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Leukemia - Acute

Acute myeloid leukemia (AML) - general

Reviewer: Syed Zaidi, M.D. (see Reviewers page)
Revised: 23 December 2011, last major update December 2011
Copyright: (c) 2001-2011, PathologyOutlines.com, Inc.

Definition
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● Also called acute myelogenous leukemia
● Clonal neoplastic proliferation of hematopoietic precursor cells, causing excessive myeloblasts and other immature myeloid cells

Clinical features
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● Malignant cells replace bone marrow, may infiltrate spleen, liver and lymph nodes and circulate in bloodstream
● Usually less nodal involvement than ALL
● 80% of adult leukemias but only 20% of childhood leukemias
● Neoplastic blasts have normal proliferation rates but reduced maturation rates compared to normal blasts

Risk factors:
● Most patients have none
● Drugs (alkylating agents, Topoisomerase II inhibition, antimetabolites, antitubulin agents), radiation therapy
● Down’s syndrome
● Bloom’s syndrome
● Fanconi’s anemia
● Neurofibromatosis
● Benzene exposure

Symptoms:
● Due to replacement of normal bone marrow cells by blasts
● Fatigue (due to anemia)
● Fever and opportunistic infections (due to neutropenia)
● Mucosal and cutaneous bleeding (due to thrombocytopenia)
● Tissue infiltration with myelomonocytic, monocytic and monoblastic leukemia, including gingival hyperplasia and leukemia cutis (monocytes tend to infiltrate)
● Sternal tenderness (due to bone marrow expansion)
● Neurological symptoms (due to CNS infiltration)

Laboratory:
● 50% have WBC > 10,000, 20% have WBC > 100,000
● Due to circulating blasts and other immature myeloid cells
● In aleukemic leukemia, peripheral blood lacks blasts, and must examine bone marrow

Diagnosis:
● Examination of blood, marrow smears and cytochemical stains is usually sufficient
● Immunostains may be required for poorly differentiated leukemia

Prognostic features
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Favorable Prognostic Factors:
● Young patients
● Rapid response to chemotherapy
● Favorable cytogenetics - see below

Unfavorable Prognostic Factors:
● Under age 2 or older than age 60
● Marked leukocytosis at diagnosis
● History of myelodysplastic syndrome
● FLT3 mutations (Blood 2006;108:3654, Blood 2002;99:4326)

Treatment
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● Chemotherapy cures 10-30% (induction, consolidation, maintenance phases)
● Allogeneic bone marrow transplantation cures 45-65%
● 5 year survival only 20% in adults, 50% in children (Oncologist 2007;12:341)

Micro description
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Peripheral smear:
● Anisopoikilocytosis (variation in size and shape of red blood cells)
● Nucleated red cells
● Neutropenia
● Thrombocytopenia
● Hypogranular and hyposegmented neutrophils
● Large atypical platelets

Aspirate Micro-Smears:
● Myeloblasts are usually larger than lymphoblasts of ALL
● Cytoplasm is more abundant, with fine azurophilic granules and Auer rods (abnormal crystallized azurophilic granules, particularly in promyelocytic leukemia)
● Delicate nuclear chromatin with 1-4 prominent nucleoli
● Often dysplastic, maturing myeloid cells

Micro-biopsy:
● Usually markedly hypercellular with immature appearing cells but no trilinear maturation
● By definition, at least 20% blasts
● Mitotic activity common
● May have myelofibrosis(though uncommon)
● See also descriptions of various AML subtypes
● Type I myeloblasts: no cytoplasmic granules; nucleus is large with delicate chromatin and prominent nucleolus
● Type II myeloblasts: 15-20 delicate cytoplasmic granules
● Type III myeloblasts: >15-20 cytoplasmic granules, but otherwise has features of a blast cell

Micro images
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Two myeloblasts each have a single prominent Auer rod


Auer rod in neutrophil

Molecular / cytogenetics description
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● 90% have chromosomal abnormalities
● De novo leukemia often has balanced translocations, but therapy related or post-myelodysplasia leukemia often has deletions or monosomy 5 or 7 without translocations

Favorable Cytogenetics:
● inv(16)(p13;q22), t(8;21)(q22;q22), t(15;17)(q22;q12)

Intermediate Cytogenetics:
● +8, t(6;9)(p23;q34), t(9;11)(p22;q23) in children
● Normal cytogenetics

Unfavorable Cytogenetics:
● -7, -5, del 7q, t(11q23), inv(3q), t(9;22)
● Complex abnormalities
● Post-chemotherapy or post-radiation therapy

Positive stains
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● Myeloid markers (CD13, CD14, CD15, CD33, CD36)
● CD99 (43% of AML, 55% of chloromas, Mod Pathol 2000;13:452)
● Often expresses B cell antigens CD20, CD7, PAX5, OCT2 or BOB.1 (Am J Clin Pathol 2006;126:916)
● VEGF expression varies by subtype (Am J Clin Pathol 2003;119:663)

Positive enzyme cytochemistry:
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● Myeloperoxidase (Mod Pathol 1991;4:733), Sudan Black B, chloroacetate esterase (stains lysosomes in granulocytes)
● Variable for acid phosphatase
● M4/M5 are positive for nonspecific esterase (alpha naphthyl butyrate esterase)
● M5/M6/M7 are positive for PAS
● Alpha-naphthyl acetate esterase (ANAE): also called modified nonspecific esterase; stains some T cells (Klin Lab Diagn 1993;6:38) and monocytic cells (Leuk Res 1998;22:25), but not erythroid cells
● Alpha-naphthyl butyrate esterase: also called nonspecific esterase; stains monocytes and some T cells (J Exp Med 1981;153:182)
● Chloroacetate esterase: also called specific esterase, naphthol AS-D chloroacetate esterase, Leder stain; stains granulocytes and mast cells, but not monocytes or lymphocytes

Negative stains
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● CD10

Flow cytometry description
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Immunohistochemmistry compared with flow cytometry:
● CD34 has similar findings
● CD15 and CD117 are more sensitive by flow
● Myeloperoxidase is more sensitive by immunohistochemistry (Arch Pathol Lab Med 2001;125:1063)

Differential diagnosis
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● Reactive process: growth factor treatment causes increased blasts
● Transient myeloproliferative disorder of newborns: resembles AML-M7, ALL, myelodysplastic syndrome

Additional references
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● eMedicine, Wikipedia, US National Cancer Institute

End of Leukemia - Acute > Acute myeloid leukemia (AML) - General

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