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1384 Part X: Malignant Myeloid Diseases Chapter 88: Acute Myelogenous Leukemia 1385

marrow (3 to 19 percent). Such cases have been referred to as oligoblastic malignancies and about one-quarter of cases occur in patients with
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myelogenous leukemia, subacute, or smoldering leukemia, or classified AML. Bone pain (approximately 80 percent of patients) and fever
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as a MDS, particularly refractory anemia with excess blasts. The clinical (approximately 70 percent of patients) are the two most common symp-
course of the untreated disease can be protracted. The disease has a high toms or signs. Anemia and thrombocytopenia, if not already present,
morbidity and mortality from infection and hemorrhage and can evolve results. White cell counts may be low or high. The blood may contain
into overt (polyblastic) AML. The smoldering or oligoblastic leukemias nucleated red cells and myeloid immaturity (approximately 50 percent
(refractory anemia with excess blasts) historically have been grouped of cases). Lactic dehydrogenase and alkaline phosphatase are elevated in
along with the clonal cytopenias as composing MDS; and, the diagnosis approximately 50 percent of cases. The marrow aspirate is often watery
and treatment of these variants are discussed in Chap. 87. Biologically and serosanguineous. An amorphous extracellular eosinophilic back-
and clinically, the disorders in this subset of the MDS with blast cell ground with disintegrating cells that have lost their staining charac-
proportions in the marrow above normal are leukemias, not dysplasias, teristics with indistinct margins and varying degrees of pyknosis and
but they have a slower rate of progression than polyblastic myelogenous karyorrhexis is characteristic. Rare cases have been described in which
leukemia. Dysmorphogenesis of red cells, neutrophils, and platelets is the marrow contained Charcot-Leyden crystals without an increase in
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more frequent and more striking than in the average case of polyblastic eosinophils or basophils. Bony spicules may also show evidence of
AML (Chap. 87), but such dysmorphogenesis also occurs in polyblastic necrosis. Destruction of spicule architecture with loss of osteocytes,
leukemia, so-called AML with trilineage dysmorphia. A discussion osteoblasts, and osteocytes may be seen. It is important not to identify
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of the spectrum of myelogenous leukemias, ranging from minimal to these changes as artifact. Usually more than 50 percent of the biopsy
severe deviation neoplasms, can be found in Chap. 83. is involved. Careful search may identify the underlying hematologic
disorder in small islands of intact cells. Technetium-99m sulfur colloid
Philadelphia Chromosome–Positive Acute Myelogenous scans show little or no uptake. Magnetic resonance imaging (MRI) may
Leukemia not be diagnostic but can show the extent of the necrosis by changes in
Approximately 2 percent of patients with AML have the Philadelphia signal intensity signifying an increase in water content in relation to fat.
(Ph) chromosome t(9;22)(q34;q11) in a significant proportion (10 Both technetium scanning and MRI can point to areas of intact marrow
to 100 percent) of leukemic blast cells. 356–358 The blast cells have sur- that may be used to make a diagnosis of the underlying disease, if it is
face antigens, such as CD13 and CD33, characteristic of myeloid unknown. The pathophysiology is uncertain but is thought to be related
leukemias. 359,360 One interpretation of the concurrence of AML with to marrow vascular injury and or thrombosis secondary to inflamma-
t(9;22) is that it represents CML presenting in myeloid blast crisis. 361–363 tory or immune factors and cytokines. The prognosis of marrow necro-
The arguments in favor of this proposal are as follows: (1) Blast crisis may sis is largely related to the underlying disease. Repair of marrow can
occur within days after diagnosis of Ph chromosome–positive CML. occur, if the patient enters remission.
(2) Cases can present with additional cytogenetic changes comparable
to CML in blast crisis. 361,363 (3) Marked hepatosplenomegaly, uncharac- NEONATAL MYELOPROLIFERATION
teristic of AML, may be present. 362,363 (4) Platelet counts may be normal,
and basophils can be increased. 361,363 (5) A long prodromal period of AND LEUKEMIA
weakness and weight loss may occur, and some features of CML, such as Four myeloproliferative syndromes related to AML have been identified
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granulocytosis, can appear after treatment with chemotherapy. (6) Ph in the neonate: transient myeloproliferative disorder, transient leuke-
chromosome–positive AML has a poor prognosis, as in myeloid blast mia, congenital leukemia, and neonatal leukemia. Transient myelopro-
crisis of CML. (7) The breakpoint on chromosome 22 in the M-bcr may liferative disorder and transient leukemia are considered to represent
be typical of CML, and the product of the fusion BCR-ABL gene is a the same phenomenon.
p210 tyrosine kinase identical to that of classic CML. 360,363–368 (8) Occa- Transient myeloproliferative disease (TMD) can be present at birth
sional cases express p210 and p190 tyrosine kinases, now known to be or occur shortly thereafter in approximately 10 percent of infants with
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features of CML. (9) Some patients enter a remission by converting Down syndrome. 378–384 The leukocyte count is markedly elevated, blast
to a phenotype analogous to chronic phase CML. An alternative view has cells are present in the blood and marrow, and anemia and thrombo-
been promulgated because (1) cases of Ph chromosome–positive AML can cytopenia may be present, but the latter are not constant findings. The
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be a mosaic (normal and abnormal karyotypes) ; (2) the Ph chromosome liver and spleen may be enlarged. Results of cytogenetic studies and
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may appear later in the course of the disease ; (3) additional chromosomal marrow cell culture studies are normal, except for trisomy 21, which
abnormalities often are different from those seen in the myeloblastic crisis is characteristic of Down syndrome. The blast cells usually have the
of CML 360,370,371 ; and (4) in some cases, the BCR-ABL gene is not encoding immunophenotype of megakaryocytes. In contrast to congenital leu-
a p210 but a p190 mutant tyrosine kinase, 357,365,368,372 the former being most kemia, the elevated white cell and blast cell counts disappear in most
characteristic of CML. Moreover, Ph chromosome–positive AML has patients (approximately 80 percent) over a period of weeks to months.
developed following Ph chromosome–negative oligoblastic myelogenous In approximately 20 percent of patients, severe and potentially lethal
leukemia. 357,373,374 Many cases of Ph chromosome–positive acute leukemia complications of hydrops fetalis, hepatic fibrosis, or cardiorespiratory
are myeloid-lymphoid hybrids. 364,368,370,375 Thus, Ph chromosome–positive failure may occur.
AML comes in two varieties: one with a break in M-BCR of chromo- In some cases, an additional cytogenetic abnormality is present,
some 22 with a p210 product, which could be considered analogous to which disappears after regression of the myeloproliferative syndrome,
acute blast crisis of CML, and one with a molecular pathology resulting in suggesting a reversible clonal disorder (transient leukemia) that is
the oncogene product being a p190 protein (m-BCR) that could be con- replaced by normal hematopoiesis. The presence of a trisomy of chro-
sidered a de novo case. mosome 21 is essential for the disease as judged by three observations:
the trisomy occurs in (1) the TMD clone of patients with constitutional
Marrow Necrosis trisomy 21, (2) the TMD clone in patients with Down syndrome with
Necrosis of the marrow is an uncommon event and can be seen in a wide a cell mosaic pattern of trisomy 21, and (3) in the TMD clone of phe-
variety of malignant and nonmalignant clinical disorders, but approx- notypically normal infants without a constitutional trisomy 21, but
imately two-thirds of cases are associated with lymphoid or myeloid with TMD. In the last case, trisomy 21 disappears with resolution of

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