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Acute leukemias may also derive from monoblasts or erythroblasts

d

Fig. 33 e Same as c Only the myelocyte in the center stains peroxidase-positive (brown tint); the monoblasts are peroxidase-negative. f In acute erythrocytic leukemia (M6) erythroblasts and myeloblasts are usually found in the blood. This image of bone marrow cytology in M6 shows increased, dysplastic erythropoiesis (e.g., 1) in addition to myeloblasts (2).

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102 Abnormalities of the White Cell Series

Acute Megakaryoblastic Leukemia (FAB Classification Type M7)

This form of leukemia is very rare in adults and occurs more often in children. It can also occur as “acute myelofibrosis,” with rapid onset of tricytopenia and usually small-scale immigration into the blood of dedifferentiated medium-sized blasts without granules. Bone marrow harvesting is difficult because the bone marrow is very fibrous. Only bone marrow histology and marker analysis (fluorescence-activated cell sorting, FACS) can confirm the suspected diagnosis.

The differential diagnosis, especially if the spleen is very enlarged, should include the megakaryoblastic transformation of CML or osteomyelosclerosis (see pp. 112ff.), in which blast morphology is very similar.

AML with Dysplasia

The WHO classification (p. 94) gives a special place to AML with dysplasia in two to three cell series, either as primary syndrome or following a myelodysplastic syndrome (see pp. 106) or a myeloproliferative disease (see pp. 114ff.).

Criteria for dysgranulopoiesis: &50% of all segmented neutrophils have no granules or very few granules, or show the Pelger anomaly, or are peroxidase-negative.

Criteria for dyserythropoiesis: &50% of the red cell precursor cells display one of the following anomalies: karyorrhexis, megaloblastoid traits, more than one nucleus, nuclear fragmentation.

Criteria for dysmegakaryopoiesis: &50% of at least six megakaryocytes show one of the following anomalies: micromegakaryocytes, more than one separate nucleus, large mononuclear cells.

Hypoplastic AML

Sometimes (mostly in the mild or “aleukemic” leukemias of the FAB or WHO classifications), the bone marrow is largely empty and shows only a few blasts, which usually occur in clusters. In such a case, a very detailed analysis is essential for a differential diagnosis versus aplastic anemia (see pp. 148f.).

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New WHO classification: AML with dysplasia and hypoplastic AML

a b

Fig. 34 AML with dysplasia and hypoplastic AML. a AML with dysplasia: megaloblastoid (dysplastic) erythropoiesis (1) and dysplastic granulopoiesis with PelgerHuët forms (2) and absence of granulation in a myelocyte (3). Myeloblast (4). b Multiple separated nuclei in a megakaryocyte (1) in AML with dysplasia. Dyserythropoiesis with karyorrhexis (2). c and d Hypoplastic AML. c Cell numbers below normal for age in the bone marrow. d Magnification of the area indicated in c, showing predominance of undifferentiated blasts (e.g., 1).

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104 Abnormalities of the White Cell Series

Acute Lymphoblastic Leukemia (ALL)

ALL are the leukemias in which the cells do not morphologically resemble myeloblasts, promyelocytes, or monocytes, nor do they show the corresponding cytochemical pattern. Common attributes are a usually slightly smaller cell nucleus and denser chromatin structure, the grainy consistency of which can be made out only with optimal smear technique (i.e., very light). The classification as ALL is based on the (often remote) similarities of the cells to lymphocytes or lymphoblasts from lymph nodes, and on their immunological cell marker behavior. Insufficiently close morphological analysis can also result in possible confusion with chronic lymphocytic leukemia (CLL), but cell surface marker analysis (see below) will correct this mistake. Advanced diagnostics start with peroxidase and esterase tests on fresh smears, performed in a hematology laboratory, together with (as a minimum) immunological marker studies carried out on fresh heparinized blood samples in a specialist laboratory. The detailed differentiation provided by this cell surface marker analysis has prognostic implications and some therapeutic relevance especially for the distinction to bilineage leukemia and AML (Table 16).

Table 16 Immunological classification of acute bilineage leukemias (adapted from Bene MC et al. (1995) European Group for the Immunological Characterization of Leukemias (EGIL) 9: 1783–1786)

*CD79a may also be expressed in some cases of precursor T-lymphoblastic leukemia/lymphoma.

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The cells in acute lymphocytic leukemia vary, and the subtypes can be reliably identified only by immunological methods

a b

c d

Fig. 35 Acute lymphocytic leukemias. a Screening view: blasts (1) and lymphocytes (2) in ALL. Further classification of the blasts requires immunological methods (common ALL). b Same case as a . The blasts show a dense, irregular nuclear structure and narrow cytoplasm (cf. mononucleosis, p. 69). Lymphocyte (2). c ALL blasts with indentations must be distinguished from small-cell non-Hodgkin lymphoma (e.g., mantle cell lymphoma, p. 77) by cell surface marker analysis. d Bone marrow: large, vacuolated blasts, typical of B-cell ALL. The image shows residual dysplastic erythropoietic cells (arrow).

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106 Abnormalities of the White Cell Series

Myelodysplasia (MDS)

Clinical practice has long been familiar with the scenario in which, after years of bone marrow insufficiency with a more or less pronounced deficit in all three cell series (tricytopenia), patients pass into a phase of insidiously increasing blast counts and from there into frank leukosis —although the evolution may come to a halt at any of these stages. The transitions between the forms of myelodysplastic syndromes are very fluid, and they have the following features in common:

Anemia, bicytopenia, or tricytopenia without known cause.

Dyserythropoiesis with sometimes pronounced erythrocyte anisocytosis; in the bone marrow often megaloblastoid cells and/or ring sideroblasts.

Dysgranulopoiesis with pseudo-Pelger-Huët nuclear anomaly (hyposegmentation) and hypogranulation (often no peroxidase reactivity) of segmented and band granulocytes in blood and bone marrow.

Dysmegakaryopoiesis with micromegakaryocytes.

The FAB classification is the best-known scheme so far for organizing the different forms of myelodysplasia (Table 17).

Table 17 Forms of myelodysplasia

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In unexplained anemia and/or leukocytopenia and/or thrombocytopenia, blood cell abnormalities may indicate myelodysplasia

c d

e

Fig. 36 Myelodysplasia and CMML. a–d Different degrees of abnormal maturation (pseudo-Pelger type); the nuclear density can reach that of erythroblasts (d). The cytoplasmic hypogranulation is also observed in normal segmented granulocytes. These abnormalities are seen in myelodysplasia or after chemotherapy, among other conditions. e Blood analysis in CMML: monocytes (1), promyelocyte (2), and pseudo-Pelger cell (3). Thrombocytopenia.

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*In the WHO classification, the category RAEBt would belong to the category of acute myeloid leukemia.

The new WHO classification of myelodysplastic syndromes defines the differences in cell morphology even more precisely than the FAB classification (Table 18).

For the criteria of dysplasia, see page 106.

The “5qsyndrome” is highlighted as a specific type of myelodysplasia in the WHO classification; in the FAB classification it would be a subtype of RA and RAS. A macrocytic anemia, the 5qsyndrome manifests with normal or increased thrombocyte counts while the bone marrow contains megakaryocytes with hyposegmented round nuclei (Fig. 37b).

Naturally, bone marrow analysis is of particular importance in the myelodysplasias.

Table 18 WHO classification of myelodysplastic syndromes

* RA = refractory anemia; RARS = refractory anemia with ring sideroblasts; RCMD = refractory cytopenia with more than one dysplastic cell line; RCMD-RC = refractory cytopenia with more than one dysplastic lineage and ring sideroblasts; RAEB = refractory anemia with elevated blast count; CMML = chronic myelomonocytic leukemia, persistent monocytosis (more than 1 #109/l) in peripheral blood; MDS-U = MDS, unclassifiable. ** Dysplasia in granulopoiesis = Dys G, in erythropoiesis = DysE, in megakaryopoiesis = DysM, multilineage dysplasia = two cell lines affected; trilineage dysplasia (TLD) = all three lineage show dysplasia.

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The classification of myelodysplasias requires bone marrow analysis

a b

Fig. 37 Bone marrow analysis in myelodysplasia. a Dysmegakaryopoiesis in myelodysplastic syndrome (MDS). Relatively small disk-forming megakaryocytes

(1) and multiple singular nuclei (2) are often seen. b Mononuclear megakaryocytes (frequent in 5q-syndrome). c Dyserythropoiesis. Particularly striking is the coarse nuclear structure with very light gaps in the chromatin (arrow 1). Some are megaloblast-like but coarser (arrow 2). d Iron staining of the bone marrow (Prussian blue) in myelodysplasia of the RARS type: dense iron granules forming a partial ring around the nuclei (ring sideroblasts).

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110 Abnormalities of the White Cell Series

Prevalence of Polynuclear

(Segmented) Cells (Table 19)

Neutrophilia without Left Shift

For clarity, conditions in which mononuclear cells (lymphocytes, monocytes) predominate were in the previous section kept distinct from hematological conditions in which cells with segmented nuclei and, in some cases, their precursors predominate. Leukocytosis with a predominance of segmented neutrophilic granulocytes without the less mature forms is called granulocytosis or neutrophilia.

Table 19 Diagnostic work-up for anomalies in the white cell series with polynucleated (segmented) cells predominating

Diagnostic steps proceed from left to right. The next step is usually unnecessary; #the next step is obligatory.

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