Page 1042 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 59 Clinical Manifestations and Treatment of Acute Myeloid Leukemia 925

may result in evolution and progression. An interesting aspect of such DIAGNOSIS AND CLASSIFICATION
a dynamic model of acquisition of genetic abnormalities is the pos-
sibility that AML therapy itself may induce further genetic changes The diagnosis of AML relies on morphologic evaluation (cytochemi-
and become a driving force in selection of some AML clones over cal stains), immunophenotyping by flow cytometry, and assessment
others. 2,3 of karyotype and molecular studies (Fig. 59.1).
Blast percentage is best determined on a 500-cell differential of
the marrow aspirate. Three broad types of myeloblasts are described
CLINICAL AND LABORATORY MANIFESTATIONS based on the granular content and nuclear features of the blasts (type
1: agranular basophilic cytoplasm, nucleus with fine chromatin, and
Signs and symptoms of AML mostly reflect the effect of cytopenias. two to four distinct nucleoli; type 2: basophilic cytoplasm with 20
Patients typically present with a short history (1–8 weeks) of consti- or fewer azurophilic granules and similar nuclear features as type 1
tutional complaints (fatigue, lack of energy, malaise, profuse sweats), blasts; type 3: basophilic cytoplasm with more than 20 azurophilic
manifestations of bleeding (such as from gums, bruising in the skin, granules), although the morphologic variety of blasts exceeds the
epistaxis, menorrhagia), or fevers. Fevers should always be presumed defined categories (Fig. 59.2). Promyelocytes have moderately baso-
to be secondary to infections even in the absence of an identifiable philic cytoplasm with numerous azurophilic granules, and monoblasts
focus and lead to rapid institution of antibiotic therapy. “Tumor and promonocytes usually exhibit folded/convoluted nuclei and may
fever” remains a diagnosis of exclusion. Extramedullary infiltrations contain prominent acidophilic nucleoli. Promyelocytes, promono-
of leukemia cells in the gingiva, skin, lymph nodes, or other organs cytes, and atypical pronormoblasts are considered blast equivalents in
occur occasionally. Bone pains are infrequent even with excessive some subgroups (e.g., APL, acute monoblastic leukemia, and acute
leukocytosis and should raise the suspicion of an acute lymphoblastic erythroleukemia, pure erythroid type). Micromegakaryocytes and
leukemia (ALL), especially in children. Likewise, signs and symptoms pronormoblasts are not considered blasts (see Fig. 59.2K and L). Auer
referable to central nervous system (CNS) involvement (cranial rods are rod-like filaments of aggregated primary granules that are
nerve defects and other focal neurologic abnormalities, mental status found in 30% to 50% of newly diagnosed patients with AML and,
changes, seizure activity) are rare, with the exception of AML with if present, are one of the hallmark morphologic features to establish
monocytic/monoblastic differentiation or in any AML with consider- a diagnosis of AML (see Fig. 59.2C). AML marrows are typically
able leukocytosis (>100,000/µL). hypercellular with decreased or absent megakaryocytes. Exceptions
Signs at physical examination are often nonspecific but in their are marrows of older patients or those with therapy-related AML,
aggregate can lead to a correct diagnosis. It is impossible to distinguish which may be hypocellular with dysplastic changes of one or several
AML from ALL based solely on clinical presentation or examination hematopoietic lineages. Prominent dysplasia may suggest a previous
findings. Patients may demonstrate pallor, ecchymoses or petechiae, diagnosis of myelodysplastic syndrome (MDS) but can also be found
enlargement of lymph nodes, or rarely, hepatosplenomegaly. Exami- in patients with de novo AML, where the prognostic significance of
nation of the lungs may reveal signs of symptoms of an infectious dysplastic changes is less clear. Cases with extensive fibrosis may
process. Some patients with AML have no abnormal findings on represent a preceding myeloproliferative neoplasm or acute mega-
physical examination. karyocytic leukemia.
The laboratory evaluation should include blood counts with evalu- Several cytochemical reactions further highlight morphologic
ation of the blood smear, a standard chemistry panel (electrolytes, characteristics (myeloperoxidase [MPO], periodic acid–Schiff, Sudan
urea nitrogen, creatinine, total bilirubin, transaminases, uric acid, black B, naphthol AS-D chloroacetate esterase [specific esterase],
lactate dehydrogenase [LDH]), and coagulation studies, including α-naphthyl acetate/butyrate esterases [nonspecific esterases], acid
prothrombin time (PT), partial thromboplastin time (PTT), and phosphatase; Fig. 59.3). MPO is the most specific granulocytic marker,
fibrinogen levels. Anemia and thrombocytopenia are universal. The and MPO positivity in at least 3% of the blasts is consistent with a
white blood cell (WBC) count can vary from low to high and will diagnosis of AML. On the other hand, lack of MPO staining does not
range from 5000/µL to 100,000/µL in most patients. The highest rule out AML because it is often not present in AML with minimal
degrees of leukocytosis can be seen in AML with myelomonocytic differentiation, acute monoblastic leukemia, and acute megakaryocytic
differentiation. Leukocytosis of 100,000/µL or higher is considered leukemia. Monoblastic leukemias are stained by nonspecific esterases.
an emergency and requires immediate efforts to reduce the disease Whereas the MPO reaction is relatively uncomplicated and results are
burden (e.g., leukapheresis, chemotherapy) because (1) leukostasis available quickly, this is not the case with most of the other cytochemi-
in some vascular beds may have catastrophic consequences (e.g., cal reactions, and their diagnostic utility is nowadays mostly outdone
lung, brain), and (2) it may elicit a systemic inflammatory response by immunophenotyping by flow cytometry.
with serious secondary organ damage (e.g., diffuse alveolar injury, The first systematic attempt of an AML classification goes back
hepatic failure). However, there is not always a good correlation to the French–American–British (FAB) group, and was based solely
between the severity of leukocytosis and immediate adverse clini- on morphology (blast percentage, degree of differentiation, lineage
cal effects, and far lower WBC levels may elicit life-threatening involvement). Because of its limited scope, the FAB system is now
symptoms. The WBC must therefore be assessed in the context considered inadequate. Rapidly growing insights from genetic muta-
of the patient’s overall physical condition and other clinical and tion analyses, their association with prognosis, and, in some cases,
laboratory abnormalities (e.g., LDH, uric acid, coagulation param- prediction of response to therapy triggered a revision of the old
eters). Disseminated intravascular coagulation (DIC) is often seen system and led to the changes in the 2008 edition of the World
in patients with myelomonocytic AML, APL, and any high-WBC Health Organization (WHO) classification of AML. The focus has
AML. PT, PTT, and fibrinogen levels should be carefully followed shifted to identification of recurrent cytogenetic–molecular abnor-
and coagulation factors be replaced as clinically indicated. Subclinical malities, information regarding exposure to prior chemotherapy and/
DIC is common in many forms of AML and can worsen with the or radiation therapy, and morphologic features related to dysplasia-
institution of therapy. Abnormalities of renal and hepatic values may related changes and remnants of the FAB system (Table 59.1). Several
represent infiltration of these organs, even in the absence of clinical categories have been defined:
symptoms.
Imaging studies are of little help in diagnosis but allow assess- 1) AML with recurrent genetic abnormalities. This includes AML
ment of complications (pneumonia, cerebral bleed). If patients with relatively common cytogenetic changes: AML with t(8;21)
present with any neurologic deficit, the threshold for computed (q22;q22), RUNX1-RUNX1T1 (Fig. 59.4); AML with inv(16)
tomography (CT) scan (noncontrast if bleeding is of concern) or (p13.1q22) or t(16;16)(p13.1;q22), CBFB-MYH11 (Fig. 59.5);
any other imaging modality of the brain should be low. Further AML with t(15;17)(q22;q12); PML-RARA (Fig. 59.6); and AML
evaluations should be based on the clinical assessment of the with t(9;11)(p22;q23), MLLT3-MLL (Fig. 59.7). Less common
patients. Text continued on p. 930