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1382 Part X: Malignant Myeloid Diseases Chapter 88: Acute Myelogenous Leukemia 1383

translocations, AML is the diagnosis. Moreover, relapse of AML can be Approximately 45 percent of cases of AML contain cells that are
identified at any increase in blast count >2 percent. In addition, patients cytogenetically normal. When five genes—NPM1, FLT3, CEPBA, MLL,
with oligoblastic leukemia with 10 to 19 percent marrow leukemic blast and NRAS—were examined in 872 adults who were younger than
cells are identical in all other phenotypic findings and survival to those 60 years of age with a normal karyotype, approximately 85 percent had
with 20 to 29 percent marrow blast cells. Any distinctions between the a mutation in at least one of these genes. Mutations in NPM1 or CEPBA
two groups in survival are a function of age, cytogenetic risk category, were associated with more favorable outcomes, analogous to the category
and molecular features, not the blast count. This arbitrary boundary of favorable cytogenetics noted above. The microarray expression signa-
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prevents patients, otherwise suitable, to enter clinical trials. ture in patients with AML younger than age 60 years who have cytogenet-
Myeloblasts are distinguished from lymphoblasts by any of three ically normal cells but high-risk molecular features, especially FLT3-ITD
pathognomonic features: reactivity with specific histochemical stains; and/or wild-type NMP1 expression, is correlated with outcome of ther-
Auer rods in the cells (see Fig. 88–2B); or reactivity with a panel of apy (see “Effect of Molecular and Cytogenetic Markers on Disease Pro-
monoclonal antibodies against epitopes present on myeloblasts (e.g., gression and Therapeutic Responsiveness” above and Table 88–2).
CD13, CD33, CD117) (see Table 88–3). Leukemic myeloblasts give MicroRNAs regulate gene expression and the downregulation of the
positive histochemical reactions for myeloperoxidase, Sudan black B, or microRNA-181 family predicts a poor outcome. The microRNAs studied
naphthyl AS-D-chloroacetate esterase stains. Auer rods can be found also revealed several important gene families that appear to be involved
in the marrow blast cells in approximately one-sixth of cases. Blast cells in the pathogenesis of AML, including genes involved in innate immu-
may express granulocytic (CD15, CD65) or monocytic (CD11b, CD11c, nity (e.g., toll-like receptors and interleukin-1β expression and regula-
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CD14, CD64) surface antigens. They typically do not express either lym- tion). (Chapters 13 and 83 provide further discussion of gene-array
phoid surface markers or membrane or cytoplasmic immunoglobulin. profiling and microRNA analysis and the section “Other Acquired
No immunoglobulin gene rearrangement or T-lymphocyte receptor Mutations” on molecular pathogenesis has a more detailed discussion
gene rearrangement is evident with molecular probes (see “Hybrid and of specific molecular markers.) Microarray-based gene-expression pro-
Mixed Leukemias” below). In a proportion of otherwise typical cases filing is anticipated to become more important in precise diagnosis and
of AML, the cells may contain terminal deoxynucleotidyl transfer- subclassification of AML in the future. 310
ase (TdT). 273,274 Variations in marrow findings are discussed below in
“Morphologic Variants of Acute Myelogenous Leukemia.” Normal ery-
thropoiesis, megakaryocytopoiesis, and granulopoiesis are decreased or PLASMA CHEMICAL FINDINGS
absent in the marrow aspirate. The biopsy may contain residual islands Prior to treatment, mild to moderate increases in serum uric acid
of erythroblasts or megakaryocytes. Dysmorphic changes in hemato- and lactic dehydrogenase levels are frequent. Both levels are higher
poietic cells, including very small or large erythroblasts with nuclear in myelomonocytic and monocytic AML than in other AML
fragmentation or binucleation or delayed nuclear condensation; small phenotypes. 200,201 Occasional patients have very elevated uric acid lev-
or monolobed megakaryocytes; or hypogranulated, bilobed, or mono- els, which usually occur after chemotherapy if proper precautions are
lobed neutrophils, may occur in 30 to 50 percent of patients with not taken (e.g., hypouricemic agents and hydration therapy). Abnor-
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de novo AML. Marrow reticulin fibrosis is common but usually malities of sodium, potassium, calcium, or hydrogen ion concentration
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is slight to moderate except in cases of megakaryoblastic leukemia, are infrequent and usually mild. 312,313 Severe hyponatremia associated
in which intense fibrosis is the rule. Increased blood vessel density with inappropriate antidiuretic hormone secretion has occurred at
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(angiogenesis) is present in the marrow of patients with AML compared presentation. 312,313 Severe hypernatremia as a consequence of diabetes
to normal subjects. 277,278 Various angiogenic factors, including vascular insipidus can be an initial event. Hypokalemia is a more frequent
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endothelial growth factor (VEGF), basic fibroblast growth factor, angio- finding at presentation and is related to kaliuresis, although the reason
genin, and angiopoietin-1, are increased. VEGF detected histochem- for the proximal renal tubular dysfunction is unclear. 312,313,315 The hypo-
ically in human marrow is closely correlated with the prevalence of kalemia can be severe and often is worsened by the effects of treatment,
279
leukemic myeloblasts in the various AML subtypes. AML cytogenetic especially use of kaliuretic antibiotics. Factitious elevations in serum
315
280
variants may result in marrow basophilia (usually t(6;9)) or marrow potassium levels have been reported in patients with hyperleukocytosis
eosinophilia (usually inv16 or t(16;16)). 281
as a result of leakage from white cells in vitro. 316,317 Factitious hypogly-
cemia and spurious hypoxia from the effects of high blast cell counts in
Cytogenetic and Genic Features blood can occur. 314,318
An abnormal number (aneuploidy) or structure (pseudodiploidy) The presence of hypercalcemia is multifactorial, but cases
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of chromosomes or both are evident in approximately 55 percent of with increased ectopic parathormone-like activity in the plasma have
cases. 282–285 The most prevalent abnormalities are trisomy 8, mono- been described. Severe lactic acidosis prior to treatment has been
320
somy 7, monosomy 21, trisomy 21, and loss of an X or Y chromosome. reported. 312,321,322 Hypophosphatemia as a result of phosphate uptake
However, any chromosome can be rearranged, added, or lost (Chap. by leukemic cells can occur. Ectopic adrenocorticotropic hormone
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13). In cases of AML following chemotherapy or radiotherapy, loss secretion, circulating immune complexes, and abnormal concen-
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of part or all of chromosomes 5 and 7 are a common features, 286–288 as trations of coagulation factors or their inhibitors may be present.
326
are the cytogenetic findings noted above for AML, occurring de novo. Although prothrombin and partial thromboplastin times usually
Table 88–4 lists the most frequent abnormalities and translocations seen are normal or near normal, abnormal concentrations of coagulation
in AML. 282,283,286–308 The t(8;21) and inv(16) confer a more favorable out- factors are frequent. Elevations of platelet factor 4 and thromboxane
come on average. t(15;17) confers a highly favorable prognosis. Dele- B occur often. Decreases in α -antiplasmin, protein C, and antith-
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2
tion of all or part of chromosomes 5 and 7 or the presence of complex rombin III levels are frequent and may be associated with venous
327
changes (greater than 3 abnormalities) confers an unfavorable progno- thrombosis. APL and acute monocytic leukemia are associated with
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sis. Other findings (e.g., normal karyotype, +8, 11q23) generally confer hypofibrinogenemia and other indicators of activation of coagula-
an intermediate prognosis (Chap. 13 has further details and discussion tion or fibrinolysis (see “Morphologic Variants of Acute Myelogenous
regarding impact of specific translocations). 282–284 Leukemia” below). 329
Kaushansky_chapter 88_p1373-1436.indd 1383 9/21/15 11:01 AM