Acute Myelogenous Leukemia

Clinical Background

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

See Also

Human T-Lymphotrophic Virus Types I, II - HTLV I, II

Leukemia Lymphoma Phenotyping

Myelodysplastic Syndromes

Myeloproliferative Diseases - MPD

Tests

Tests generally appear in the order most useful for common clinical situations

Test name: Chromosome Analysis, Bone Marrow

ARUP #: 0097605

Methodology: Giemsa-Band Analysis

Use:

Detect chromosome abnormalities in bone marrow aspirate consistent with the diagnosis of AML, some of which also have classification and prognostic significance

Limitations:

Follow-up:

Repeat testing as clinically indicated to monitor disease progression

Test name: Chromosome Analysis, Leukemic Blood

ARUP #: 0097635

Methodology: Giemsa-Band Analysis

Use:

Detect chromosome abnormalities in the peripheral blood consistent with the diagnosis of AML, some of which also have classification and prognostic significance

Limitations:

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

Follow-up:

Test name: Chromosome Analysis, FISH-Interphase

ARUP #: 0092615

Methodology: Fluorescence in situ Hybridization

Use:

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

Limitations:

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

Follow-up:

Repeat testing as clinically indicated to monitor disease progression

Test name: PML/RARa t(15;17) Translocation by RT-PCR

ARUP #: 0056100

Methodology: Reverse Transcription Polymerase Chain Reaction

Use:

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)

Limitations:

Limit of detection is 1 in 1000 cells; test does not detect minimal residual disease

Follow-up:

Test name: NPM1 Mutation by PCR and Fragment Analysis, Paraffin

ARUP #: 0040179

Methodology: Polymerase Chain Reaction/ Fragment Analysis

Use:

Detect mutations in the NPM1 gene associated with AML prognosis

Limitations:

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

Test name: NPM1 Mutation by PCR and Fragment Analysis, Fluid

ARUP #: 0040174

Methodology: Polymerase Chain Reaction/ Fragment Analysis

Use:

May be useful in providing prognostic information

Limitations:

Results must be interpreted in context of morphologic and other relevant data

Should not be used to establish a diagnosis of malignancy

Test name: inv(16) for AML(CBFB-MYH11) by RT-PCR

ARUP #: 0092209

Methodology: Reverse Transcription Polymerase Chain Reaction

Use:

Detect presence of CBFB-MYH11 fusion transcripts in patients with AML-M4Eo or an indication of inv(16)

Limitations:

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

Follow-up:

Test name: FLT3 Mutation Detection by PCR

ARUP #: 0080377

Methodology: Polymerase Chain Reaction

Use:

Detect mutations in FLT3 gene in patient with AML

Limitations:

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

Follow-up:

Test name: AML1-ETO, t(8;21) Translocation by RT-PCR

ARUP #: 0050444

Methodology: Reverse Transcription Polymerase Chain Reaction

Use:

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

Limitations:

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

Follow-up:

Test name: Immunohistochemistry Stain Offering

ARUP #: arup005

Methodology: Immunohistochemistry

Use:

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), TdT and Glycoprotein A are available.

Additional Tests Available

Test name: Esterase Stain, Nonspecific

ARUP #: 0049050

Methodology: Cytochemical Stain

Comments: Determine monocytic lineage in acute myelogenous leukemia per World Health Organization (WHO) classification

Test name: Esterase Stain, Specific

ARUP #: 0049055

Methodology: Cytochemical Stain

Comments: Determine myeloid lineage in blasts of acute leukemiasUsed less often than the other stains for myeloid lineage because it is regarded as less sensitive and less consistent

Test name: Sudan Black B Stain

ARUP #: 0049040

Methodology: Stain

Comments:

Test name: Myeloperoxidase Stain

ARUP #: 0049030

Methodology: Cytochemical Stain

Comments:

Test name: Periodic Acid Schiff Stain

ARUP #: 0049045

Methodology: Stain

Comments: Will stain blasts in the majority of cases of acute lymphoblastic leukemia

Test name: Lysozyme, Serum or Body Fluid

ARUP #: 0050367

Methodology: Radial Immunodiffusion

Comments:

Test name: Lysozyme, Urine

ARUP #: 0050368

Methodology: Radial Immunodiffusion

Comments:

References

General References

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

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.

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.

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

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

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.

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

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

References from the ARUP Institute for Clinical and Experimental Pathology Research®

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.

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.

Medical Reviewers

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