Diagnostic Pediatric Hematopathology
Introduction
Pediatric hematopathology is a special and highly challenging field. Despite its importance, however, and despite the sea
of publications that exist in the field of hematopathology, few
texts focus on the diagnosis of benign and malignant hematologic disorders found in children. As a result, even though
the uniqueness of developmental factors and pathology in children is well recognized and appreciated, the specifics are not
widely known or understood, which poses great difficulties for
the diagnosis of hematologic diseases in children.
Diagnostic Pediatric Hematopathology presents an accurate
and up-to-date examination of such diseases in children –
both non-neoplastic and neoplastic. One goal is to provide
knowledge about how the hematopoietic and lymphoid systems
develop and how this development affects what can be considered normal and abnormal findings in children at various ages.
A second key goal is to focus on the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of
most pediatric-specific hematologic diseases so as to provide
a resource that can be helpful in reaching a proper diagnosis
when evaluating pediatric peripheral blood, bone marrow, and
lymph nodes. The text addresses these goals through a team
of experienced pediatric hematopathologists and clinical scientists drawn from major academic children’s hospitals in the
United States, Canada, and Europe, and this text is a result of
our collaborative efforts.
Several major differences between pediatric and adult
hematopathology are especially important and create the need
for a separate text such as this book.
First, the hematopoietic system is not fully developed at
birth. Instead, it continues to evolve during childhood to reach
its maturity during the teenage years. As a result, both the
peripheral blood and the bone marrow findings will be related
to the developmental stage, such that what should be considered normal will depend upon the age of the child. These
differences – both between children of various ages and between
children and adults – can be substantial and have great clini1 Swerdlow SH, Campo E, Harris NL, et al. (eds.). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (4th edn.).
Lyon: IARC Press; 2008.
cal relevance. They are explored in the chapters on hematologic
values in the healthy fetus, neonate, and child and normal bone
marrow.
Age, along with underlying genetic abnormalities, has been
recognized as integral to the diagnosis of certain hematologic
malignancies. The latest WHO Classification of Tumours of
Haematopoietic and Lymphoid Tissues,
1 for example, includes
several disorders, such as juvenile myelomonocytic leukemia,
childhood myelodysplastic syndrome, and myeloid proliferations related to Down syndrome, as conditions with unique
morphologic features, underlying genetic mechanisms, and different treatment outcomes in children as compared to the adult
counterparts. It also identifies disorders that are exclusively seen
in children, such as systemic EBV+ T-cell lymphoproliferative
diseases of childhood. The unique features of these hematologic
malignancies are explored in the appropriate chapters.
Second, there are differences in the type and prevalence
of hematologic diseases in children as compared to adults.
For instance, acute leukemias, particularly lymphoblastic
leukemias, are frequent in children, and lymphomas are rare.
This is in contrast to adults, where mature B-cell lymphomas/
leukemias are much more frequent, and acute leukemias are relatively rare. The pediatric leukemias have specific morphologic
features and underlying genetic mechanisms that are explored
in the chapters on precursor B- and T-lymphoblastic leukemias,
acute myeloid leukemias, chromosomal abnormalities, and
expression profiling in pediatric hematologic malignancies.
Third, the treatment for pediatric leukemia differs and the
outcomes themselves are far superior than is the case for adults.
The better outcomes are due in part to the unique pathogenetic
mechanisms causing these diseases in children, but they are also
due to the unusual speed with which advances have taken place
in the treatment of the diseases in children. Those advances
are based upon standardized protocols that have been developed for the treatment of children through randomized clinical trials. The trials have been conducted through the pediatric
Hematologic values in the healthy fetus,
neonate, and child
The hematopoietic system is not fully developed at birth, and
the normal hematologic values of newborns and infants differ as compared to older children and adults
. The differences
are a manifestation of the unique characteristics
Of the embryonal and fetal development of the hematopoietic system that
continues to evolve after birth
. Furthermore, preanalytical and
analytical factors unique for neonates and young children also
contribute to these differences. This chapter will explore these
factors and discuss how they define the normal hematologic
values for different age groups
Developmental hematopoiesis:
a general view
The hematopoietic development, unlike any other organ system, occurs in successive anatomic sites where the hematopoietic stem cells (HSCs) are generated, maintained, and differentiate into various cell types [1]
. The hematopoiesis begins in
The yolk sac with the generation of angioblastic foci or “blood
islands” that contain primitive erythroblasts
. It then progresses
further in several waves involving multiple anatomic sites: the
aorta–gonadal–mesonephros (AGM) region, fetal liver, and
bone marrow (BM) [2, 3]. Depending on the site of major
hematopoietic activity, the hematopoiesis has been divided into
three stages: the mesenchymal, hepatic, and myeloid stages
with the yolk sac, liver, and bone marrow as major hematopoietic sites where hematopoietic cells with characteristic features
are generated [4] (Fig. 1.1)
. There is a considerable temporal
overlap between different stages. At birth and thereafter, the
hematopoiesis is restricted to the bone marrow and continues
to evolve in order to adapt to the new oxygen-rich environment
and the needs of the growing organism.
It is currently accepted that the HSCs develop from hemangioblasts, which are mesodermal multipotent progenitors that
give rise to hematopoietic as well as endothelial and vascular
smooth muscle cells (Fig. 1.2A) [2, 5]. The first blood islands
consisting of primitive erythroblasts surrounded by endothelial
cells are formed in the yolk sac between days 16 and 19 of gestation [6]. During this stage, the hematopoiesis generates mostly
primitive and only a few definitive erythroblasts, as well as a
few megakaryocytes at the sixth and seventh weeks of gestation. The primitive erythroblasts differ from the definitive erythroblasts in several aspects (Table 1.1). They are macrocytic
[mean corpuscular volume (MCV) of 250 fL/cell]. They differentiate within the vascular network and remain nucleated for
their entire lifespan. These cells have an increased sensitivity
to erythropoietin (EPO) and a shorter lifespan as compared
to the later fetal, definitive erythroblasts and adult counterparts.The hallmark of the primitive erythroid cells is the expression of embryonic hemoglobins such as Gower 1 ( 2ε2), Gower
2 (2ε2), and Portland ( 22). The yolk sac hematopoiesis
declines after the eighth week of gestation.
The ventral aspect of the aorta is another site of erythropoietic activity in the human embryo from 20 to 40 days of gestation [6]. This region corresponds to the aorta, genital ridge
.
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