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Disease Categories > Oncologic Disease > Lymphoma-Leukemia

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Acute Myelogenous Leukemia - AML

Acute myelogenous leukemia (AML) is a malignant neoplasm of hematopoietic cells.

Epidemiology

Incidence – about 11,000 new cases per year in the U.S.
Age – peaks in 6th decade
Gender – slight male predominance

Risk Factors

Acquired diseases – chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, idiopathic myelofibrosis
Environmental risk factors – alkylating agents, radiation, benzene paint and pesticides
Genetic – Down syndrome, Fanconi anemia, sibling with AML

Pathophysiology

Abnormal proliferation of myeloid precursor cells characterized by:
- Decreased rate of cell self-destruction
- Arrest of cellular differentiation
Leukemic cells have survival advantage
- Blasts and immature cells may populate peripheral blood but some patients present with leukopenia
- Leukemic cells infiltrate bone marrow
Current classification
- Based on blast cytogenetic features, cell of origin and morphology
- Genetic typing is important in classification and prognosis
- World Health Organization classification based on genetics and morphology
  - I. AML with recurrent genetic abnormalities
  - II. AML with multilineage dysplasia
  - III. AML & myelodysplastic syndrome; therapy mediated
  - IV. AML not otherwise categorized
    - M0 Minimally differentiated leukemia
    - M1 Myeloblastic without maturation
    - M2 Myeloblastic
    - M4 Myelomonocytic
    - M5b Monocytic
    - M5a Monoblastic
    - M6 Erythroleukemia
    - M7 Megakaryoblastic
  - V. AML of ambiguous lineage

Clinical Presentation

Nonspecific symptoms such as weakness, fever, lymphadenopathy, bruising, weight loss
Leukocytosis, infection
Thrombocytopenia, anemia
Disseminated intravascular coagulopathy (promyelocytic – AML-M3)
Chloroma – mass lesion of leukemic cells in tissue
Prognostic features include cytogenetics, age, pre-existing dysplasia

Diagnosis

Prompted by findings of anemia, thrombocytopenia and blasts on peripheral smear
Flow cytometry immunophenotyping is often necessary to establish that blasts are of myeloid lineage and can also detect low-level, post-treatment disease
- Bone marrow biopsy with chromosome analysis
  - Cytogenetics – Allow classification of leukemia
    - AML-M2 – t(8;21)
    - AML-M3 – t(15;17)
    - AML-M4Eo – t(16;16) or Inv(16)
    - Therapy-related AML – -7 or del(7q) and/or -5 or del(5q)
- Mutations
  - FLT3 (in cytogenetically normal AML) – worse prognosis if mutation present
  - NPM1 – associated with better prognosis
  - MLL-PTD – worse prognosis if present
  - BAALC – worse prognosis for high-level expression
  - MN1 – worse prognosis if present
  - CEBPA – better prognosis if present

Differential Diagnosis

Aplastic anemia
Drug-induced agranulocytosis
Myelodysplastic disorder

Disease Monitoring

Bone marrow biopsy with chromosome analysis

Indications for Ordering

Tests generally appear in the order most useful for common clinical situations
Click on number for test-specific information in the ARUP Laboratory Test Directory

Test Name and Number	Recommended Use	Limitations	Follow Up
Chromosome Analysis, Bone Marrow 0097605 Method: Giemsa-Band Analysis	Detect chromosome abnormalities in bone marrow aspirate consistent with the diagnosis of AML, some of which also have classification and prognostic significance		Repeat testing as clinically indicated to monitor disease progression
Chromosome Analysis, Leukemic Blood 0097635 Method: Giemsa-Band Analysis	Detect chromosome abnormalities in the peripheral blood consistent with the diagnosis of AML, some of which also have classification and prognostic significance	Number of dividing cells in the peripheral blood may be insufficient to allow for a full analysis of metaphase cells; bone marrow aspirate may be more informative
Chromosome Analysis, FISH-Interphase 0092615 Method: Fluorescence in situ Hybridization	Monitor disease and identify specific abnormalities suspected clinically Specific FISH probes must be requested and for this indication include t(15;17), t(8;21), inv(16), 11q23 rearrangements, monosomy 7 or 7q deletion, 5q deletion, +8, and 20q deletion	Limit of detection is probe dependent and around 1-5% in interphase nuclei Some of these abnormalities can also be detected in myelodysplastic and myeloproliferative disorders and therefore are not sufficient for diagnosis, but rather consistent with the suspected diagnosis	Repeat testing as clinically indicated to monitor disease progression
PML/RARa t(15;17) Translocation by RT-PCR 0056100 Method: Reverse Transcription Polymerase Chain Reaction	Identify AML-M3 (RUNX1/RUNX1T1) fusion Primer sets are designed to detect all 3 gene fusion patterns: type A (short, S-form, bcr-3), type B (long, L-form, bcr-1) and type B variant (variable, V-form, bcr-2)	Limit of detection is 1 in 1000 cells; test does not detect minimal residual disease
NPM1 Mutation by PCR and Fragment Analysis, Paraffin 0040179 Method: Polymerase Chain Reaction/ Fragment Analysis	Detect mutations in the NPM1 gene associated with AML prognosis	Results must be interpreted in context of morphologic and other relevant data Should not be used alone for diagnosis of malignancy A negative result does not preclude the presence of NPM1 mutations in rare AML cells below the detection limit of this test
NPM1 Mutation by PCR and Fragment Analysis, Fluid 0040174 Method: Polymerase Chain Reaction/ Fragment Analysis	May be useful in providing prognostic information	Results must be interpreted in context of morphologic and other relevant data Should not be used to establish a diagnosis of malignancy
inv(16) for AML(CBFB-MYH11) by RT-PCR 0092209 Method: Reverse Transcription Polymerase Chain Reaction	Detect presence of CBFB-MYH11 fusion transcripts in patients with AML-M4Eo or an indication of inv(16)	Test not intended to detect minimal residual disease Results must be interpreted in context of morphologic and other relevant data Should not be used alone for diagnosis of malignancy Negative result does not preclude: Presence of CBFB-MYH11 fusion transcripts below limit of detection Presence of type other than A, D or E
FLT3 Mutation Detection by PCR 0080377 Method: Polymerase Chain Reaction	Detect mutations in FLT3 gene in patient with AML	Negative result does not entirely exclude presence of FLT3 gene mutation Assay is a qualitative test and should not be used to detect minimal residual disease Must be interpreted in context of morphologic and other relevant data Should not be used alone for diagnosis of malignancy
AML1-ETO, t(8;21) Translocation by RT-PCR 0050444 Method: Reverse Transcription Polymerase Chain Reaction	Monitor persistent disease and when a diagnosis is suspected but standard cytogenetics are not available or do not show the abnormality Identify AML type FAB-M2	A negative result does not entirely exclude the presence of the t(8;21) Results of this test must always be interpreted in the context of morphologic and other relevant data and should not be used alone for a diagnosis of malignancy This test is not intended to detect minimal residual disease
Immunohistochemistry Stain Offering arup005 Method: Immunohistochemistry	For fixed tissue samples, consultative services as well as immunohistochemical staining for myeloperoxidase, CD15 (Leu M1), CD42b, CD45 (LCA), CD34(QBEND10), CD68 (Kp-1), CD117 (c-kit), Muramidase (lysozyme), myeloperoxidase, TdT and Glycoprotein A are available.

Additional Tests Available

Click on number for test-specific information in the ARUP Laboratory Test Directory

Test Name and Number	Comments
Esterase Stain, Nonspecific 0049050 Method: Cytochemical Stain	Determine monocytic lineage in acute myelogenous leukemia per World Health Organization (WHO) classification
Esterase Stain, Specific 0049055 Method: Cytochemical Stain	Determine myeloid lineage in blasts of acute leukemias Used less often than the other stains for myeloid lineage because it is regarded as less sensitive and less consistent
Sudan Black B Stain 0049040 Method: Stain
Myeloperoxidase Stain 0049030 Method: Cytochemical Stain
Periodic Acid Schiff Stain 0049045 Method: Stain	Will stain blasts in the majority of cases of acute lymphoblastic leukemia
Lysozyme, Serum or Body Fluid 0050367 Method: Radial Immunodiffusion
Lysozyme, Urine 0050368 Method: Radial Immunodiffusion

General References

Bain BJ. Diagnosis from the blood smear. N Engl J Med. 2005;353(5):498-507. (Link to PubMed)

Baldus CD, Mrozek K, Marcucci G, Bloomfield CD. Clinical outcome of de novo acute myeloid leukaemia patients with normal cytogenetics is affected by molecular genetic alterations: a concise review. Br J Haematol. 2007;137(5):387-400. (Link to PubMed)

Brunning RD et al. Acute Myeloid Leukaemia. In Jaffe ES et al. eds. WHO Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. pp. 75-108.

Estey E. Acute myeloid leukemia and myelodysplastic syndromes in older patients. J Clin Oncol. 2007;25(14):1908-1915. (Link to PubMed)

Haferlach T, Kern W, Schnittger S, Schoch C. Modern diagnostics in acute leukemias. Crit Rev Oncol Hematol. 2005;56(2):223-234. (Link to PubMed)

Lowenberg B, Downing JR, Burnett A. Acute myeloid leukemia. N Engl J Med. 1999;341(14):1051-1062. (Link to PubMed)

McKenna RW. Acute Myeloid Leukemia. In Kjeldsberg C, ed. Practical Diagnosis of Hematologic Disorders, 4th ed. Chicago: ASCP Press, 2006. pp. 457-498.

Pui CH, Schrappe M, Ribeiro RC, Niemeyer CM. Childhood and adolescent lymphoid and myeloid leukemia. Hematology (Am Soc Hematol Educ Program ). 2004;118-145. (Link to PubMed)

Pui CH. Childhood leukemias. N Engl J Med. 1995;332(24):1618-1630. (Link to PubMed)

Staudt LM. Molecular diagnosis of the hematologic cancers. N Engl J Med. 2003;348(18):1777-1785. (Link to PubMed)

References from the ARUP Institute for Clinical and Experimental Pathology®

Chen Z, Pasquini M, Hong B, DeHart S, Heikens M, Tsai S. The human Penumbra gene is mapped to a region on chromosome 7 frequently deleted in myeloid malignancies. Cancer Genet Cytogenet. 2005;162(2):95-98. (Link to PubMed)

Yang DT, Greenwood JH, Hartung L, Hill S, Perkins SL, Bahler DW. Flow cytometric analysis of different CD14 epitopes can help identify immature monocytic populations. Am J Clin Pathol. 2005;124(6):930-936. (Link to PubMed)

Reviewed by

Bahler, David W., M.D., Ph.D. Medical Director, Hematologic Flow Cytometry, and Acting Medical Director, Molecular Hematopathology at ARUP Laboratories; Associate Professor, Pathology, University of Utah

Lamb, Allen N., Ph.D. Medical Director, Cytogenetics, ARUP Laboratories; Associate Professor, Department of Pathology, University of Utah

Layfield, Lester , M.D. Fine-Needle Aspiration Services and Molecular Diagnostics at ARUP Laboratories; Professor and Division Head, Anatomic Pathology, University of Utah

Perkins, Sherrie L. , M.D., Ph.D. Medical Director, Hematopathology at ARUP Laboratories; Professor, Anatomic Pathology, University of Utah

South, Sarah T. , Ph.D. Medical Director, Cytogenetics at ARUP Laboratories; Assistant Medical Director, CGH Microarray Laboratory, and Assistant Professor, Department of Pediatrics, University of Utah

Comprehensive Review: January 2008
Last Update: January 2008