Bone marrow neoplastic
Bone marrow - neoplastic myeloid
General
AML general
Author: Syed Zaidi, M.D.
Topic Completed: 1 December 2011
Minor changes: 12 February 2021
Copyright: 2001-2021, PathologyOutlines.com, Inc.
PubMed Search: Acute myeloid leukemia AML [title] pathology
Table of Contents
Definition / general | Clinical features | FLT3 mutations | Prognostic factors | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Positive enzyme cytochemistry | Negative stains | Flow cytometry description | Molecular / cytogenetics description | Differential diagnosis | Additional referencesCite this page: Zaidi S. AML general. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/leukemiaAMLgeneral.html. Accessed March 7th, 2021.
Definition / general
- Also called acute myelogenous leukemia
- Clonal neoplastic proliferation of hematopoietic precursor cells causing excessive myeloblasts and other immature myeloid cells
Clinical features
- 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 syndrome
- Bloom syndrome
- Fanconi 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
FLT3 mutations
Definition / general:
Prognostic factors:
Treatment:
Microscopic (histologic) description:
Molecular / cytogenetics description:
- Not a WHO diagnosis
- Mutations of FMS related tyrosine kinase 3 (FLT3, gene located on 13q12) occur in all types of AML and MDS (Atlas of Genetics and Cytogenetics: FLT3 [Accessed 29 March 2018])
- Most frequent molecular abnormality in AML (20 - 40% of cases)
- AML: mutations occur most often in t(6;9)(p23;q34), APL t(15;17), AML with normal karyotype
- Usually peripheral leukocytosis and normal cytogenetics
- CD135 is receptor for FLT3 ligand / FLT3L
Prognostic factors:
- Mutations include internal tandem duplication within juxtamembrane domain (ITD, 75 - 80%) and tyrosine kinase domain (TKD) in codon 836 (20 - 35%)
- FLT3-ITD: poor prognosis (Blood 2002;100:1532)
- FLT3-ITD with NPM1, t(15;17), t(8;21), inv(16) and t(16;16): worse prognosis
- FLT3-ITD with CEBPA: unclear prognosis
- FLT3-TKD: doesn't affect prognosis (Blood 2008;111:2527)
Treatment:
- C220 and midostaurin are in phase II clinical trials for AML patients with FLT3 mutations (Clinical Trials)
- Sorafenib may show significant activity (Blood 2009;113:6567, J Natl Cancer Inst 2008;100:184)
Microscopic (histologic) description:
- Monocytic differentiation
- Usually AML M2, M4, M5b (Blood 2008;111:2527)
Molecular / cytogenetics description:
- Usually normal cytogenetics
- Most common mutation is internal tandem duplication mutation (ITD)
- Cooperating mutations with NPM1, CEBPA and MLL-PTD
Prognostic factors
Favorable prognostic factors:
Unfavorable 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
- 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)
Microscopic (histologic) description
Peripheral smear:
Aspirate micro smears:
Micro biopsy:
- 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
Microscopic (histologic) images
AFIP images
Two myeloblasts each have a single prominent Auer rod
Auer rod in neutrophil
Positive stains
- 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
- 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
Flow cytometry description
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)
Molecular / cytogenetics description
- 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
- Postchemotherapy or postradiation therapy
Differential diagnosis
- Reactive process: growth factor treatment causes increased blasts
- Transient myeloproliferative disorder of newborns: resembles AML-M7, ALL, myelodysplastic syndrome
