C h a p t e r 1 1
Disorders of White Blood Cells and Lymphoid Tissues
251
a proto-oncogene that is the cellular homolog of
the Abelson murine leukemic virus. The
ABL
gene is
received at a specific site on 22q called the
breakpoint
cluster region
(BCR). The resulting
BCR–ABL
fusion
gene codes for a novel protein that allows affected cells
to bypass the regulated signals controlling normal cell
growth and differentiation, and instead undergo malig-
nant transformation to become leukemic cells. The
Philadelphia chromosome translocation is found in
more than 90% of persons with chronic myelogenous
leukemia and in some persons with acute leukemia.
7
The recent development of tyrosine kinase inhibitors
(e.g., imatinib mesylate) has contributed to the targeted
approach for treatment of leukemias that display the
Philadelphia chromosome translocation.
19
Acute Leukemias
The acute leukemias are cancers of the hematopoietic
progenitor cells. They usually have a sudden and stormy
onset with signs and symptoms related to depressed
bone marrow function.
19–29
There are two main forms
of acute leukemia: acute lymphocytic (lymphoblas-
tic) leukemia (ALL) and acute myeloid (myelogenous)
leukemia (AML). Acute lymphocytic (lymphoblastic)
leukemia is the most common form of leukemia in chil-
dren. It accounts for three of four cases of childhood
cancer, with AML accounting for most of the remain-
ing cases.
22,23
Acute myeloid (myelogenous) leukemia is
mainly a disease of older adults, but it is also seen in
children and young adults.
24,29
Acute lymphocytic (lymphoblastic) leukemia encom-
passes a group of neoplasms composed of precursor B
(pre-B) or T (pre-T) lymphocytes referred to as
lympho-
blasts
(see Fig. 11-3). Most cases (about 85%) of ALL
are of pre–B-cell origin.
4,7
Approximately 90% of per-
sons with ALL have numeric and structural changes in
the chromosomes of their leukemic cells. They include
hyperploidy (i.e., more than 50 chromosomes), poly-
ploidy (i.e., three or more sets of chromosomes), and
chromosomal translocations and deletions. Many of
these chromosomal aberrations serve to dysregulate
the expression and function of transcription factors
required for normal hematopoietic cell development.
The AMLs are a diverse group of neoplasms affect-
ing myeloid precursor cells in the bone marrow.
4,7
Most
are associated with acquired genetic alterations that
inhibit terminal myeloid differentiation. As a result,
normal marrow elements are replaced by an accumu-
lation of relatively undifferentiated blast cells. The
result is suppression of the remaining progenitor cells
and subsequent anemia, neutropenia, and thrombocy-
topenia. Specific chromosomal abnormalities, includ-
ing translocations, are seen in a large number of AMLs.
One subtype of AML, acute promyelocytic leukemia,
which represents 10% of adult cases of AML, is associ-
ated with a (15;17) chromosomal translocation.
26
This
translocation results in the fusion of the retinoic acid
receptor
α
(RARA) gene on chromosome 17 with the
promyelocytic leukemia (PML) gene on chromosome
15. This change in the retinoic acid receptor produces
a block in myeloid differentiation at the promyelocytic
stage (see Fig. 11-3), probably by inhibiting the action
of normal RARA receptors. This block can be overcome
by pharmacologic preparations of retinoic acid (a vita-
min A analog), causing the neoplastic promyelocytes to
differentiate into neutrophils and die.
Manifestations.
Although ALL and AML are distinct
disorders, they typically present with similar clinical
features. Both are characterized by an abrupt onset of
symptoms, including fatigue resulting from anemia;
low-grade fever, night sweats, and weight loss due to the
rapid proliferation and hypermetabolism of the leuke-
mic cells; bleeding due to a decreased platelet count; and
bone pain and tenderness due to bone marrow expan-
sion.
20–26
Infection results from neutropenia, with the
risk of infection rising steeply as the neutrophil count
falls below 500 cells/
μ
L. Generalized lymphadenopathy,
splenomegaly, and hepatomegaly caused by infiltration
of leukemic cells occur in all acute leukemias but are
more common in ALL.
In addition to the common manifestations of acute
leukemia (i.e., fever, fatigue, weight loss, easy bruising),
infiltration of malignant cells in the skin, gums, and
other soft tissues is particularly common in the mono-
cytic form of AML. The leukemic cells may also cross
the blood–brain barrier and establish sanctuary in the
CNS. Central nervous system involvement is more com-
mon in ALL than AML, and is more common in children
than adults. Signs and symptoms of CNS involvement
include cranial nerve palsies, headache, nausea, vomit-
ing, papilledema, and occasionally seizures and coma.
Leukostasis
is a condition inwhich the circulating blast
count is markedly elevated (usually 100,000 cells/
μ
L).
The high number of circulating leukemic blasts increases
blood viscosity and predisposes to the development of
leukoblastic emboli with obstruction of small blood ves-
sels in the pulmonary and cerebral circulations. Occlusion
of the pulmonary vessels leads to vessel rupture and infil-
tration of lung tissue, resulting in sudden shortness of
breath and progressive dyspnea. Cerebral leukostasis
leads to diffuse headache and lethargy, which can prog-
ress to confusion and coma. Once identified, leukostasis
requires immediate and effective treatment to lower the
blast count rapidly. Initial treatment uses apheresis to
remove excess blast cells, followed by chemotherapy to
stop leukemic cell production in the bone marrow.
22
Hyperuricemia
occurs as the result of increased pro-
liferation or increased breakdown of purine nucleotides
(i.e., one of the components of nucleic acids) secondary
to leukemic cell death that results from chemotherapy. It
may increase before and during treatment. Prophylactic
therapy with allopurinol, a drug that inhibits uric acid
synthesis, is routinely administered to prevent renal
complications secondary to uric acid crystallization in
the urine filtrate.
Diagnosis and Treatment.
A definitive diagnosis of
acute leukemia is based on blood and bone marrow
studies; it requires the demonstration of leukemic cells
in the peripheral blood, bone marrow, or extramedullary
