eMedicine Specialties > Pediatrics: General Medicine > Oncology

Acute Myelocytic Leukemia: Differential Diagnoses & Workup

Author: Mark E Weinblatt, MD, Chief, Division of Pediatric Hematology/Oncology, Professor of Clinical Pediatrics, Department of Pediatrics, Winthrop University Hospital
Contributor Information and Disclosures

Updated: Jul 15, 2009

Differential Diagnoses

Other Problems to Be Considered

Aplastic anemia
Drug-induced pancytopenia
Transient myeloproliferative syndrome in Down syndrome

Workup

Laboratory Studies

• Blood counts and blood smears
  • The hallmark of acute myeloid leukemia (AML) is a reduction or absence of normal hematopoietic elements. Anemia is usually normocytic, with a reticulocyte count lower than expected for the level of the hemoglobin. The decrease in hemoglobin levels can range from minimal to profound.
  • Platelet counts are usually low and generally commensurate with the degree of bleeding. Patients with spontaneous petechiae usually have platelet counts of less than 20 X 10⁹/L (<20,000/μL).
  • WBC counts may be decreased or elevated. Hyperleukocytosis with WBC counts of more than 100 X 10⁹/L (>100,000/μL) are occasionally observed; with high numbers, the blood specimen appears white. The WBC differential is usually the key to evaluating suspected leukemia; primitive granulocyte or monocyte precursors are observed on peripheral smears. Numbers of mature neutrophils are usually diminished.
  • Upon careful examination of the blood smears, Auer rods (thin, needle-shaped eosinophilic cytoplasmic inclusions) are revealed in specimens of circulating blood obtained from many patients acute myelocytic leukemia. They are particularly prominent in children with acute promyelocytic leukemia (APL).
• Blood chemistries and other blood work
  • Both serum uric acid and lactic dehydrogenase levels are frequently elevated as a consequence of increased cell proliferation and destruction.
  • Serum muramidase (lysozyme) levels are usually increased in patients with monocytic leukemias.
  • Other signs of tumor lysis, including hyperkalemia, hypocalcemia, and lactic acidosis, may be present.
  • Blood and urine cultures should always be obtained in a child with fever and leukemia.
  • Coagulation tests should also be performed during initial diagnosis to look for evidence of disseminated intravascular coagulation that might suggest APL.

Imaging Studies

Imaging studies are not required for the diagnosis or extent of disease evaluation of children with acute myeloid leukemia. They can be helpful in managing complications that arise.

• Radiography
  • Routine chest radiography should be performed to rule out mediastinal masses, particularly in patients with respiratory symptoms or suspected superior vena cava syndrome.
  • If the patient has abdominal pain and distention, abdominal images often depict free air suggestive of a perforation.
  • Radiograph examination of the extremities may reveal findings such as metaphyseal bands at the distal femurs (most commonly observed in young children with ALL), periosteal new bone formation, focal lytic lesions, or pathologic fractures.
• CT and MRI
  • If the patient has abdominal pain and possible infection of the large bowel, CT may reveal thickening and edema of the bowel wall suggestive of typhlitis.
  • If a patient has neurologic symptoms, CT or MRI of the head, spine, or other involved region is mandatory to rule out intracranial hemorrhage or infiltrative disease.
  • CT scanning may also allow early detection of asymptomatic sinusitis that might cause persistent, unexplained fevers.
• Sonography
  • Because serious infections that affect heart function are routinely observed in this patient population, periodic cardiac monitoring is important.
  • Perform echocardiography before chemotherapy.
  • Most treatment regimens include anthracyclines, such as daunomycin and idarubicin, which may cause clinically significant cardiomyopathy.
• Radionuclide imaging
  • Radionuclide imaging is often used to detect occult infection that cultures and other imaging modalities do not reveal.
  • Technetium bone scans often help in localizing an occult osteomyelitis.
  • Whole-body gallium or indium scanning often reveals an occult deep tissue infection and can help with appropriate antibiotic management.

Other Tests

• Tests of cytogenetic markers, histochemical staining, and immunophenotyping
  • Leukemia cells demonstrate clonal cytogenetic abnormalities in more than 85% of patients. These changes are often unique to the subtype. For example, the t(15;17) translocation is nearly always found in patients with APL, whereas t(8;21) is most commonly found in those with myeloblastic leukemia. Some of the cytogenetic abnormalities have now been shown to confer either greater risk of recurrent disease (eg, monosomy 7 and monosomy 5) or lower risk (eg, t[8;21] and inv[16]/t[16;16]).
  • In addition to standard Wright-Giemsa stains, histochemical stains help in differentiating the various acute leukemias. Positive periodic acid-Schiff stains indicate acute biphenotypic leukemia or undifferentiated leukemia with lymphoblastic features. Most acute myeloid leukemia cells have strong positive reactions to myeloperoxidase and Sudan black stains. Esterase stains findings usually help in differentiating myeloid (specific esterase positive) from monocytic (nonspecific esterase positive) leukemia.
  • Monoclonal antibodies specific for different cell lineages and stages of development are routinely used to further characterize the leukemic cells. The most common myeloid markers are CD13, CD14, CD15, and CD33, with more than 90% of leukemic cells demonstrating positivity to some of these antigens. CD34 is frequently found in acute myeloid leukemia blasts.
• Molecular studies
  • In addition to the established prognostic cytogenetic abnormalities, increasing evidence has revealed various molecular abnormalities that have an impact on outcome. The presence of the FLT3/ITD mutation, a receptor tyrosine kinase mutation, has been established as a predictor of worse outcome. These findings on the blast cells are now used to further stratify patients into risk groups with different treatment strategies. 
  • Another gene affecting prognosis is the nucleophosmin (NPM1) mutation. The presence of this mutation has been shown to confer a favorable prognosis for event-free survival, although the combination of NPM1 and FLT3 mutations found in many patients is not favorable.
  • The presence of MLL gene is usually an unfavorable prognostic marker. The presence of the Wilms tumor gene (WT1) is also an adverse prognostic marker, with patients often failing to achieve complete remission.
• Human leukocyte antigen (HLA) typing
  • HLA-matched family donors should be identified because bone marrow transplantation (or hematopoietic stem cell transplantation) may be considered in high-risk patients.
  • At the time of diagnosis, the donor screening process should be started by obtaining blood for HLA matching from the patient and immediate family members.

Procedures

• Bone marrow examination
  • Bone marrow examination is necessary to establish the diagnosis of AML. The sample is examined under the microscope at which time the percentage of different cells are tabulated. The hallmark of leukemia is the presence of a high proportion of primitive cells and a paucity of normal hematopoietic elements.
  • Bone marrow aspirates and biopsy samples demonstrate the characteristic replacement of normal marrow elements with the monotonous sheets of leukemic blasts.
  • Acute myeloid leukemia can be divided into subtypes on the basis of marrow findings. Some of these subtypes have characteristic clinical pictures. The French-American-British classification system recognizes 7 primary types of AML (M1-M7), which can usually be established with additional marrow studies. The World Health Organization has classified acute myeloid leukemias into groups, including the following: acute myeloid leukemia with recurrent cytogenetic translocations (eg, promyelocytic leukemia with typical t[15;17]), acute myeloid leukemia with multilineage dysplasia, acute myeloid leukemia and myelodysplasia syndromes secondary to therapy (eg, those following alkylating agents), and acute myeloid leukemia not otherwise categorized (eg, erythroid leukemias, monocytic leukemias).
  • The preferred site is the iliac crest, either anterior or posterior. The tibia may be an alternative source of marrow for diagnostic purposes in infants, although rarely required as a preferred site. Rarely, a sternal biopsy is necessary; this can sometimes be required in children with extensive marrow fibrosis. The sternal site is generally more painful and entails the risk of heart damage if the needle penetrates deeply beyond the sternal bone.
  • Although bone marrow aspiration is usually sufficient to establish the diagnosis and to follow up the progress of the disease, a core biopsy may be necessary if one encounters a "dry tap."  This can happen when a marrow is heavily infiltrated or when significant fibrosis of the bone marrow is present.
  • Biopsy is necessary to gauge the cellularity of a marrow specimen and was the former standard during follow-up to aid subsequent therapeutic decisions. However, biopsy is now less commonly used as the disease status can usually be evaluated with marrow aspirations and immunologic and cytogenetic testing.
• Lumbar puncture and cerebrospinal fluid (CSF) examination
  • Lumbar puncture is necessary for diagnostic and therapeutic reasons.
  • Even if the marrow is not involved at the time of diagnosis, CNS seeding can occur later. Therefore, periodic surveillance lumbar puncture with the administration of intrathecal chemotherapy is necessary.
  • Although the CSF is less frequently involved in acute myeloid leukemia than in acute lymphoblastic leukemia (ALL), leukemic infiltration has been reported in 5-20% of patients with acute myeloid leukemia, depending on the study. The greatest risk is seen in patients with monocytic subtypes, in infants, and in children with hyperleukocytosis on presentation.
  • CSF samples should be obtained before any therapy is begun. Fluid should be sent for cytologic evaluation in addition to the usual cell counts and chemical tests.
  • Intrathecal chemotherapy is administered simultaneously and repeated intermittently to treat or prevent CNS involvement. 
• Placement of a central venous catheter
  • Because of the patient's need for intense chemotherapy and supportive care, guaranteed venous access is critical. An indwelling central venous catheter with at least 2 lumens is usually placed before the start of therapy. This catheter provides access for infusing chemotherapeutic drugs and for providing intravenous nutritional support, transfusions, antibiotics, and other supportive medications. In addition, they allowing for blood withdrawal for required testing.
  • Subcutaneous ports and peripheral indwelling central catheters in the cubital area are sometimes used. These are sometimes added when patients require additional therapy, such as stem cell transplantation, or when a temporary access situation develops (as when an indwelling central line is removed because of infection).

Histologic Findings

• Bone marrow examination usually reveals characteristic hyperplastic marrow with monotonous replacement with leukemia cells.
• Patients with low blast count t(8;21) can also present a diagnostic challenge, sometimes considered a myelodysplastic syndrome, and often require multiple marrow examinations before the diagnosis of leukemia is confirmed.   Other patients with myelodysplasia have less than 20% of blast cells, megaloblastic features, and a decrease in the normal hematopoietic cell population.
• Pronounced fibrosis is often observed, particularly in the acute megakaryoblastic subtype (M7).

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