Figure 2-4. Composite photograph of blood smears from two different patients with CMML. This illustrates the heterogeneity of CMML, ranging from blood smears that show elevated WBC counts due to neutrophilia and monocytosis, to normal or even low WBC cell counts. In both patients illustrated, the number of monocytes exceeded 1,000 x 109/L.

Figure 2-4. Composite photograph of blood smears from two different patients with CMML. This illustrates the heterogeneity of CMML, ranging from blood smears that show elevated WBC counts due to neutrophilia and monocytosis, to normal or even low WBC cell counts. In both patients illustrated, the number of monocytes exceeded 1,000 x 109/L.

3.6 Diagnosis of CMML 3.6.1 Clinical Findings

Most patients are 60-70 years old when they are first diagnosed to have CMML, but young adults have been reported as well.24, 28, 49, 51, 52 In most series, men are affected 2-3 times more commonly than women. Symptoms most often include fever, infection, or hemorrhagic episodes in up to 30% of patients, and thrombotic complications in 10-15%.28, 49, 51, 52 Up to 10% of patients have clinical manifestations of an autoimmune disease, such as vasculitic syndromes, arthritis, or even classical connective tissue diseases.53 The incidence of any of these symptoms does not appear to be related to the magnitude of the WBC count.49, 53

Splenomegaly and hepatomegaly are found in 30-40% of patients, and are more common in those with leukocytosis. Lymphadenopathy is found in up to 15% of patients and skin involvement in 5-10%, and both are also more common in patients with high WBC counts.28, 49

3.6.2 Laboratory Findings Hematologic and morphologic findings in blood, marrow, and extramedullary tissue

The criteria for the diagnosis of CMML are listed in Table 2-2. A review of the WBC counts commonly reported in patients with CMML underscores the variable manifestations of the disease. The counts range from 2.0 to nearly 500 x 109/L, with median values usually between 10 - 20 x 109/L.2,24,

' Patients usually have modest thrombocytopenia, i.e., 80 to but values from 1 to have been reported for platelet counts.

Anemia is likewise usually mild, but hemoglobin values as low as 5 g/dL can occur.2, 24, 28, 49

Monocytosis is, by definition, present in all cases. When considered in absolute numbers, the range of monocytosis reported is also impressive, from 1 x 109/L to more than 200 x 109/L.24,28 (Figure 2-4) In the varying majority of patients, the monocyte count is below 2, 28 but the percentage of monocytes is almost always >10% of the WBCs.48 This is an important point to note because, in diseases with a markedly elevated WBC counts, only 1-2% monocytes in the leukocyte differential might result in an "absolute" monocytosis. The monocytes in the peripheral blood are generally mature in CMML, with unremarkable morphology, but they can exhibit abnormal granulation, unusual nuclear lobation, or finely dispersed nuclear chromatin.54 Blasts and promonocytes may be present, but if their sum totals 10% or more of the WBCs, a diagnosis of CMML-2 should be made; if more than 20%, the diagnosis is AML rather than CMML, according to WHO recommendations.4

Table 2-2. Diagnostic criteria for CMML_

1. Persistent peripheral blood monocytosis >1 x 109/L

2. No Philadelphia chromosome or BCR/ABL fusion gene

3. Less than 20% blasts in the blood or bone marrow

4. Dysplasia in one or more myeloid Lineages. If myelodysplasia is absent or minimal, the diagnosis of CMML may still be made if the other requirements are present and:

-an acquired, clonal cytogenetic abnormality is present in the marrow cells, or -the monocytosis has been persistent for at least 3 months and -all other causes of monocytosis have been excluded

Neutrophils may range from 0.3 to nearly 200 x 109/L, but are usually normal in number. Dysgranulopoiesis, including neutrophils with hypolobated or abnormally segmented nuclei or abnormal cytoplasmic granulation, is found in most cases.52, 49 It is a commonly held belief that patients with higher WBC counts have less dyspoiesis than do those with lower counts, but some authors have reported that there is no significant relationship between the severity of dysplasia and the leukocyte count.49 Immature neutrophils (promyelocytes, myelocytes) usually account for fewer than 10% of the WBCs. Mild basophilia is sometimes present, but basophils usually account for fewer than 2% of the WBCs. Eosinophilia is not uncommonly observed, and if persistently more than a diagnosis of CMML with eosinophilia should be made.4 Although a number of such cases are associated with translocations that involve PDGFRbeta on chromosome 5,12-14 in most cases of CMML with eosinophilia a specific genetic defect has not yet been identified (Figure 2-5).

Bone marrow specimens are hypercellular in more than 75% of cases, but

normocellular or even hypocellular specimens may be encountered. Granulocytes are often the most prominent bone marrow component, but an increase in erythroid precursors may be seen as well (Figure 2-6). Dysplastic features are usually present in one or both of these lineages.49, 52 Monocytic proliferation is invariably present, but can be difficult to appreciate in the biopsy or even on bone marrow smears. Cytochemical studies that aid in the identification of monocytes, such as alpha naphthyl acetate esterase or alpha naphthyl butyrate esterase, used alone or in a combined stain with napthol ASD chloroacetate esterase, are recommended when a diagnosis of CMML is considered (Figure 2-7). Micromegakaryocytes and/or megakaryocytes with abnormally lobated nuclei are observed in more than 80% of cases.24, 52 Substantial increases in marrow reticulin fibers are reported in nearly 30% of cases.55 Lymphoid nodules are not uncommonly observed in the biopsy sections.51

Peripheral Blood Eosinophilia
Figure 2-5. Patient with CMML associated with t(5; 12)(q33;p 13). This patient had significant eosinophilia in the peripheral blood as well as in the bone marrow specimen. Many of the

The number of blasts and promonocytes should be carefully enumerated in both the blood and bone marrow. If their combined percentage is 5-19% in the blood, or 10-19% in the bone marrow, a diagnosis of CMML-2 should be made (Table 2-3). If Auer rods are noted, they also provide sufficient reason to include the patient in the CMML-2 category even if the blasts + promonocytes in the blood and bone marrow are less than 20%. Because patients who have increased numbers of blasts are reported to do poorly, patients who have CMML-2 would be expected to have a worse prognosis and a more rapid transformation to AML than do those with fewer blasts.28, 52 (Figure 2-8) When the blast + promonocyte percentage is 20% or more, a diagnosis of overt acute leukemia should be made (see Table 2-3).

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