Hematologic laboratory findings demonstrate peripheral blood cytopenias in one or more cell lines associated with dysmorphic features. These reflect dysmatura-tion of one or one or more of the cell lines and are detailed in Table 39.1. These maturational defects may be identified not only in the lines with diminished production but may also be seen in the lines where bone marrow production is still conserved. The bone marrow is most often hypercellular and features morphologic abnormalities involving one, two, or all of the cell lineages (Table 39.1 and Figures 39.1 and 39.2). The dys-morphic features are critical to establish the diagnosis, and both the French-American-British (FAB) and World Health Organization (WHO) classification systems are based primarily on these findings (see Chapter 38). A diagnosis without maturational abnormalities in at least one cell line would be difficult to support.

Histologic examination of bone marrow trephine biopsies by Tricot and colleagues have pointed to abnormalities of the microenvironment.14 They noted the presence of clusters of immature precursor cells in the central intertrabecular region of the marrow, rather than along the endosteal surfaces. They cited this as evidence of abnormal localization of immature precursors (ALIP).14'15 ALIP was detected even before bone marrow smears revealed an excess of blasts. In a series of 40 patients, the presence of ALIP correlated significantly with shortened survival and was associated with an increased risk of transformation to AML. These findings were independent of the FAB subtype and were detected even in patients with refractory

Table 39.1

Morphologic and functional cellular abnormalities

Erythrocytes Morphology Anisocytosis Poilkilocytosis Oval macrocytes Microcytes Basophilic stippling Howell-Jolly bodies Circulating nucleated red cells Ringed sideroblasts Increased stainable iron Megaloblastoid maturation* Multinucleated precursors* Nuclear fragmentation* Nuclear budding* Karryohexis*

Defective hemoglobinization* Leukocytes Morphology Pseudo Pelger-Huet Cells Monocytosis

Defective granule formation (hypogranulation) Megaloblastoid maturation Auer rods

Abnormal chromatin clumping Abnormal nuclear bridging Increased myeloblasts Megakaryocytes Morphology Circulating megakaryocyte fragments Giant platelets Micromegakaryocytes* Hypolobulated nuclei* Hyperlobulated nuclei* Large mononulcear forms* Erythrocytes Function

Decrease or loss of blood group antigens Increased fetal hemoglobin Aberrant globin chain synthesis Disordered ferrokinetics

Enzymes Increased hexokinase decreased pyruvate kinase decreased 2,3 diphophoglycerate mutase decreased phosphofructokinase increased adenosine deaminase increased pyruvate kinase Leukocytes Function

Increased leukocyte alkaline phosphatase Decreased myeloperoxidase Increased muramidase (CMML) Loss of granule membrane glycoproteins Inappropriate surface antigens Decreased adhesion Defective chemotaxis Deficient phagocytosis Impaired bacteriocidal activity Megakaryocytes Function Defective platelet aggregation Deficiency in thromboxane A2 Bernard-Soulier-like defect Immune Deficiencies Decreased T-cell IL-2 receptors Decreased IL-2 production Decreased NK activity

Decreased NK response to gamma inteferon Decreased gamma interferon production Decreased response to mitogens Decreased T4 cells Immunoglobulin abnormalities Autoanibodies Autoimmune phenomenon Impaired self-recognition

CMML, Chronic myelomonocytic leukemia *Bone marrow findings

CMML, Chronic myelomonocytic leukemia *Bone marrow findings

Figure 39.1 Bone marrow smear with marked erythrodys- Figure 39.2 Bone marrow smear with increased poiesis and binucleared erythroid progenitors myeloblasts

anemia. Care must be applied to differentiate true ALIP from pseudo-ALIP. In the latter case, the clusters of cells are either of erythroid or megakaryocytic origin and do not convey the same prognostic information compared to the former, where the immature cells are of myeloid origin. The determination of the immature precursor phenotype by immunohistochemical methods may be helpful in distinguishing pseudo and true ALIP, and thus permit identification of specific MDS subgroups with a poor prognosis.16 ALIP is not, however, specific to patients with MDS, and therefore not useful as a diagnostic tool.16

Functional abnormalities can occur in all three cell lines and range in severity from minor laboratory defects to those impairments associated with major clinical manifestations. These functional defects may exacerbate underlying existing cytopenias (i.e., anemia, neutropenia, and thrombocytopenia) or may produce a functionally deficient state even when peripheral blood counts remain in the normal range. Thus, patients with normal neutrophil counts may still experience recurrent bacterial infections reflecting functional neutropenia. Erythroid enzyme defects, aberrant expression of red cell surface antigens, and abnormalities of hemoglobin production and iron metabolism have all been described. Some of the changes in enzyme activity, such as those that occur with pyruvate kinase, may affect red cell survival.1718 Impaired activity of A and H transferase and galactosyltransferase has resulted in changes in blood types.19 20 Hemoglobin production is affected with increased fetal hemoglobin, aberrant globin chain synthesis, and disordered ferrokinetics.2122 Acquired alpha-thalassemia has been described secondary to a deletion of the alpha-globin chain cluster or an inactivating mutation of the tran-scriptional factor ATRX, resulting in down-regulation of the alpha-globin chain synthesis.23

The myeloid series often reveals leukopenia with immature forms and increased numbers of large unstained cells. Neutropenia is more commonly found in patients with refractory anemia with excess blasts (RAEB) and RAEB-T than in patients with refractory anemia (RA) and refractory anemia with ringed sider-oblasts (RARS).8 Leukocytosis most often accompanies CMML, and by definition requires an absolute mono-cytosis (>1 X 109/L) for diagnosis. Monocytosis may, however, also be present in the other MDS subtypes.8 Cytoplasmic abnormalities result in cells with hypogran-ule or defective granule formation, Auer rods, or abnormal azurophilic granules. Histocytochemical studies reveal cells with increased or decreased levels of leukocyte alkaline phosphatase, decreased myeloperoxidase staining, and loss of granule membrane glycopro-teins.24-28 Surface antigen analysis has shown loss of lineage-specific antigens, with persistent or increased expression of inappropriate antigens and lineage infi-delity.29-32 In some instances, the abnormal persistence of antigens or an increased proportion of cells express ing those antigens was associated with an increased risk of leukemic transformation and shortened survival. Abnormal expression of an activated surface phenotype on monocytes has been demonstrated in patients within all FAB subtypes, while expression of activated surface antigens on granulocytes was almost exclusively seen in patients with excess blasts.33 Impaired granulocyte function includes impaired respiratory burst, deficit in chemotaxis and superoxide release, as well as a defect in neutrophil stimulation signaling.33 34 Nuclear abnormalities such as pseudo Pelger-Huet cells and functional abnormalities are further outlined in Table 39.1.35

Megakaryocytes can be decreased and their morphology is often bizarre (Table 39.1). Patients with RAEB and RAEB-T more commonly have thrombocy-topenia, decreased megakaryocytes, and greater degrees of dysmegakaryopoiesis.8 Megakaryocyte fragments and giant thrombocytes may circulate in the peripheral blood. Hemorrhagic symptoms in these patients may be due to thrombocytopenia and functionally defective platelets. Dysfunction can result from defective platelet aggregation, deficiencies in thromboxane A2 activity, or the development of a Bernard-Soulier-type platelet defect. This latter defect has developed from a deficiency in the membrane glycoprotein GP 1b-IX complex.36'37

A small percentage of patients present with hypoplastic bone marrows and cytopenias which morphologically may be difficult to distinguish from aplas-tic anemia.38 Cytogenetic analysis with or without interphase FISH may be helpful in establishing a diagnosis.

The relationship of MDS to abnormalities of the immune system is of particular interest given the broad range of abnormalities described. There is a decrease in the number of T-cell interleukin-2 (IL-2) receptors, as well as IL-2 production. The latter is due in part to a failure of immunoregulatory B cells.39 Natural Killer (NK) cell activity and responsiveness to alpha-interferon is decreased, as is alpha-interferon production, while total numbers of NK cells are variable.39 There are decreases in the number of T cells, responsiveness to mitogenic stimulation, the total number of cells, and the T4/T8 ratio.314041 The latter is due predominantly to a decrease in T4 cells. Overexpression of HLA-DR15 may occur in some patients, and may be a useful predictive factor for response to immunotherapeutic inter-ventions.42

Immunoglobulin abnormalities manifest as autoan-tibodies or a positive direct Coombs' test.4344 The relationship of the disease to the immune abnormalities is poorly understood. A general dysregulation of the immune system is prevalent in many patients. Many patients will present with evidence of associated autoimmune disorders.13 This may include polyserositis with frank, nonspecific inflammatory pericarditis and pleuritis with significant effusions,13 or it may be associated with other autoimmune diseases, such as Crohn's and Behcet's disease.45 46 Additional autoimmune mediated conditions associated with MDS include relapsing polychondritis, arthritis, polyneuropathy, hemolytic anemia, and immune thrombocytopenia. Recent reports have also described glomerulonephritis and nephrotic syndrome.4748 In some cases, increased serum lyzozyme (muramidase) in patients with CMML may be the inciting nephrotoxic agent. Although the pathophysiologic relationship of these autoimmune phenomenas and MDS is uncertain, it appears that the prognostic factors relating to MDS are the primary determinants for outcome, rather than the autoimmune disease.49 Consistent with this is the finding of altered antibody repertoires of self-reactive IgM and IgG in MDS patients, indicating a disturbance in self-recognition mechanisms.50 Whether some abnormalities relate in part to the number of red cell transfusions, or whether they are reversible with effective treatment, is unknown. Given the nature of the defect in a multipotent stem cell with the potential to differentiate along multiple pathways,51 the dysreg-ulation of T and B cells is not surprising. A report of 20 patients with nontherapy-related MDS and concurrent lymphoid or plasmacytic malignant neoplasms provides further evidence to the multipotency of the stem cell affected, and to the derivative generalized immune dysregulation.8'43

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