eMedicine Specialties > Hematology > Stem Cells and Disorders

Chronic Myelogenous Leukemia: Differential Diagnoses & Workup

Author: Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Coauthor(s): Ulrich Woermann, MD, Consulting Staff, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland
Contributor Information and Disclosures

Updated: Feb 6, 2009

Differential Diagnoses

Agnogenic Myeloid Metaplasia With Myelofibrosis
Myelodysplastic Syndrome
Myeloproliferative Disease
Polycythemia Vera

Other Problems to Be Considered

Acute myeloid leukemia
Chronic myelomonocytic leukemia
Chronic neutrophilic leukemia
Essential thrombocytosis/thrombocythemia
Leukemoid reactions from infections (chronic granulomatous [eg, tuberculosis])
Myelodysplasia
Tumor necrosis

Workup

Laboratory Studies

• Peripheral blood findings in patients with chronic myelogenous leukemia (CML) show a typical leukoerythroblastic blood picture, with circulating immature cells from the bone marrow (see Image 4 and below).
  

  

  Bone marrow film at 400X magnification demonstrates clear dominance of granulopoiesis. The number of eosinophils and megakaryocytes is increased. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

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  Bone marrow film at 400X magnification demonstrates clear dominance of granulopoiesis. The number of eosinophils and megakaryocytes is increased. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

• The increase in mature granulocytes and normal lymphocyte counts (low percentage due to dilution in the differential count) results in a total WBC count of 20,000-60,000 cells/μL. A mild increase in basophils and eosinophils is present and becomes more prominent during the transition to acute leukemia.
  • These mature neutrophils, or granulocytes, have decreased apoptosis (programmed cell death), resulting in accumulation of long-lived cells with low or absent enzymes, such as alkaline phosphatase (ALP). Consequently, the leukocyte alkaline phosphatase stains very low to absent in most cells, resulting in a low score.
  • Early myeloid cells such as myeloblasts, myelocytes, metamyelocytes, and nucleated red blood cells are commonly present in the blood smear, mimicking the findings in the bone marrow. The presence of the different midstage progenitor cells differentiates this condition from the acute myelogenous leukemias, in which a leukemic gap (maturation arrest) or hiatus exists that shows absence of these cells.
  • A mild to moderate anemia is very common at diagnosis and is usually normochromic and normocytic.
  • The platelet counts at diagnosis can be low, normal, or even increased in some patients (>1 million in some).
• The bone marrow is characteristically hypercellular, with expansion of the myeloid cell line (eg, neutrophils, eosinophils, basophils) and its progenitor cells. Megakaryocytes (see Image 5 and below) are prominent and may be increased. Mild fibrosis is often seen in the reticulin stain.
  

  

  The Philadelphia chromosome, which is a diagnostic karyotypic abnormality for chronic myelogenous leukemia, is shown in this picture of the banded chromosomes 9 and 22. Shown is the result of the reciprocal translocation of 22q to the lower arm of 9 and 9q (c-abl to a specific breakpoint cluster region [bcr] of chromosome 22 indicated by the arrows). Courtesy of Peter C. Nowell, MD, Department of Pathology and Clinical Laboratory of the University of Pennsylvania School of Medicine.

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  The Philadelphia chromosome, which is a diagnostic karyotypic abnormality for chronic myelogenous leukemia, is shown in this picture of the banded chromosomes 9 and 22. Shown is the result of the reciprocal translocation of 22q to the lower arm of 9 and 9q (c-abl to a specific breakpoint cluster region [bcr] of chromosome 22 indicated by the arrows). Courtesy of Peter C. Nowell, MD, Department of Pathology and Clinical Laboratory of the University of Pennsylvania School of Medicine.

• Cytogenetic studies of the bone marrow cells, and even peripheral blood, should reveal the typical Ph1 chromosome, which is a reciprocal translocation of chromosomal material between chromosomes 9 and 22. This is the hallmark of chronic myelogenous leukemia (CML), found in almost all patients with the disease, and is present in CML throughout its entire clinical course.
  • The Ph translocation is the translocation of the cellular oncogene c-abl from the 9 chromosome, which encodes for a tyrosine protein kinase, with a specific breakpoint cluster region (bcr) of chromosome 22, resulting in a chimeric bcr/c-abl messenger RNA that encodes for a mutation protein with much greater tyrosine kinase activity compared with the normal protein (see Image 5 and above). The latter is presumably responsible for the cellular transformation in chronic myelogenous leukemia (CML). This m-RNA can be detected by polymerase chain reaction (PCR) in a sensitive test that can detect it in just a few cells. This is useful in monitoring minimal residual disease (MRD) during therapy.
  • Karyotypic analysis of bone marrow cells requires the presence of a dividing cell without loss of viability because the material requires that the cells go into mitosis to obtain individual chromosomes for identification after banding, which is a slow, labor-intensive process. The new technique of fluorescence in situ hybridization (FISH) (see Image 6 and below) uses labeled probes that are hybridized to either metaphase chromosomes or interphase nuclei, and the hybridized probe is detected with fluorochromes. This technique is a rapid and sensitive means of detecting recurring numerical and structural abnormalities.
    

    

    Fluorescence in situ hybridization using unique-sequence, double-fusion DNA probes for bcr (22q11.2) in red and c-abl (9q34) gene regions in green. The abnormal bcr/abl fusion present in Philadelphia chromosome–positive cells is in yellow (right panel) compared with a control (left panel). Courtesy of Emmanuel C. Besa, MD.

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    Fluorescence in situ hybridization using unique-sequence, double-fusion DNA probes for bcr (22q11.2) in red and c-abl (9q34) gene regions in green. The abnormal bcr/abl fusion present in Philadelphia chromosome–positive cells is in yellow (right panel) compared with a control (left panel). Courtesy of Emmanuel C. Besa, MD.

  • Two forms of the BCR/ABL mutation are present, depending on the location of their joining regions on bcr 3' domain. Approximately 70% of patients who have the 5' DNA breakpoint have a b2a2 RNA message, and 30% of patients have a 3' DNA breakpoint and a b3a2 RNA message. The latter is associated with a shorter chronic phase, shorter survival, and thrombocytosis.
  • Chronic myelogenous leukemia (CML) should be differentiated from Ph-negative diseases with negative PCR results for BCR/ABL m-RNA. These diseases include other myeloproliferative disorders and chronic myelomonocytic leukemia, which is now classified with the myelodysplastic syndromes.
  • Additional chromosomal abnormalities, such as an additional or double Ph-positive chromosome or trisomy 8, 9, 19, or 21; isochromosome 17; or deletion of the Y chromosome, have been described as the patient enters a transitional form or accelerated phase of the blast crisis as the Ph chromosome persists.
  • Patients with conditions other than chronic-phase chronic myelogenous leukemia (CML), such as newly diagnosed acute lymphocytic leukemia (ALL) or nonlymphocytic leukemia, may also be positive for the Ph chromosome. Some consider this the blastic phase of CML without a chronic phase. The chromosome is rarely found in patients with other myeloproliferative disorders, such as polycythemia vera or essential thrombocythemia, but these are probably misdiagnosed chronic myelogenous leukemia (CML). It is rarely observed in myelodysplastic syndrome.
• Other laboratory abnormalities include hyperuricemia, which is a reflection of high bone marrow cellular turnover and markedly elevated serum vitamin B-12 – binding protein (TC-I). The latter is synthesized by the granulocytes and reflects the degree of leukocytosis.

Imaging Studies

• Typical hepatomegaly and splenomegaly may be imaged by using a liver/spleen scan. Most often, these are so obvious that radiologic imaging is not necessary.

Histologic Findings

The diagnosis of chronic myelogenous leukemia (CML) is based on the histopathologic findings in the peripheral blood and the Ph1 chromosome in the bone marrow cells.

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