The peripheral blood shows leukocytosis and anemia (Fig. 3.8). There may be anisocytosis, poikilocytosis, macrocytosis, or dimorphism. The platelet count is often reduced but may be normal or increased. In comparison with CML, anemia tends to be more severe and thrombocytopenia more common. There is an increase in neutrophils and their precursors. Eosinophils and basophils are often increased but less consistently than in CML. However, some patients have prominent eosinophilia. The monocyte count is relatively higher than in CML; it may be more than 1  ×  10⁹/l, but monocytes are not usually more than 10 % of leucocytes. Granulocyte precursors are also present. In comparison with chronic myelomonocytic leukemia, promyelocytes, myelocytes, and metamyelocytes are at least 10 % of leucocytes and sometimes 15 % or higher. These may include blast cells but, by definition, blast cells (plus promonocytes) are less than 20 % in the blood (and the bone marrow). Dysplastic features are present in neutrophils; hypolobation, abnormal nuclear shapes, increased chromatin clumping, and reduced granularity may be seen. Monocytes may also be dysplastic, showing hyperlobation or hypolobation, increased cytoplasmic basophilia, and increased granularity. The neutrophil alkaline phosphatase score is variable and is not diagnostically useful.

The bone marrow aspirate shows increased cellularity with an increase mainly in neutrophils and their precursors. Monocytes and their precursors may be increased and a nonspecific esterase stain can help in their detection. Megakaryocytes may be present in normal numbers or may be decreased or increased. There is dysplasia, which is often of trilineage. Dysgranulopoiesis is usual, but there may also be ring sideroblasts and other features of dyserythropoiesis, hypolobated megakaryocytes, and micromegakaryocytes.

Immunophenotyping is not known to be diagnostically useful.

Karyotypic abnormalities are common and can include ­trisomy 8, 20q–, i(17q) and abnormalities of chromosomes 12, 13, 14, 17, and 19. NRAS. KRAS, CBL, and TET2 may be mutated. Patients with BCR-ABL1 or rearrangement of PDGFRA, PDGFRB, or FGFR1 are specifically excluded from this diagnostic category.

Cellularity is increased as a result of an increase in neutrophils and precursors and a variable increase in monocyte precursors. There is dysplasia and the architecture is disorganized. Reticulin may be increased and collagen fibrosis and osteosclerosis occasionally occur. Immunohistochemistry is useful to highlight dysplastic megakaryocytes (CD42b and CD61) and increased monocytes (CD14 and CD68R).

The peripheral blood shows a normocytic or macrocytic anemia. Red cells are sometimes dimorphic. Leukocytosis is usual but not invariable. There is monocytosis with, by definition, a monocyte count of more than 1  ×  10⁹/l (Fig. 3.9). Neutrophils may be increased, normal, or decreased. Neutrophil precursors may be present but, in contrast to aCML, they are less than 10 % of the cells and usually less than 5 %. There may be small numbers of blast cells and promonocytes; by definition, they total less than 20 % of the cells, but they are usually much less. The number of blast cells (plus promonocytes) in the blood is of prognostic significance and the presence of 5 % or more leads to a classification as CMML-2. A minority of patients have prominent eosinophilia. The platelet count is often reduced but can be normal or high.

Dysplastic features may be present, but are usually less prominent than in aCML. Monocytes may be immature (cytoplasmic basophilia, reduced chromatin condensation, or reduced nuclear lobulation).

The bone marrow shows increased cellularity due to an increase of neutrophils and monocytes and their precursors but a nonspecific esterase stain may be necessary to demonstrate the increase in cells of monocyte lineage. Blasts plus promonocytes are less than 20 %. The number of blast cells (plus promonocytes) in the marrow is of prognostic significance and the presence of 10 % or more leads to the classification as CMML-2. Auer rods are rarely present but, when present, also lead to classification as CMML-2; a myeloperoxidase or Sudan black B stain is useful for their detection. Some patients have an increase of eosinophils and precursors. There is variable dysplasia, which may include ring sideroblasts.

Immunophenotyping may show monocytes to be phenotypically abnormal with reduced, increased, or aberrant expression of various antigens. An abnormal phenotype may be the result of immaturity of monocytes (e.g., reduced CD14 expression) or of aberrant antigen expression (e.g., expression of CD2).

Karyotypic abnormalities are detected in a quarter to a half of patients. They include trisomy 8, monosomy 7, del(7)(q) and rearrangements with a 12p breakpoint. Common molecular changes include mutations of RAS group genes, RUNX1, TET2, and CBL. By definition, BCR-ABL1 and rearrangement of PDGFRA and PDGFRB are absent.