Chapter 40: Classification and Clinical Manifestations of the Clonal Myeloid Disorders

• These disorders result from a mutation(s) of DNA within a single pluripotential marrow hematopoietic stem cell or very early multipotential progenitor cell. Mutations disturb the function of the gene product(s).

• Overt cytogenetic abnormalities can be found in 50% to 80% of cases of acute myelogenous leukemia (AML) in cytogenetic laboratories (see Williams Hematology, 9th ed, Chap. 13, Figure 13–3).

  — Translocations (eg, t(15;17); t(8;21)) and inversions of chromosomes (eg, inv16) can result in the expression of fusion genes that encode fusion proteins that are oncogenic.

  — Overexpression or underexpression of genes that encode molecules critical to the control of cell growth, or programmed cell death, often within signal transduction pathways or involving transcription factors occur.

  — Deletions of all or part of a chromosome (eg, -5, 5q-, -7, or -7q) or duplication of all or part of a chromosome may be evident (eg, trisomy 8).

• An early multipotential hematopoietic cell undergoes clonal expansion but retains the ability to differentiate and mature, albeit with varying degrees of pathologic features, into various blood cell lineages (Figure 40–1).

• The result is often abnormal blood cell concentrations (either above or below normal), abnormal blood cell structure and function; the abnormalities may range from minimal to severe.

• Resulting disease phenotypes are numerous and varied because of the eight myeloid and three lymphoid differentiation lineages from a multipotential hematopoietic stem cell.

• Neoplasms that result can be grouped, somewhat arbitrarily, by the degree of loss of differentiation and maturation potential and by the rate of disease progression.

• Most patients can be grouped into the classic diagnostic designations listed in Table 40–1.

• High degree of differentiation and maturation within the clone usually permit a majority of patients to have life spans measured in decades without treatment or with minimally toxic treatment approaches (Table 40–2).

Ineffective Hematopoiesis (Precursor Apoptosis) is Prominent

• Clonal anemia, bicytopenia, or pancytopenia is the usual manifestation.

• Cytopenias resulting from ineffective hematopoiesis (exaggerated apoptosis) are the most characteristic feature.

• Dysmorphogenesis of blood cells is striking.

• Altered size (macrocytosis and microcytosis) is present.

• Altered shape (poikilocytosis) is present.

• Altered nuclear or organelle structure of blood cells and their precursors (pathologic sideroblasts, acquired Pelger-Hüet neutrophil nuclear malformation, hypogranulation or hypergranulation, abnormal platelet granulation) is apparent.

• Increase in leukemic blast cells in marrow or blood are not evident in these syndromes.

• Blast cells above an upper limit of 2% combined with multilineage abnormalities indicate the presence of oligoblastic myelogenous leukemia (synonym: refractory anemia with excess blasts). The often arbitrary use of a less than 5% blast threshold is not based on classical pathologic diagnostic decisions in which the presence of tumor (leukemic blast) cells is the principal basis for the diagnosis.

• These disorders have a propensity to evolve into polyblastic myelogenous leukemia (eg, AML).

Overproduction of Precursor and Mature Cells Prominent

• Disorders are polycythemia vera and essential thrombocythemia.

• Leukemic blast cells are not present in the marrow or blood.

• Differentiation and maturation in clone is maintained, resulting in functional blood cells.

• Regulation of blood cell concentration is faulty with increased concentrations of some combination of red cells, granulocytes (especially neutrophils), and platelets.

• Survival of cohorts of patients with these diseases is modestly less than expected for age- and gender-matched persons.

• Disorders are chronic myelogenous leukemia (CML) and primary myelofibrosis.

• Blast cells are slightly increased in marrow and blood in most patients with these disorders.

• Median life span is usually measured in years but is significantly decreased when compared with age- and gender-matched unaffected cohorts. The introduction into standard therapy of inhibitors of the BCR-ABL oncoprotein (tyrosine kinase inhibitors) has prolonged median survival dramatically in most patients with CML.

• Although virtually all patients with polycythemia vera and approximately 50% percent of patients with essential thrombocythemia and primary myelofibrosis have similar JAK2 V617 mutational burdens, on average primary myelofibrosis is a more morbid disease with a significantly shorter life expectancy than polycythemia vera or essential thrombocythemia.

• Oligoblastic myelogenous leukemia (eg, refractory anemia) with excess myeloblasts may occur.

• Chronic myelomonocytic leukemia is such a disease.

  — This leukemic state has low or moderate concentration of leukemic blast cells in marrow and often blood.

  — Anemia, often thrombocytopenia, and prominent monocytic maturation of cell is found.

  — Disorders fall into a group that progress less rapidly than AML and more rapidly than CML.

  — These subacute syndromes produce more morbidity than do the chronic syndromes and patients have a shorter life expectancy.

• Oligoblastic myelogenous leukemia constitutes about 30% to 50%t of the cases that have been grouped under the designation myelodysplastic syndromes.

• Atypical clonal myeloid syndromes (also known as atypical CML) are uncommon syndromes with trilineage abnormalities that do not fall easily into classifiable designations. They are usually seen in patients older than 65 years of age.

AML and Its Subtypes

• There is an unlimited possibility for phenotypic variation based on the matrix of differentiation of the leukemic multipotential hematopoietic cell and the maturation of leukemic progenitor cells (Figure 40–2).

• Subtype alerts the physician to special epiphenomena:

  — Hypofibrinogenic hemorrhage with promyelocytic or monocytic leukemia

  — Tissue and central nervous system infiltration in monocytic leukemia

• Subtype identification requires some or all of the following:

  — Morphology of cells on stained films of blood and marrow

  — Identification of cell antigenic phenotype (CD array) by flow analysis

  — Histochemical characteristics of marrow and blood cells

  — Cytogenetic or molecular diagnostic techniques for recurring genotypes

  — Cytogenetic subclassification, which is more restricted because most cases have any of a variety of infrequently observed abnormalities, making this approach complex

  — Cytogenetic and molecular findings very useful for determining treatment approach, estimating prognosis, and measuring minimal residual disease by polymerase chain analysis, especially in cases in which the cells contain t(8;21), t(15;17), Inv 16, t(16;16), or 11q-

• Patients with minimal, moderate, and moderately severe clonal myeloid disorders have an increased likelihood of progressing to a more severe syndrome or to florid AML by a process of clonal evolution describing the acquisition of additional cooperating mutations, with a frequency ranging from:

  — About 1% of patients with paroxysmal nocturnal hemoglobinuria develop AML.

  — About 10% of patients with clonal anemia (eg, refractory sideroblastic anemia) progress to AML.

  — About 35% of patients with clonal pancytopenia progress to florid AML.

  — About 1% to 5% of patients with polycythemia vera not treated with ³²P or an alkylating agent (larger proportion of those so treated) develop AML.

  — About 15% of patients with polycythemia vera evolve to a syndrome indistinguishable from primary myelofibrosis.

  — About 5% of patients with essential thrombocythemia progress to AML.

  — About 15% of patients with primary myelofibrosis evolve to AML.

• Most patients with CML progress to acute leukemia as a feature of its natural history. (Current therapy with tyrosine kinase inhibitors has markedly delayed or prevented the onset of acute leukemia in most patients.)

• Patients with CML may enter a phase that behaves like oligoblastic leukemia (accelerated phase) before progression to florid acute leukemia (now much less frequent because of tyrosine kinase therapy).

• Proto-oncogene mutations develop in a multipotential hematopoietic or pluripotential lymphohematopoietic cell and result in most of the clonal myeloid diseases, especially in older patients.

• In CML, the mutation is in a pluripotential lymphohematopoietic cell.

• In other syndromes, the evidence for involvement of B- and T-lymphocyte lineages or multiple myeloid lineages is inconsistent.

• In AML, there is evidence for three levels of onset: pluripotential, multipotential, and bipotential progenitor cells.

• Leukemic transformation in some (young) patients can occur in progenitor cells (eg, colony-forming unit, granulocyte-macrophage [CFU-GM]) and can result in a true acute “granulocytic” leukemia without apparent intrinsic involvement of erythroid and megakaryocytic lineages.

• In t(15;17) promyelocytic AML, a subset of patients with acute monocytic leukemia, and a subset of patients with t(8;21) AML, the leukemia derives from the transformation of a granulocyte progenitor cell without intrinsic involvement of erythroid and megakaryocytic lineages.

• In the clonal myeloid diseases, residual polyclonal lymphohematopoietic stem cells are present in the marrow.

• These polyclonal, normal stem cells are suppressed by the effects of the malignant clone.

• These effects may be mediated by leukemic stem cells occupying or disrupting stem cell niches or by the malignant cells elaborating chemicals inhibitory to normal stem cell differentiation.

• Induction of remission in acute myelogenous leukemia involves the suppression of leukemic hematopoiesis, usually involving a reduction in leukemic cells of approximately three logs (eg, 10¹² to 10⁹), which would clear the marrow of microscopically evident leukemic cells. In this setting, polyclonal stem cells regain hegemony, at least for a time, and normal hematopoiesis is restored. This sequence of events defines a remission. See Figure 40–3.

Deficiency, Excess, or Dysfunction of Blood Cells

• Abnormal blood cell concentrations are the primary manifestation of clonal myeloid diseases.

• Clonal myeloid diseases may have overt qualitative abnormalities of blood cells.

• Abnormal red cell shapes, red cell enzyme activities, or red cell membrane structures may occur.

• Abnormal neutrophil granules, bizarre nuclear configurations, disorders of neutrophil chemotaxis, phagocytosis, or microbial killing may be present.

• Giant platelets, abnormal platelet granules, and disturbed platelet function may be apparent.

Extramedullary Tumors

• Myeloid sarcomas (synonym: granulocytic sarcomas, chloromas, myeloblastomas, or monocytomas) are discrete tumors of leukemic myeloblasts or occasionally leukemic monocytes:

  — These develop in skin and soft tissues, periosteum and bone, lymph nodes, gastrointestinal tract, pleura, gonads, urinary tract, central nervous system, and other sites.

  — Uncommonly, they may be the first manifestation of AML, preceding the onset in marrow and blood by months or years.

  — They are mistaken for large cell lymphomas by microscopy because of the similarity of the histopathology in biopsy specimens from soft tissues.

  — Immunohistochemistry should be used on such lesions to identify myeloperoxidase, lysozyme, CD117, CD61, CD68/KP1, and other relevant CD markers of myeloid cells. One of four histopathologic patterns usually is evident by immunocytochemistry: myeloblastic, monoblastic, myelomonoblastic, or megakaryoblastic.

  — They may usher in the accelerated phase of CML.

• Ph-chromosome-positive lymphoblastomas are the tissue variant of the capability of CML to transform into a terminal deoxynucleotidyl transferase-positive lymphoblastic leukemia in 25% to 30% of cases.

• Monocytomas are collections of leukemic promonocytes or monoblasts that may invade the skin, gingiva, anal canal, lymph nodes, central nervous system, or other sites.

• Hemorrhage from disseminated intravascular clotting or exaggerated fibrinolysis is a feature of acute promyelocytic leukemia.

• Hemorrhage from procoagulant-fibrinolytic state sometimes occurs in other forms of acute leukemia, especially hyperleukocytic monocytic leukemia.

• The plasma levels of protein C activity, free protein S, and antithrombin are decreased in some patients with AML, notably but not exclusively with acute promyelocytic leukemia.

• Leukemic cells may express a procoagulant tissue factor or a plasminogen activator (eg, annexin II on leukemic promyelocytes).

• Microvascular thrombosis is characteristic of the procoagulant effect. Large vessel thrombosis occurs and can result in stroke or loss of parts of extremities, but is uncommon.

• Five percent of patients with AML and 15% of those with CML have extraordinarily high blood leukocyte counts at diagnosis.

• In AML, leukemic cell counts over 100 × 10⁹/L and in CML, leukemic cell counts over 300 × 10⁹/L are usually present when the hyperleukocytic syndrome manifests itself.

• Metabolic effects (especially elevated serum uric acid and marked uricosuria) can result when massive numbers of leukemic cells in blood, marrow, and tissues are simultaneously killed by cytotoxic drugs. This can result in obstructive uropathy and renal failure.

• Leukostasis in AML and CML may be associated with effects in the pulmonary, central nervous system, special sensory, or penile circulation (Table 40–3).

• Sudden death can occur in patients with hyperleukocytic acute leukemia as a result of intracranial hemorrhage.

• 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 prominent neutrophilia.

• In polycythemia vera, essential thrombocythemia, and primary myelofibrosis, the height of the white cell count is a predictor of thrombosis and the height of the platelet count correlates with likelihood of bleeding (platelet count > 1000 × 10⁹/L increases bleeding risk).

• Hemorrhagic or thrombotic episodes can occur initially or can develop during the course of thrombocythemia.

• Procoagulant factors, such as the content of platelet tissue factor and blood platelet neutrophil aggregates, are higher in patients with essential thrombocythemia than normal persons and are higher among patients with the V617F JAK2 mutation than patients with the wild-type gene.

• Arterial vascular insufficiency and venous thrombosis are the major vascular manifestations of thrombocythemia.

• Peripheral vascular insufficiency with gangrene and cerebral vascular thrombi can occur in thrombocythemia.

• Mesenteric, hepatic, portal, or splenic venous thrombosis can develop.

• Thrombotic complications occur in about one-third of patients with polycythemia vera and, also, may occur in patients with essential thrombocythemia.

• Gastrointestinal hemorrhage and cutaneous hemorrhage, the latter especially after trauma, are most frequent, but bleeding from other sites can also occur.

• Thrombosis of the veins of the abdomen, liver, and other organs are characteristic complications in approximately half the patients with paroxysmal nocturnal hemoglobinuria.

  — Thrombosis is more common in the purely hemolytic type than in the type associated with marrow aplasia.

• 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 high proportion of patients with apparent idiopathic hepatic or portal vein thrombosis. These cases may have blood cells with the Janus kinase 2 (JAK2) gene mutation without a clinically apparent myeloproliferative phenotype.

• Budd-Chiari syndrome may occur in patients with polycythemia vera or essential thrombocythemia.

• Fever, weight loss, and malaise may occur as an early manifestation of AML.

• Fever during cytotoxic therapy, when neutrophil counts are extremely low, is nearly always a sign of infection.

• Weight loss occurs in nearly one-fifth of patients with AML at the time of diagnosis.

• Hyperuricemia and hyperuricosuria are very common manifestations of AML and CML.

• Acute gouty arthritis and hyperuricosuric nephropathy are less common.

• Saturation of the urine with uric acid accentuated by cytotoxic therapy can lead to precipitation of urate, formation of gravel or stones, and obstructive uropathy.

• Hyponatremia can occur in AML, and in some cases, is a result of inappropriate antidiuretic hormone secretion.

• Hypokalemia is commonly seen in AML.

• Hypercalcemia occurs in about 2% of patients with AML.

• Lactic acidosis has also been observed in association with AML.

• In some cases, hypophosphatemia may occur because of rapid utilization of plasma inorganic phosphate in cases of myelogenous leukemia with a high blood blast cell count and a high fraction of proliferative cells.

• Hypoxia can result from the hyperleukocytic syndrome as a consequence of pulmonary vascular leukostasis.

• Elevations of serum potassium levels from the release of potassium in clotted blood if there is an extreme elevation of platelets or, less often, leukocytes.

• Glucose can be falsely decreased if autoanalyzer techniques omit glycolytic inhibitors in collection tubes in cases with high leukemic cell counts.

• Factitious hypoglycemia can also occur as a result of red cell utilization of glucose in polycythemic patients.

• Large numbers of leukocytes can lower blood oxygen content spuriously as a result of its utilization in vitro during measurement.

• Infiltration of the larynx, central nervous system, heart, lungs, bone, joints, gastrointestinal tract, kidney, skin, or virtually any other organ may occur in AML.

• Splenic enlargement in about one-third of cases of AML and is usually slight in extent.

• Splenomegaly is present in a high proportion of cases of primary myelofibrosis (virtually 100%), CML (~80%), and polycythemia vera (~70%).

• In essential thrombocythemia, splenic enlargement is present in about 60% of patients.

  — Splenic vascular thrombi, microinfarctions, and splenic atrophy lower the frequency of splenic enlargement in thrombocythemia.

• 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 primary myelofibrosis.

• In primary 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 also contributes to these changes.

• Bleeding and, occasionally, encephalopathy can result from the portosystemic venous shunts in primary myelofibrosis.