CHAPTER 91 CLASSIFICATION AND CLINICAL MANIFESTATIONS OF THE CLONAL MYELOID DISORDERS
CHAPTER 91 CLASSIFICATION AND CLINICAL MANIFESTATIONS OF THE CLONAL MYELOID DISORDERS
MARSHALL A. LICHTMAN
Minimal-Deviation Myeloid Clonal Disorders
Ineffective Hematopoiesis (Precursor Apoptosis) Prominent
Overproduction of Cells Prominent
Moderate-Deviation Clonal Myeloid Disorders
Moderately Severe-Deviation Clonal Myeloid Disorders
Severe-Deviation Clonal Myeloid Disorders
Transitions among Clonal Myeloid Diseases
Pathogenesis of Clonal Myeloid Diseases
Phenotype of Myeloid Clonal Diseases as a Result of the Matrix of Differentiation and Maturation
Pluripotential Stem Cell Pool as Site of the Lesion
Progenitor Cell Leukemia
Quantitativeness of Clonal Myeloid Diseases
Interplay of Clonal and Polyclonal Hematopoiesis
Deficiency, Excess, or Dysfunction of Blood Cells
Effects of Leukemic Blast Cells
Factitious Laboratory Results
Specific Organ Involvement
The clonal myeloid disorders result from a mutation of DNA within a pluripotential marrow stem cell or very early progenitor cell. The primary alteration causing the mutation is often evident when cytogenetic analysis is performed. Translocations, inversions, and deletions of chromosomes can result (1) in the expression of fusion genes that encode fusion proteins that are oncogenic or (2) in the over- or underexpression of genes that encode molecules critical to the control of cell growth or programmed cell death.
The different mutations may result in variable phenotypes that range from mild impairment of the steady-state levels of blood cells, insignificant functional impairment of cells, and little consequence on longevity to severe deficiencies in normal blood cell concentration and death in hours to days, if untreated. Although very mild disease expression can be considered a “benign” neoplasm as compared to acute myelogenous leukemia, that term has not been used to classify disorders like idiopathic sideroblastic anemia, because they do have measurable alterations in blood cells and have a propensity to progress to acute myeloid leukemia as compared to age- and gender-matched unaffected persons.
The somatically mutated (neoplastic) stem cell from which the clonal expansion of hematopoietic cells derive retains the ability, albeit imperfectly, to differentiate and mature into each blood cell lineage. The effects of the disorder may alter blood cell numbers, structure, and function and may range from minimal to severe in the various blood cell lineages. The effects occur on one lineage or another in an unpredictable way, even in subjects within the same category of disease. The resulting phenotypes are numerous and varied. In polycythemia vera or thrombocythemia, the maturation of progenitors results in cells nearly normal in appearance and function, although excessive in their level in the blood. Moreover, overlapping features are common, such as thrombocythemia as a feature of polycythemia or chronic myelogenous leukemia. The acquired idiopathic refractory anemias may have insignificant or very consequential neutropenia or thrombocytopenia or sometimes thrombocytosis. This reflects the unpredictable expression of stem cell capabilities for which the genic explanations are largely unknown. In only a few circumstances are there tight relationships between the cytogenetic alteration and the phenotype and even these are imperfect; for example t(9;22)(q34;q11) with chronic myelogenous leukemia or t(15;17)(q22;q21) with acute promyelocytic leukemia. However, most patients can be grouped into the classical diagnostic designations listed in Table 91-1.
An important feature of the clonal myeloid diseases is that there is potentially reversible suppression of the expression of normal stem cells by the clonally expanded cells. This coexistence and competition forms the basis for the remission-relapse pattern seen in acute myelogenous leukemia after intensive chemotherapy and for the reappearance of polyclonal, normal hematopoiesis in some patients with chronic myelogenous leukemia after interferon-a therapy.
TABLE 91-1 NEOPLASTIC (CLONAL) MYELOID DISORDERS
Acronyms and abbreviations that appear in this chapter include: AML, acute myelogenous leukemia; BFU–E, burst-forming unit–erythroid; CFU–Baso, colony forming unit–basophil; CFU–Eo, colony forming unit–eosinophil; CFU–G, colony-forming unit–granulocyte; CFU–M, colony-forming unit–monocyte-macrophage; CFU–Meg, colony-forming unit–megakaryocyte; 2N, diploid megakaryoblast; CML, chronic myelogenous leukemia.
A wide array of clonal (neoplastic) syndromes or diseases can result from a somatic mutation in a stem cell or an early multipotential hematopoietic cell. These several diseases can be grouped, somewhat arbitrarily, by their degree of malignancy, using the classic terminology of experimental carcinogenesis, which logically considers the degree of loss of differentiation potential and the rate of progression of the disease. The term deviation relates to the relationship to normal cellular differentiation potential and the regulation of cell population homeostasis (birth and death rates). This terminology has been used to array the well-known diagnostic categories into a framework for the reader.
MINIMAL-DEVIATION MYELOID CLONAL DISORDERS
These neoplasms retain a higher degree of differentiating capability and usually permit life-spans measured in decades without treatment or with minimally toxic treatment approaches,1 (see Chap. 61, Chap. 92, Chap. 118). The use of the term minimal deviation should not be construed as indicating that these conditions do not have morbidity, shorten life, and have other consequences to the patient. It is a term that is used relative to acute myelogenous leukemia with an expected life-span if untreated measured in days to weeks.
INEFFECTIVE HEMATOPOIESIS (PRECURSOR APOPTOSIS) PROMINENT
These are a subgroup of clonal hemopoietic stem cell diseases in which cytopenias resulting from ineffective hematopoiesis is the most characteristic feature. A common secondary characteristic is striking dysmorphogenesis of blood cells. These cytologic abnormalities, characteristic of the acquired anemias, bicytopenias, or pancytopenias, include changes in the size (macro- and microcytosis), shape (poikilocytosis), and nuclear or organelle structure (hypo- or hypergranulation, nuclear hypolobulation) of blood cells and their precursors (see Chap. 92). Abnormal maturation of blood cells leads to morphologic, biochemical, and functional alterations of the cells. Ineffective erythropoiesis, the intramedullary death of erythroblasts before they reach full maturation, is a common feature, and ineffective granulopoiesis and thrombopoiesis also can occur. An increase in (leukemic) blast cells is not evident in these syndromes. If they are elevated above the upper limit of 2 percent, they should be considered oligoblastic leukemia (or refractory anemia with excess blasts). Because of the variability of marrow differential counts and marrow sampling, such distinctions require several observations.
The term hematopoietic dysplasia, later simplified to myelodysplasia, has become ensconced as the category into which some of these syndromes, but not others, are grouped. This nomenclature resulted from a meeting in Paris in 1975.2 In strict pathologic terms, a dysplasia is a nonclonal, nonmalignant change in the cells of a tissue. These myeloid syndromes are clonal, sometimes have aneuploid or pseudodiploid cells in the clone, and can be associated with significant morbidity and premature death and thus fit the features of a neoplasia rather than a dysplasia. They each have a propensity to evolve into acute myelogenous leukemia that far exceeds that of the general population. The term dysplasia was used at a time when the prominent dysmorphogenesis was thought to be the singular abnormality. However, the derivation from a single mutant stem cell (monoclonality) mark the syndromes all as neoplasias, and that is the primary feature of these diseases.
OVERPRODUCTION OF CELLS PROMINENT
Polycythemia vera (see Chap. 61), and primary thrombocythemia (see Chap. 118) are clonal hematopoietic stem cell disorders, so named because of the excessive production and overaccumulation of red cells, neutrophils, and platelets in polycythemia and platelets and to a lesser extent neutrophils in thrombocythemia, although each cell lineage is affected in each disorder, reflecting a stem cell origin. The magnitude of the effects is different, however. The effect on red cell production in thrombocythemia is usually slight. Polycythemia vera and primary thrombocythemia do not show morphologic evidence of leukemic hemopoiesis, and differentiation and maturation are maintained. The proportion of blast cells in the marrow is not increased over normal, and blast cells are not present in the blood. The survival of cohorts of patients with these diseases is slightly less than expected for age- and gender-matched unaffected persons.1
MODERATE-DEVIATION CLONAL MYELOID DISORDERS
CML (Chap. 94) and idiopathic myelofibrosis (agnogenic myeloid metaplasia) (Chap. 95) classically share the features of overproduction of granulocytes and platelets and impaired production of red cells. Idiopathic myelofibrosis, however, has the invariable association of marrow fibrosis and striking tear-drop shaped red cells. The cells in the disorder have no specific cytogenetic change. Whereas CML invariably has a rearrangement of BCR on chromosome 22, in about 90 percent of patients this mutation is reflected in t(9;22) at the light microscopic level. Splenomegaly and a gradually progressive course are common to both. Blast cells are very slightly increased in marrow and blood in most patients with these disorders. CML has a very high propensity to transform to acute leukemia. Idiopathic myelofibrosis terminates in acute leukemia in about one out of six patients. Life span in these disorders is usually measured in years but is significantly decreased when compared to age- and gender-matched unaffected cohorts. Therapy is required in virtually all cases of chronic myelogenous leukemia and most cases of idiopathic myelofibrosis at the time of diagnosis. Both diseases can be cured only by stem cell transplantation, although life span has been increased in CML with the use of hydroxyurea and interferon-a therapy.
MODERATELY SEVERE-DEVIATION CLONAL MYELOID DISORDERS
These disorders fall into a group that progresses less rapidly than acute and more rapidly than chronic leukemia. They also have a predisposition to develop with a granulocytic and monocytic phenotype, either morphologically or cytochemically. These diseases also have been called oligoblastic or smoldering leukemia, refractory anemia with excess myeloblasts, subacute myelomonocytic leukemia, and atypical myeloproliferative syndromes. The latter designation is sometimes used for uncommon syndromes that did not fall into easily classifiable designations and usually are seen in patients over 65 years of age. The subacute syndromes produce more morbidity than do the chronic syndromes, and patients have a shorter life expectancy. These are leukemic states that have low or moderate concentrations of leukemic blast cells in marrow and often blood, as well as anemia, thrombocytopenia, and sometimes prominent monocytic maturation of cells (see Chap. 92). The oligoblastic leukemias compose about 80 percent of the cases that have been grouped under the title myelodysplastic syndromes. Subacute myelomonocytic leukemia has been withdrawn from the category of myelodysplastic diseases, highlighting the confusion surrounding that term. In all other malignancies, the presence of tumor cells result in the same diagnosis, i.e., carcinoma of the colon or the uterine cervix, whether in situ, invasive, or metastatic. It is illogical to use the percentage of leukemic cells as the basis of a diagnostic distinction. Hence, the preference for oligoblastic leukemia rather than myelodysplasia for patients with increased blast cells, monoclonality, and dysmorphic cell maturation.
SEVERE-DEVIATION CLONAL MYELOID DISORDERS
In 1975, at a conference on the classification of acute leukemia in Paris, Galton and Dacie proposed a classification for the most frequent phenotypic subtypes of AML.3 They suggested the designation M0 through M6 for seven variants and considered morphology (for example, erythroid, monocytic, granulocytic) and the evidence of maturation in the categorization. Those in attendance at the conference from France (F), America (A), and Britain (B) adopted the proposal and modified it, and it was given the acronym the FAB classification.4 The latter group used the designations M1 through M7 to indicate the previously recognized, morphologic phenotypes of AML. They later added M0 for another type of undifferentiated myeloblastic leukemia and M7 for megakaryocytic leukemia (see Chap. 93).
Morphologic subclassification of acute myelogenous leukemia is of some importance because it alerts the physician to special epiphenomena (for example, hypofibrinogenic hemorrhage in association with promyelocytic or monocytic leukemia, tissue and central nervous system infiltration in hyperleukocytic monocytic leukemia, etc.). It would be of great significance if it correlated with drug sensitivity. The principal therapy for all morphologic variants of AML is the same. From a clinical standpoint, the most useful classification of acute leukemia would be by drug sensitivity (for example, cytosine arabinoside–sensitive leukemia, glucocorticoid-sensitive leukemia, etc.). There is no set of in vitro tests to accomplish such a prospective classification, but not for lack of trying. Acute promyelocytic leukemia, which uniquely responds to all-trans-retinoic acid and arsenic trioxide, is the sole example of the strong correlation of the morphologic subtype of AML with drug sensitivity, and, even in this case, continuous intensive cytotoxic drug use also is required for a sustained effect of therapy (see Chap. 93).
Morphologic and histochemical characteristics of cells on stained films of blood and marrow provide the major basis for the classification of AML. To these two approaches has been added the reactivity pattern of blast cells to monoclonal antibodies with specificity for epitopes on the surface of myeloid or lymphoid cells5,6 and 7 (see Chap. 93). The correlations among observers and between the morphologic method of classification and the monoclonal antibody reactivity–dependent classification of AML is rather imperfect. Cytogenetic characteristics also are used in the classification of some cases of AML (see Chap. 10 and Chap. 93). The importance of these various approaches differs. The morphologic plus cytochemical approach is the most inclusive, since virtually all cases can be placed into a morphologic subtype. Occasionally this requires supplementation by analysis of immunophenotype (the CD representation). Since immunophenotyping has approached the routine in most laboratories in first- and second-world countries, these results are readily available. Classification by cytogenetics is more limited, since many cases have infrequent abnormalities making this approach complex. However, in many cases knowing the cytogenetic alterations is very useful for determining treatment, estimating prognosis, and measuring minimal residual disease by polymerase chain analysis. Thus, combined microscopy, cytochemistry, and immunophenoyping to designate a morphologic classification, supplemented by cytogenetics or molecular diagnostic approaches, is the best approach, currently.
TRANSITIONS AMONG CLONAL MYELOID DISEASES
Patients with minimal, moderate, and moderately severe clonal myeloid disorders have an increased likelihood of progressing to florid AML, with a frequency ranging from about 1 percent of patients with paroxysmal nocturnal hemoglobinuria, 10 percent of patients with acquired refractory sideroblastic anemia, and about 35 percent of patients with pancytopenia with hypercellular marrow. About 15 percent of patients with polycythemia vera evolve to a syndrome indistinguishable from idiopathic myelofibrosis. AML develops as a terminal event in about one percent of patients with polycythemia vera not treated with 32P or alkylating and a larger proportion of those so treated.
About 5 to 15 percent of patients with primary thrombocythemia and idiopathic myelofibrosis and virtually all patients with CML progress to AML. In the case of patients with CML, they may enter a phase that behaves like oligoblastic leukemia before progression to AML.
PATHOGENESIS OF CLONAL MYELOID DISEASES
In AML the mutation in a single stem cell results in a clone that is severely defective and contains precursor cells that are unable to mature. Proliferation of primitive progenitors is excessive when considered in absolute terms, that is, the total number of blast cells proliferating. AML is considered a clinical disease with many forms of morphologic expression. This variation of phenotype is consistent with the behavior of the leukemic stem cell, which is capable of differentiation into all the blood cell lineages (Fig. 91-1). Hence, the asymmetric maturation of leukemic progenitor cells may allow one or another cell type to predominate. There is little difference in the course of these different morphologic variants of AML. There are important epiphenomena related to special features of certain morphologic types of leukemia, such as tissue infiltration (monocyte leukemia), hypofibrinogenemia (promyelocytic leukemia), heart and lung fibrosis (eosinophilic leukemia), marrow fibrosis (megakaryocytic leukemia), and others (see Chap. 93). These morphologic subtypes and epiphenomena are determined by the effect of genic differences. These differences may be evident in gross cytogenic abnormalities that correlate with, and may determine, some phenotypes, for example, t(15;17) with promyelocytic leukemia, t(8;21) with myelomonocytic leukemia, inversion of chromosome 16 with prominent eosinophilic maturation in the marrow (see Chap 93). In CML, the injury to a single cell results in a clone in which there is an enormous expansion of progenitors for granulocytic and, often, megakaryocytic cells. Erythropoiesis is effective but decreased. Unlike AML, maturation of progenitor cells in CML is nearly normal; hence, the predominant leukemic cells in the blood are amitotic, mature, or partially matured cells, such as segmented neutrophils and myelocytes, erythrocytes, and platelets.
FIGURE 91-1 Hematopoiesis in acute myelogenous leukemia. The malignant process evolves from a single mutant multipotential cell.45,46,47 and 48 This cell is represented at either level 1 or level 2 in Fig. 91-3. This cell is capable of multivariate commitment to leukemic erythroid, granulocytic, and megakaryocytic progenitors. In most cases, granulocytic commitment predominates, and myeloblasts and monoblasts or their immediate derivatives are the dominant cell types. Leukemic blast cells accumulate in the marrow. The leukemic blast cells may become amitotic (sterile) and undergo programmed cell death, may stop dividing for prolonged periods (blasts in G0) but have the potential to reenter the mitotic cycle, or may divide and undergo varying degrees of maturation. The maturation may lead to mature cells, such as red cells, segmented neutrophils, monocytes, or platelets. A severe block in maturation is characteristic of AML, whereas a high proportion of leukemic blast cells mature in CML. The disturbance in commitment and maturation in myelogenous leukemia is quantitative, and thus many patterns are possible. At least four major steps in hemopoiesis are regulated: (1) stem cell self-renewal and (2) differentiation into hematopoietic cell lineages (red cells, granulocytes, platelets), (3) proliferation (multiplication) and maturation of progenitor and precursor cells, (4) release of mature cells into the blood. These control points are partially or totally defective in myelogenous leukemia.
Since hemopoiesis is generated by leukemic stem cells, in most patients with AML, CML, and other clonal hemopathies, erythropoiesis and thrombopoiesis as well as granulopoiesis are leukemic, and qualitative abnormalities of structure and function and clonal cytogenic abnormalities affect erythroblasts, megakaryocytes, and granulocyte precursors in most cases of AML (see Chap. 93) and all cases of CML (see Chap. 94).
PHENOTYPE OF MYELOID CLONAL DISEASES AS A RESULT OF THE MATRIX OF DIFFERENTIATION AND MATURATION
The phenotype of the hemopoietic stem cell diseases is a reflection of a neoplastic stem cell’s capability to differentiate into committed progenitor cells and the ability of those progenitor cells to mature into identifiable cells of the erythroid, granulocytic (neutrophilic, basophilic, mastocytic, eosinophilic), monocytic, or megakaryocytic lineage8,9,10,11,12 and 13 (Fig. 91-2).
FIGURE 91-2 Differentiation and maturation of hematopoietic stem cells. The functioning stem cell pool is thought to be at level 1, the pluripotential cells. In healthy human beings, two multipotential progenitor cell pools may be operative (level 2). The multipotential progenitors differentiate further to unipotential progenitors, which are sensitive to cytokines (level 3). The committed progenitor cells are referred to as colony-forming units (CFU) or colony-forming cells (CFC), since they form colonies of cells in semisolid medium in the presence of the appropriate growth factors. These growth factors are capable of inducing proliferation and maturation of the committed progenitor cells so that they achieve level 4, at which the first morphologically identifiable precursors are present, such as myeloblasts and proerythroblasts, and ultimately level 5, the fully mature, functional blood cells.
Differentiation represents the changes from the multipotential stem cell to multiple unipotential lineage progenitors. Maturation represents the physical and chemical changes from a unipotential progenitor through a sequence of precursors to the fully mature and functional blood cell, including progression from a BFU-E to proerythroblast to erythrocyte, a CFU-G to myeloblast to segmented neutrophil, a CFU-Eo to a segmented eosinophil, a CFU-Baso to a mature basophil, a colony forming unit–mast cell to a mature mast cell, a CFU-M to promonocyte to monocyte to macrophage, a CFU-Meg to a 2N megakaryoblast to the polyploid megakaryocyte. This matrix, composed of the options of commitment to different lineages and the progressive stages of maturation at which partial or complete arrest can occur, results in the potential for a wide array of morphologic syndromes by which a mutant stem cell can dominate hemopoiesis (see Fig. 91-2).
In the stem cell diseases in which differentiation and maturation capability is retained, one of the cell lines, for example, erythrocytes, granulocytes, or platelets, tends to accumulate in the blood to a more prominent extent and results in a phenotypic expression of the disease that determines the nosology. In AML, the phenotypic expression may be predominantly myeloblastic (granuloblastic), erythroid, monocytic, megakaryocytic, or combinations thereof. Certain patterns are favored. In AML, myeloblastic leukemia and monocytic leukemia or mixtures of the two are more common than erythroid, megakaryocytic, or eosinophilic leukemia. AML, however, usually has a disturbance in all cell lines. In myeloblastic or myelomonocytic leukemia there may be overt, qualitative abnormalities of erythroblasts and megakaryocytes. The prevalence of the abnormalities in the latter two lineages may not be great enough or evident enough for the observer to designate a case as erythroid or megakaryocytic leukemia.
The continuum of maturation can be completely or partially blocked at various levels, leading to morphologic variants such as acute myeloblastic, promyelocytic, subacute myelogenous, or chronic myelogenous leukemia.
PLURIPOTENTIAL STEM CELL POOL AS SITE OF THE LESION
Evidence points to a lesion in the pluripotential stem cell pool in most of the clonal myeloid diseases, especially in those over age 50, who account for the great proportion of cases. In CML patients, the mutation is in the pluripotential stem cell. In other syndromes, the evidence for involvement of B and T lymphocytes is variable. B lymphocytes are derived from the clone in many cases, whereas evidence for T lymphocyte involvement is less compelling. Evidence that affected T lymphocytes undergo apoptosis before entering the blood in patients with CML may explain their absence in blood lymphocytes in other clonal myeloid disorders.13
Thus, the mutation of the cell may be at level 1, between levels 1 and 2, or at level 2 in different patients (see Fig. 91-3).
FIGURE 91-3 Phenotypic subtypes of acute myelogenous leukemia. Acute myelogenous leukemia has variable morphologic expression and a variable degree of maturation of leukemic cells into recognizable precursors of each blood cell type. This phenotypic variation is a consequence of the fact that the leukemic lesion resides in a cell normally capable of all the different commitment decisions. (a) The morphologic variants of AML can be considered differentiation variants in which the cells derived from one of the options of commitment accumulate prominently (e.g., leukemic erythroblasts, leukemic monocytes, leukemic megakaryocytes, etc.). In promyelocytic leukemia and some cases of acute leukemia in younger individuals, the somatic mutation may arise in a somewhat more differentiated progenitor.8,48 (b) Acute myeloblastic leukemia, promyelocytic leukemia, subacute leukemia, and chronic leukemia can be considered maturation variants in which blocks at different levels of maturation are present.
PROGENITOR CELL LEUKEMIA
An analysis of cases of AML in girls and women who were heterozygous for isotypes A and B of the enzyme glucose-6-phosphate dehydrogenase indicated that the AML clone in the girls was restricted to the granulocyte-monocyte pathway, but in the older women monoclonality was expressed in all cell lines, in keeping with all prior studies of CML and AML by enzymes or chromosome markers.8,9 These findings support the possibility that a leukemic transformation in some (young) patients can occur in progenitor cells (e.g., CFU-GM) (level 3 in Fig. 91-3) and result in a true acute “granulocytic” leukemia. If progenitor cell leukemia is common in young people, this pattern could explain their better response to treatment. In a subset of patients with acute monocytic leukemia,31 t(8;21) AML, and t(15;17) AML, their leukemia derives from the neoplastic transformation of a progenitor cell.10,11 and 12
QUANTITATIVENESS OF CLONAL MYELOID DISEASES
The lesions of the hematopoietic stem cell compartment are qualitative in the sense that there is a distinct alteration from normal in the function of the cell pool, and this is a reflection of a change in the genome of one hematopoietic stem cell. This qualitative change, however, is such that the stem cell can express all or some of the normal differentiation and maturation options. This expression can mimic the differentiation (commitment) and maturation expected of normal hemopoietic cells such as occurs in CML and polycythemia vera.15,16
Most cases tend to conform to readily recognized patterns, but the opportunity for a large number of variations on the most common themes is possible. Thus, some mixed and so-called in-between syndromes occur in which features of ineffective hemopoiesis and myeloproliferation of different cell lineages are present. For example, extreme thrombocytosis, usually confined to primary thrombocythemia, may accompany CML or idiopathic myelofibrosis. Erythrocytosis may accompany CML rarely. Atypical myeloproliferative syndromes or other clonal hemopathies may have mixtures of anemia, granulocytopenia, and thrombocytosis or of anemia, granulocytosis, and thrombocytopenia rather than pancytopenia. Qualitative abnormalities of red cell, granulocyte, or platelet structure or function may be more or less prominent in a given patient. For example, qualitative abnormalities of erythroblast development may result in acquired a thalassemia (hemoglobin H disease) in patients with idiopathic myelofibrosis or other stem cell diseases. In AML, unusual patterns of phenotypic expression occur frequently. For example, one may see patients in whom leukemic erythroblasts and monocytes or eosinophils and monocytes are prominent. Indeed, there is so much opportunity for variation in disease expression among patients with AML that it is unusual to see patients in whom the phenotypes of leukemic cells are identical to those of others. Choice of treatment is little affected by these variations. The decisions about whether to treat and which drugs to use are greatly influenced by whether a patient has a chronic, subacute, or acute clonal myeloid disease; by the rate of progression of the disease; by the extent of the leukemic blast cell infiltrate; and by the severity of the cytopenias. The diagnostician and therapist usually can identify variants as diseases of a clonal myeloid disorder and can manage them as dictated by their manifestations regardless of precise subclassification.
INTERPLAY OF CLONAL AND POLYCLONAL HEMATOPOIESIS
Although potentially curative chemotherapy of myelogenous leukemia was introduced to kill “the last leukemic cell,” two important factors were not explicitly discussed. The first was whether there were residual normal stem cells in marrow to restore polyclonal (normal) hematopoesis if ablation of the leukemia was accomplished. The second was whether, given the early estimates of 1 trillion leukemic cells in a patient, the therapist had to eliminate them all to achieve cure. A corollary of the latter was whether the disease was the result of a mutant stem cell and if so was that the only cell that mattered, ultimately, in the eradication process. We now recognize that remission is the result of sufficient suppression of the leukemic population by intensive chemotherapy to permit restitution of polyclonal hematopoiesis by normal stem cells. Since relapse is the rule, two understudied, nearly ignored, therapeutic approaches should include determining and interfering with the chemicals elaborated by leukemic cells that suppress normal hematopoiesis and assessing whether agents that foster normal stem cell recruitment could tip the balance in favor of those cells. It is unclear also why clonal hematopoiesis is so difficult to subdue, even temporarily, in the chronic myeloid neoplasms (e.g., CML) as compared to the acute myeloid neoplasms (AML). Evidence has accumulated that sustained remission (clinical cure) may occur in some cases with posttherapy minimal residual disease suggesting that a new symbiotic relationship can occur after intensive therapy that suppresses the growth potential of leukemic cells. This phenomenon may be more evident in lymphoid than myeloid neoplasms.
DEFICIENCY, EXCESS, OR DYSFUNCTION OF BLOOD CELLS
Alterations in blood cell concentration are the primary manifestations of hematopoietic stem cell disorders. The clinical manifestations of deficiencies or excesses of individual blood cell types are described in the chapters on clinical manifestations of disorders of erythrocytes (see Chap. 30), granulocytes, and monocytes (see Chap. 70 and Chap. 76), and platelets (see Chap. 115).
Several hematopoietic stem cell diseases have as frequent manifestations qualitative abnormalities of blood cells. Abnormal red cell shapes, red cell or granulocyte enzyme deficiencies, abnormal neutrophil granules, bizarre nuclear configurations, disorders of neutrophil chemotaxis, phagocytosis or microbial killing, giant platelets, abnormal platelet granules, and disturbed platelet function can occur in some patients with oligoblastic myelogenous leukemia and idiopathic myelofibrosis. In oligoblastic myelogenous leukemia, the effects of severe cytopenia usually dominate, and the disturbances of cell function are less important. In idiopathic myelofibrosis and primary thrombocythemia, functional platelet abnormalities may contribute to the hemorrhage diathesis, especially if surgery or injury occurs. Paroxysmal nocturnal hemoglobinuria is a hemopoietic stem cell disease in which a highly specific alteration in blood cell membranes renders the cells exquisitely sensitive to complement lysis (see Chap. 36). Patients with CML or polycythemia vera do not usually have clinically significant functional abnormalities of cells, although in polycythemia vera neutrophils are often activated with heightened metabolic rates and enhanced phagocytosis.
Secondary clinical manifestations occur as a result of the proliferation and accumulation of the malignant (leukemic) cells themselves.
EFFECTS OF LEUKEMIC BLAST CELLS
Granulocytic sarcomas (also called chloromas or myeloblastomas) are discrete tumors of leukemic myeloblasts and partially matured granulocytes that form in skin and soft tissues, periosteum and bone, lymph nodes, gastrointestical tract, pleura, gonads, urinary tract, central nervous system, and other sites17 (see Chap. 93). They can develop in patients with AML or the accelerated phase of CML and, rarely, may be the first manifestation of AML, preceding the onset in marrow and blood by months or years.18 Granulocytic sarcomas can be mistaken for large-cell lymphomas because of the similarity of the histopathology in biopsy specimens from soft tissues. The presence of eosinophils or other granulocytes may arouse suspicion of a granulocytic sarcoma; however, chloracetate esterase, antilysozyme immunoperoxidase stains, or antimyeloblast monoclonal antibodies may be required to establish the granulocytic nature of the process, and these assays should be performed on biopsies of such lesions.17
Extramedullary tumors may usher in the accelerated phase of CML. These tumors may be composed of myeloblasts or lymphoblasts, although in each case the Ph chromosome is present in the cells, indicating that the extramedullary Ph-positive lymphoblastomas are the tissue variant of the predisposition of CML to transform into a terminal deoxynucleotidyl transferase–positive lymphoblastic leukemia in about 30 percent of patients who enter blast crisis19 (see Chap. 27).
Monocytomas are more diffuse collections of leukemic promonocytes or monoblasts that invade the skin, gingiva, anal canal, lymph nodes, or central nervous system of patients with AML and form tumors in those locations. Leukemic monocytes tend to mature to the point at which they develop many of the cytoplasmic and membrane features required for motility and tissue entry.20,21 and 22 Moreover, monocytes proliferate and survive in tissues for long periods. Consequently, this AML phenotype has a higher frequency of overt infiltrative tissue lesions than do other forms of AML.
RELEASE OF PROCOAGULANTS AND FIBRINOLYTIC ACTIVATORS
Microvascular thrombosis is a feature of promyelocytic type of AML, although it can occur in other forms of acute leukemia, especially monocytic leukemia, as well. The leukemic promyelocytes are thought to liberate a procoagulant tissue factor or a plasminogen activator. Each may ultimately contribute to hypofibrinogenemia and hemorrhage. Thrombin generation may mediate the microvascular thrombotic aspect of this process, which can occur in acute promyelocytic, acute monocytic, or acute myelomonocytic leukemia, especially after cytotoxic treatment. A cysteine proteinase procoagulant different from tissue factor may also play a role in thrombosis formation associated with AML. An increase in fibrinolytic activity further complicates the coagulopathy in patients with promyelocytic leukemia23,24 (see Chap. 93).
A small proportion of patients with AML (5 percent) and CML (15 percent) manifest extraordinarily high blood leukocyte counts.25,26 These patients present special problems because of the effects of blast cells in the microcirculation of the lung, brain, eye, ear, and penis and the metabolic effects that result when massive numbers of leukemic cells in blood, marrow, and tissues are simultaneously killed by cytotoxic drugs. Cell concentrations over 75,000/µl (75 × 109/liter) in AML and over 250,000/µl (250 × 109/liter) in CML are usually required to produce such problems. A respiratory distress syndrome attributed to pulmonary leukostasis occurs in some patients with acute promyelocytic leukemia after all-trans-retinoic acid therapy. The syndrome is usually but not always associated with neutrophilia. Some cases, however, have been observed in the absence of extreme leukocytosis.27
The viscosity of blood is related to the total cytocrit and is usually not increased in hyperleukocytic leukemias because the reduction in hematocrit compensates for the increase in leukocrit. Occasional patients with hyperleukocytic CML who are transfused with red cells may have an increase in blood viscosity above normal.
Leuko-occlusion and vascular invasion in small vessels of the lung, brain, or other sites have been identified in pathologic studies. Since viscosity in the microcirculation is a function of the plasma viscosity and the deformability of individual cells in capillaries, leukocytes should transiently raise the viscosity in such small channels. Flow in microchannels will fall if poorly deformable blast cells enter capillary channels.28 With high leukocyte counts, chronically reduced flow may reduce oxygen transport to tissues, since the probability of leukocytes being in microchannels should be increased as a function of white cell count. Moreover, trapped leukemic cells have an oxygen consumption rate that could contribute to deleterious effects in the microcirculation. Leukocyte aggregation, leukocyte microthrombi, release of toxic products from leukocytes, endothelial cell damage, and microvascular invasion can contribute to vascular injury and flow impedance.
High leukemic blast cell counts in acute and chronic myelogenous leukemia may be associated with pulmonary, central nervous system, special sensory, or penile circulatory impairment (Table 91-2). Sudden death can occur in patients with hyperleukocytic acute leukemia as a result of intracranial hemorrhage.29,30 Hyperleukocytosis should be treated promptly with leukapheresis and with cytotoxic therapy, usually hydroxyurea (see Chap. 93 and Chap. 94). In CML, leukapheresis reverses the hyperleukocytic syndrome, can be used immediately without having to wait for the effect of allopurinol to reduce the risk of uric acid nephropathy, and can reduce the extent of cytolysis-induced hyperuricemia, hyperkalemia, and hyperphosphatemia by reducing the tumor cell mass. The effect of leukapheresis in AML on patient survival appears to be negligible, however.31
TABLE 91-2 CLINICAL FEATURES OF THE HYPERLEUKOCYTIC SYNDROME
Hemorrhagic or thrombotic episodes can be the presenting manifestation of thrombocythemia or can develop during the course of primary thrombocythemia.32,33 Arterial vascular insufficiency and venous thrombosis are the major vascular manifestations of thrombocythemia. Peripheral vascular insufficiency with gangrene and cerebral vascular thrombi can occur. Thrombosis of superficial or deep veins of the extremities occurs frequently. Mesenteric, hepatic, portal, splenic, or penile venous thrombosis can develop. Hemorrhage is a frequent manifestation of thrombocythemia and often occurs concomitantly with thrombotic episodes. Gastrointestinal hemorrhage and cutaneous hemorrhage, the latter especially after trauma, are most frequent, but bleeding from other sites can also occur (see Chap. 118).
Thrombotic complications occur in about one-third of patients with polycythemia vera.34 Erythrocytosis and thrombocytosis may interact to cause hypercoagulability, especially in the abdominal venous circulation. A syndrome of splanchnic venous thrombosis associated with endogenous erythroid colony growth, the latter characteristic of polycythemia vera, but without blood cell count changes indicative of a myeloproliferative disease, has accounted for a very high proportion of patients with apparent idiopathic hepatic or portal vein thrombosis.35,36 Thrombosis of the veins of the abdomen, liver, and other organs, characteristic complications of paroxysmal nocturnal hemoglobinuria, may result from a qualitative abnormality of platelets, which makes them very sensitive to activation of the factor V and X complex because of the absence of cell surface complement inhibitors37 (see Chap. 36).
Fever, weight loss, and malaise occur as an early manifestation of AML. At the time of diagnosis, low-grade fever is present in nearly 50 percent of patients.37 Although minor infections may be present, systemic infection is relatively uncommon at the time of diagnosis in AML.37,38 However, fever during cytotoxic therapy, when neutrophil counts are extremely low, is nearly always a sign of infection. Fever also may be a manifestation of the acute leukemic transformation of CML and can occur in some patients with oligoblastic leukemia.
Weight loss occurs in nearly one-fifth of patients with AML.38 Loss of well-being and intolerance to exertion may be out of proportion to the extent of anemia and may not be corrected by red cell transfusions; the pathogenesis of these effects is still unknown.
Hyperuricemia and hyperuricosuria are very common manifestations of AML and CML. Acute gouty arthritis and hyperuricosuric nephropathy are less common. If therapy is instituted without a reduction in plasma uric acid and without adequate hydration, saturation of the urine with uric acid can lead to precipitation of urate (gravel) and obstructive uropathy. If the uropathy is severe, urine flow can be obliterated, and renal failure ensues. Hyponatremia can occur in AML and in some cases is a result of inappropriate antidiuretic hormone secretion.39 Hyponatremia can also be a result of an osmotic diuresis of urea, creatinine, urate, and other substances released from blast cells and wasting muscles. Hypokalemia is commonly seen in AML, and it has been thought to be caused by injury to the kidney by increased plasma and urine lysozyme and subsequent kaliuresis. The hypokalemia is related to excessive urinary potassium loss, but the correlation with lysozymuria is imperfect, and other mechanisms are probably responsible in most cases, including osmotic diuresis and tubular dysfunction. Kaliuretic antibiotics, often used in patients with AML, may accentuate the hypokalemia.
Hypercalcemia occurs in about 2 percent of patients with myelogenous leukemia. Several causes have been proposed, including bone resorption as a result of leukemic infiltration. This explanation is in keeping with the normal serum inorganic phosphate in most patients. Occasional patients have had hypercalcemia and hypophosphatemia, and ectopic parathyroid hormone secretion by leukemic blast cells was strongly suggested in one carefully studied case. Lactic acidosis has also been observed in association with myelogenous leukemia, although the mechanism is obscure. Hypoxia can result from the hyperleukocytic syndrome as a consequence of pulmonary vascular leukostasis. Hypophosphatemia can occur because of rapid utilization of plasma inorganic phosphate in some cases of myelogenous leukemia with a high blood blast cell count and a high fraction of proliferative cells.
Increased serum concentrations of lipoprotein A and decreased concentrations both of low- and high-density lipoproteins have been observed in a high proportion of patients with AML.41 The increase in lipoprotein A, which returns to normal after successful treatment, is correlated with the presence of leukemic blast cells. Serum prolactin is also increased in patients with AML.41 Leukemic blast cells may be an ectopic source of this hormone.41
Colony-stimulating factor 1 is elevated in a variety of lymphoid and hemopoietic malignancies, including AML and CML.42 It has been proposed that the malignant cells are the source of the excess cytokine.
The plasma levels of protein C antigen, functional protein C, and free protein S are decreased in patients with AML. These changes are not related to liver disease or white cell count.42
FACTITIOUS LABORATORY RESULTS
Elevations of serum potassium levels have resulted from the release of potassium from platelets or, less often, leukocytes in patients with myeloproliferative diseases and extreme elevations in those blood cell concentrations.43 If blood is collected in a tube that contains an anticoagulant and the plasma is removed after high-speed centrifugation, the potassium concentration is normal. Glucose can be falsely decreased, especially since autoanalyzer techniques call for the omission of glycolytic inhibitors such as sodium fluoride in collection tubes. Blood with high leukocyte counts that stands prior to separation of the plasma may have a significant amount of plasma glucose utilized by leukocytes. Factitious hypoglycemia can also occur as a result of red cell utilization of glucose, especially in polycythemic patients. True hypoglycemia has been observed rarely in patients with leukemia. Blood oxygen content also can be lowered spuriously as a result of utilization in vitro by large numbers of leukocytes.
SPECIFIC ORGAN INVOLVEMENT
Myeloproliferative diseases lead to disturbances principally in marrow, blood, and spleen. Although clusters of cells may be found in all organs, major infiltrates and organ dysfunction are unusual. In AML and the acute phase of CML, clinically significant infiltration of the larynx, central nervous system, heart, lungs, bone, joints, gastrointestinal tract, kidney, skin, or virtually any other organ may occur. Splenic enlargement is a feature of the acute and chronic myeloproliferative diseases. In AML, palpable splenomegaly is present in about one-third of cases and is usually slight in extent. In the chronic myeloproliferative diseases, palpable splenomegaly is present in a high proportion of cases (polycythemia vera, 80 percent; CML, 90 percent; idiopathic myelofibrosis, 100 percent). In primary thrombocythemia, splenic enlargement is present in about 60 percent of patients. A predisposition to silent splenic vascular thrombi and splenic atrophy analogous to that which occurs in sickle cell anemia has been postulated for the lower frequency of splenic enlargement. Early satiety, left upper quadrant discomfort, splenic infarctions with painful perisplenitis, diaphragmatic pleuritis, and shoulder pain may occur in patients with splenomegaly, especially in the acute phase of CML and in myeloid metaplasia. In idiopathic myelofibrosis, the spleen can become enormous, occupying the left hemiabdomen. Blood flow through the splenic vein can be so great as to lead to portal hypertension and gastroesophageal varices. Usually, reduced hepatic venous compliance is also present (see Chap. 95). Bleeding and, occasionally, encephalopathy can result from the portosystemic venous shunts.
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Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn