytopenia or bicytopenia No or rare blasts (

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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

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visit http://www.abbottdiagnostics.com/.Figure D. Dysmyelopoiesis: Pseudo-Pelger-Huet neutrophil (Wright-Giemsa, x1000).

Figure E. Dysmyelopoiesis: Hypogranulated band (Wright-Giemsa, x1000).

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

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

Figure H. Refractory anemia with excess blasts (RAEB-2): PB smear showing circulating blasts (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

Acute Myeloid Leukemia and Related Precursor NeoplasmsClick on a topic below to jump to a specific section. Or use the arrows at the bottom of the page to navigate within this chapter.

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

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

M0 AML with minimal differentiation

M1 AML without maturation

M2 AML with maturation

M3 Acute promyelocytic leukemia

M3 v Acute promyelocytic leukemia, microgranular variant

M4 Acute myelomonocytic leukemia

M4 eos Acute myelomonocytic leukemia with eosinophilia

M5a Acute monoblastic leukemia

M5b Acute monocytic leukemia

M6 Acute erythroid leukemia

M7 Acute megakaryoblastic leukemia

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 classification of this group of diseases. In

1976, the French-American-British Cooperative

Group (FAB) proposed a classification system for

acute leukemia based on morphologic features of

blasts and cytochemical study results, with later

minor modifications (Table 2-1). Although the FAB

classification system provided the standardization

for defining and diagnosing acute leukemias,

its correlation with prognosis is limited. With

an increased recognition of the significance of

cytogenetic changes, the presence of multilineage

dysplasia and previous therapy in AML, the WHO

proposed a new classification of AML (Table 2-2),

which incorporated these features with some

morphologic features of the FAB AML classification.

Here, we illustrate cases based on the 2008

WHO classification of AML, in combination with

morphology described by the FAB classification.



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table 2-2. The 2008 WHO Classification 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

AML, not otherwise specified

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 myelofibrosis

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

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

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.

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 configuration 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.

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

Figure B. Eosinophilia present in a BM biopsy (H&E, x1000).

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


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Figure D. Leukemic cells positive for Sudan Black B (SBB) (SBB, x1000).

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

Figure F. Promyelocytes in a BM biopsy, immunoreactive for MPO (MPO, x1000).

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

Figure C. Leukemic cells MPO-positive by cytochemical stain (MPO, x1000).


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

AML With 11q23 (MLL) Abnormalities

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 infiltrate. 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 fine azurophilic

granules are sometimes present. Monoblasts and

promonocytes are strongly positive by nonspecific

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 nonspecific esterase (NSE) in blasts (NSE, 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

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

Figure F. Marked BM fibrosis present (reticulin stain, x400).

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

AML With Myelodysplasia-Related Changes

This disease category is defined 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 specific 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 myelodysplasia-related changes generally have a poor prognosis.

Figure A. Dysplastic blasts showing lobulated nuclei (Wright-Giemsa, x1000).

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


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Therapy-Related AML (t-AML)

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 identified 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).

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

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


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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 flow cytometric

immunophenotyping.

Figure B. Blasts cytochemically reactive for MPO (MPO, x1000).

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).


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AML Without Maturation, NOS (FAB M1)

This type of AML is characterized by a predominance

of myeloblasts and 10% promyelocytes

or other mature granulocytes in the BM (Figure A). In

rare cases, eosinophilia with dysplastic changes is

present (Figure A).

Figure A. The BM components are predominantly myeloblasts (Wright-Giemsa, x1000).

Figure B. MPO reaction showing strong peroxidase reactivity in 40% of the blasts (MPO, 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 MPO-

positive (Figure B), and monoblasts, including

promonocytes, are NSE-positive (Figure C).

Figure A. BM aspirate smear showing myeloblasts, monoblasts and promonocytes (Wright-Giemsa, x1000).

Figure B. Positive MPO reaction in blasts (MPO, x1000).

Figure C. Positive NSE reaction in blasts (NSE, x1000).


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Acute Erythroid Leukemia, NOS (FAB M6)

This AML category is characterized by a combined

proliferation of myeloblasts and red-cell precursors.

There are two subtypes: (1) Erythroleukemia

(erythroid/myeloid) is defined 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 defined as a

neoplastic proliferation of immature cells committed

exclusively to the erythroid lineage (80% of BM

cells) with no evidence of a significant 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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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 findings 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).

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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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-five 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 difficulty 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, fine chromatin and prominent nucleoli (Wright-Giemsa, x1000).

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

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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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).

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

Figure L. Pleomorphic variant: Some blasts show cytomegaly, florid nuclei or multinucleation (Wright-Giemsa, 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).

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

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 immunodeficiency-associated. Pathologically,

the typical features of BL are the proliferation of

monotonous, intermediately sized lymphoid cells,

which show round nuclei with finely 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 infiltrate

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

immunodeficiency 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 infiltrate with starry-sky pattern (H&E, x400).

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Figure D. Atypical BL: The tumor cells are pleomorphic and varied in size. Nuclei show convolution and marked irregularity (Wright-Giemsa, x1000).

Figure E. Atypical BL: Blue-gray cytoplasm with rare vacuoles in some tumor cells (Wright-Giemsa, x1000).


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Metastatic NeoplasmsClick on a topic below to jump to a specific section. Or use the arrows at the bottom of the page to navigate within this chapter.

Alveolar Rhabdomyosarcoma

Ewing Sarcoma

Neuroblastoma

Nasopharyngeal Carcinoma (NPC)

Classical Hodgkin Lymphoma (cHL)

Non-Hodgkin Lymphoma (NHL)

Langerhans Cell Histiocytosis (LCH)


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Metastatic NeoplasmsNon-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 flow

cytometric analysis and immunohistochemical

stain, are complementary to one another and are

necessary and important for the assessment of

metastatic tumors in the BM.

Alveolar Rhabdomyosarcoma

Rhabdomyosarcoma is the most common

soft-tissue sarcoma of childhood, with skeletal-

muscle 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 A. Myoblasts are small, lymphoblast-like with scanty cytoplasm, and have central or slightly eccentric nuclei (Wright-Giemsa, x400).

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 infiltrate. The tumor cells show pink cytoplasm (H&E, x400).


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Ewing Sarcoma

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 infiltrate. 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 confirms the diagnosis.

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).

Figure E. A cluster of tumor cells (center) is identified in a BM biopsy (H&E, x400).

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

Figure D. BM biopsy showing tumor necrosis (H&E, x200).


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Neuroblastoma

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 magnification, 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 infiltrate

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-specific enolase

(Figure G).

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

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

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


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

Figure C. Neuropils (gray material) noted adjacent to the tumor cells (Wright-Giemsa, x400).

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

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

Figure F. Tumor cells showing ganglionic differentiation (H&E, x400).

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


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Nasopharyngeal Carcinoma (NPC)

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 confirms the epithelial nature of the tumor cells (Figure B).

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 inflammatory cells (Figure A). RS cells and variants are immunoreactive for CD15 (Figure B) and CD30 (Figure C). BM fibrosis is often present in the BM metastatic cases.

Figure A. BM biopsy showing tumor infiltrate. 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 inflammatory cells (H&E, x400).

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


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Non-Hodgkin Lymphoma (NHL)

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).

Figure C. RS cells are CD30-positive (CD30, x400).

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

Figure A. Scattered large anaplastic tumor cells are identified in a BM aspirate smear and show abundant gray cytoplasm and prominent nucleoli in a patient with diffuse large B-cell lymphoma (DLBCL) (Wright-Giemsa, x400).


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Langerhans Cell Histiocytosis (LCH)

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 confined

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

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

Figure C. BM biopsy showing diffuse infiltrate by DLBCL. The tumor cells are large and pleomorphic. Some of them mimic RS cells (H&E, x400).

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


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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).

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


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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

Acute myeloid leukemia (AML) . . . . . . . . . 5, 13, 14, 15, 16, 18-28

Acute myelomonocytic leukemia (M4) . . . 13, 14, 16, 18, 24

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

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 classification . . . . . . . . . . . . . . . . . . . 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)

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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)

M3 v (acute promyelocytic leukemia, . . . . 13, 16 microgranular variant)

M4 (acute myelomonocytic leukemia) . . . . 13, 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

M7 (acute megakaryoblastic leukemia) . . . 13, 14, 19, 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

Nasopharyngeal carcinoma (NPC) . . . . . . 40

Neuroblastoma . . . . . . . . . . . . . . . . . . . . . 38

Neurofibromatosis . . . . . . . . . . . . . . . . . . 8

Non-Hodgkin lymphoma (NHL) . . . . . . . . . 41

Nonspecific 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), Classification 13, 14

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