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attributes of these diseases are onset inmiddle age, develop-
ment of splenomegaly, and slow disease progression (Table 20).
In 95% of cases, CML shows a specific chromosome aberration
(Philadelphia chromosome with a specific BCR-ABL translocation) and
may make the transition into a blast crisis.
PV and ET often show similar traits (high thrombocyte count or high
Hb) and have a tendency to secondary bone marrow fibrosis. OMS is pri-
marily characterized by fibrosis in bone marrow and splenomegaly (see
p. 122).
Abnormalities of theWhite Cell Series
 
 
115
Table 20 Clinical characteristics and differential diagnostic criteria in chronic
myeloproliferative disease
CML
(seep. 116)
PV
(seep. 162)
OMS
(seep. 122)
ET
(seep. 170)
Spleno-
megaly
+ No + No
Changes in
the CBC for
granulopoie-
sis and/or
erythropoie-
sis
Leukocytosis
with left shift,
eosinophilia,
basophilia !!
Leukocytosis,
hematocrit
! !!
Tear-drop-
shaped eryth-
rocytes, left
shift in the
granulopoiesis,
normoblasts
No
Thrombo-
cytes
(!) (!)
Giant forms
" to (!) # 450000/
µl !
giant forms
Bonemarrow
cytology
Very hyper-
cellular,
basophilia,
megakaryo-
cytes, and
eosinophilia
!
Markedly
hypercellular,
erythropoie-
sis!
In most cases
dry tap
Mega-
karyo-
cytes
clearly
elevated
and
arranged
in nests
Bonemarrow
histology
Granulopoie-
sis!, mega-
karyocytes!
Number of
cells!
Advanced
fibrosis !
Mega-
karyo-
cytes
clearly
elevated,
arranged
in nests
Philadelphia
chromosome
Yes! No No No
Other chro-
mosomal
alterations
In the accel-
eration phase
and blast cri-
sis
del (20q), +8,
+9, +1q, and
others
-7, +8, +9,
+1q, and others
Very rare
Alkaline
Leukocyte-
phosphatase
(ALP)
"" ! !! Normal to! Normal to
!
Vitamin B12
# 900 pg/ml
! ! Normal Normal
Prevalence of Polynuclear (Segmented) Cells
 
 
116
Characteristics of CML
Age of onset: Any age. Peak inicidence about 50 years.
Clinical findings: Slowly developing fatigue, anemia; in some cases
palpable splenomegaly; no fever.
CBC: Leukocytosis and a left shift in the granulocyte series; possibly
Hb", thrombocytes" or!.
Advanced diagnostics: Bone marrow, cytogenetics, and molecular
genetics (Philadelphia chromosome and BCR-ABL rearrangement).
Differential diagnosis: Reactive leukocytoses (alkaline phosphatase,
trigger?); other myeloproliferative disorders (bone marrow, cyto-
genetics, alkaline phosphatase).
Course, therapy: Chronic progression. Acute transformation after
years. New, curative drugs are currently under development. Evaluate
the possibility of a bone marrow transplant (up to age approx. 60
years).
Steps in the Diagnosis of Chronic Myeloid Leukemia
Left-shift leukocytosis in conjunction with usually low-grade anemia,
thrombocytopenia or thrombocytosis (which often correlates with the
migration of smallmegakaryocyte nuclei into the blood stream), and clini-
cal splenomegaly is typical of CML. LDH and uric acid concentrations are
elevated as a result of the increased cell turnover.
The average “typical” cell composition is as follows (in a series analyzed
by Spiers): about 2% myeloblasts, 3% promyelocytes, 24% myelocytes, 8%
metamyelocytes, 57% band and segmented neutrophilic granulocytes, 3%
basophils, 2% eosinophils, 3% lymphocytes, and 1% monocytes.
In almost all cases of CML the hematopoietic cells display a marker
chromosome, an anomalously configured chromosome 22 (Philadelphia
chromosome). The translocation responsible for the Philadelphia chromo-
some corresponds to a special fusion gene (BCR-ABL) that can be deter-
mined by polymerase chain reaction (PCR) and fluorescence in situ hy-
bridization (FISH).
Abnormalities of theWhite Cell Series
 
 
117
b c
a
Left shift as far as myeloblasts, proliferation of eosinophils and
basophils suggest chronic myeloid leukemia (CML)
Fig. 39 CML. a Blood analysis in chronic myeloid leukemia (chronic phase): seg-
mented neutrophilic granulocytes (1), band granulocyte (2) (looks like a meta-
myelocyte after turning and folding of the nucleus), myelocyte with defective gra-
nulation (3), and promyelocyte (4). b and c Also chronic phase: myeloblast (1),
promyelocyte (2), myelocyte with defective granulation (3), immature eosinophil
(4), and basophil (5) (the granules are larger and darker, the nuclear chromatin
denser than in a promyelocyte).
 
 
118
Bone Marrow Analysis in CML. In many clinical situations, the findings
from the CBC, the BCR-ABL transformation and the enlarged spleen un-
equivocally point to a diagnosis of CML. Analysis of the bone marrow
should be performed because it provides a series of insights into the dis-
ease processes.
Normally, the cell density is considerably elevated and granulopoietic
cells predominate in the CBC. Cells in this series mature properly, apart
from a slight left shift in the chronic phase of CML. CML differs from reac-
tive leukocytoses because there are no signs of stress, such as toxic granula-
tion or dissociation in the nuclear maturation process.
Mature neutrophilsmay occasionally showpseudo-Pelger forms (p. 43)
and the eosinophilic and, especially, basophilic granulocyte counts are
often elevated. The proportion of cells from the red blood cell series
decreases. Histiocytes may store glucocerebrosides, as in Gaucher syn-
drome (pseudo-Gaucher cells), or lipids in the form of sea-blue precipi-
tates (sea-blue histiocytes after Romanowsky staining).
Megakaryocytes are usually increased and are often present as micro-
megakaryocytes, with one or two nuclei which are only slightly larger than
those of promyelocytes. Their cytoplasm typically shows clouds of
granules, as in the maturation of thrombocytes.
Abnormalities of theWhite Cell Series
 
 
119
a
b c
Bone marrow analysis is not obligatory in chronic myeloid leuke-
mia, but helps to distinguish between the various chronicmyelo-
proliferative disorders
Fig. 40 Bone marrow cytology in CML. a Bone marrow cytology in the chronic
phase: increased cell density due to increased, left-shifted granulopoiesis, e.g.,
promyelocyte nest (1) and megakaryopoiesis (2). Eosinophils are increased (ar-
rows), erythropoiesis reduced. b Often micromegakaryocytes are found in the
bone marrow cytology. c Pseudo-Gaucher cells in the bone marrow in CML.
 
 
120
Blast Crisis in Chronic Myeloid Leukemia
During the course of CML with or without therapy, regular monitoring of
the differential smear is particularly important, since over periods of vary-
ing duration the relative proportions of blasts and promyelocytes in-
creases noticeably. When the blast and promyelocyte fractions together
make up 30%, and at the same time Hb has decreased to less than 10g/dl
and the thrombocyte count is less than 100000/µl, an incipient acute blast
crisis must be assumed. this blast crisis is often accompanied or preceded
by a markedly increased basophil count. Further blast expansion—usually
largely recalcitrant to treatment—leads to a clinical picture not always
clearly distinguishable from acute leukemia. If in the chronic phase the
disease was “latent” and medical treatment was not sought, enlargement
of the spleen, slight eosinophilia and basophilia, and the occasional pres-
ence of normoblasts, together with the overwhelming myeloblast frac-
tion, are all signs indicating CML as the cause of the blast crisis.
As in AML, in two-thirds of cases cytological and immunological tests
are able to identify the blasts as myeloid. In the remaining one-third of
cases, the cells carry the same markers as cells in ALL. This is a sign of de-
differentiation. A final megakaryoblastic or a final erythremic crisis is ex-
tremely rare.
Bonemarrow cytology is particularly indicatedwhen clinical symptoms
such