Articles on Medical Diseases and Conditions

Tag: Chronic Myelogenous Leukemia

  • Differential Diagnosis of Chronic Myelogenous Leukemia, Agnogenic Myeloid Metaplasia, and Leukemoid Reaction

    When CML has the typical picture of a WBC count more than 100,000/mm3 (100 x 109/L) with myelocytic predominance, increased platelets, and basophilia, the diagnosis is reasonably safe. Otherwise, the two conditions that most frequently enter the differential diagnosis are agnogenic myeloid metaplasia and leukemoid reaction. CML tends to have a greater degree of leukocytosis than AMM or leukemoid reactions, so that WBC counts more than 100,000/mm3 are more likely to be CML. An increased basophil count is more likely to occur in CML than in AMM and is not expected in leukemoid reactions. More than an occasional teardrop cell is more often seen in AMM than in CML, whereas teardrop cells are not expected in leukemoid reactions.

    Bone marrow examination is a valuable differentiating procedure for CML, AMM, and leukemoid or leukoerythroblastic reactions. CML has a hypercellular marrow with a moderate degree of immaturity; AMM most often has a marrow with varying degrees of fibrosis (although a hypercellular marrow may occur); and bone marrow in leukoerythroblastic reactions due to metastatic tumor frequently contains tumor cells. Clot sections as well as smears are desirable to increase diagnostic accuracy. In some patients with AMM and occasionally in patients with bone marrow tumor metastasis, no marrow can be obtained by aspiration, and a bone biopsy is necessary to be certain that the problem was not due to technical factors but to actual absence of marrow.

    Although these distinguishing features suggest that differentiation between CML and AMM should be easy, the differences may be slight and the differentiating elements may at times appear in either disease. In fact, CML and AMM have been classified together under the term “myeloproliferative syndrome.” Some workers include the whole spectrum of leukemic-type proliferations of granulocytes, RBCs, and platelets within this term.

    Leukocyte alkaline phosphatase (LAP) stain is the second useful test for differentiating leukemoid reaction, CML, and AMM. A fresh peripheral blood smear is stained with a reagent that colors the alkaline phosphatase granules normally found in the cytoplasm of mature and moderately immature neutrophils. One hundred neutrophils are counted, each neutrophil is graded 0 to 4+, depending on the amount of alkaline phosphatase it possesses, and the total count (score) for the 100 cells is added up. In most patients with leukemoid reaction or simple leukocytosis due to infection, or leukocytosis of pregnancy or estrogen therapy (birth control pills), and in 80%-90% of patients with polycythemia vera, the score is higher than reference range. About two thirds of patients with AMM have elevated values, about 25% have values within normal limits, and about 10% have low values. In CML, about 90% of patients have below-normal values, but 5%-10% reportedly have normal values. Values may be normal in CML during remission, blast crisis, or superimposed infection. In acute leukemia, each cell type differs in percentage of LAP values that are low, normal, or high, but results are not sufficiently clear cut to provide adequate cell type diagnosis. Overlap and borderline cases limit the usefulness of LAP in establishing a definitive diagnosis; however, values that are elevated are substantial evidence against CML, whereas values that are definitely low suggest CML rather than AMM. An experienced technician is needed to make the test reliable because the test reagents often give trouble, and the reading of the results is subjective and sometimes is not easy. Therefore, diagnosis should not be based on this test alone. In obvious cases, there is no need to do this test.

    The LAP value is elevated in many patients with “active” Hodgkin’s disease. Infectious mononucleosis in early stages is associated with low or normal values in 95% of cases. In sickle cell anemia, LAP values are decreased even though WBCs are increased; however, if infection is superimposed, there may be an LAP increase (although a normal LAP value does not rule out infection). Low values are found in paroxysmal nocturnal hemoglobinuria.

    A cytogenetic or DNA probe study for the Philadelphia chromosome is a third test that may be helpful in occasional diagnostic problems. Presence of the Philadelphia chromosome in a clinical and laboratory setting suspicious for chronic leukemia would be strong evidence in favor of CML.

  • Chronic Myelogenous (granulocytic) Leukemia (CML)

    CML is most common between the ages of 20 and 50 and is rare in childhood. It comprises about 20% of all leukemias. There is an increased (total) peripheral WBC count in more than 95% of patients, with about 70% more than 50,000/mm3 (50 Ч 109/L) and about 45% more than 100,000/mm3. There is usually a predominance of myeloid cells having intermediate degrees of maturity, such as the myelocyte and early metamyelocyte. In fact, the peripheral blood smear often looks like a bone marrow aspirate. Anemia is usually present, although initially it is often slight. Later, anemia becomes moderate. There may be mild reticulocytosis with polychromatophilia, and occasionally there are a few nucleated RBCs in the peripheral blood. Platelets are normal in about 75% of patients and increased in the remainder, with about 8% having thrombocytosis more than 1,000,000/ mm3. Average patient survival is 2-4 years after onset. Terminally, 70%-80% of patients develop a picture of acute leukemia (the blast crisis); about 70% of these are AML and about 30% are ALL or rarely some other type.

    Bone marrow aspiration in CML shows a markedly hypercellular marrow due to the granulocytes, with intermediate degrees of immaturity. In this respect it resembles the peripheral blood picture. Some patients develop varying degrees of marrow fibrosis and can therefore simulate myelofibrosis (myeloid metaplasia, discussed later).

    On physical examination there are varying degrees of adenopathy and organomegaly. The spleen is often greatly enlarged, and the liver may be moderately enlarged. Lymph nodes are often easily palpable but generally are only slightly to moderately increased in size.

    Many patients with CML have an increased number of basophils in the peripheral blood. The reason for the basophilia is not known.

    An interesting aspect of CML is the presence of a specific chromosome abnormality called the Philadelphia chromosome in the leukemic cells of most patients. No other neoplasm thus far has such a consistent cytogenetic abnormality. The abnormality involves the breaking off of a portion of the long arm of chromosome number 22 (formerly thought to be number 21) of the 21-22 group in the Denver classification (G group by letter classification); the broken-off chromosome segment is usually translocated to chromosome number 9. The abnormal chromosome 22 (Philadelphia chromosome) using standard cytogenetic methods is found in approximately 85%-90% of patients with CML (reported range, 60%-95%). Those not having it seem as a group to have a worse prognosis. Interestingly, the Philadelphia chromosome has also been reported in about 25% of patients with adult-onset ALL and in some patients with the ALL variant of CML blast crisis.

    Philadelphia chromosome detection usually involves cytogenetic chromosome analysis, that is, separating the chromosomes from several body cells and visually inspecting each chromosome for abnormality. It is now possible to use the nucleic acid probe (see “DNA Probe,” Chapter 14) technique for the same purpose. There is a gene area called bcr (breakpoint cluster region) in chromosome 22 that develops a crack or fissure to which a genetic area called c-abl (located at one end of the long arm of chromosome 9) becomes attached and fused. The restructured chromosome 22 with the grafted DNA material from chromosome 9 now has a hybrid gene bcr-abl at the fusion area. There is some evidence that this abnormal hybrid gene may have a role in the events that lead to the development of CML (therefore it acts as an oncogene). A DNA probe has been constructed to detect the new hybrid gene; this has been called by some “bcr gene rearrangement assay.” The DNA probe method has certain advantages over the cytogenetic method. The DNA probe can be used on peripheral blood specimens, does not require bone marrow, does not need dividing cells, and analyzes thousands of cells—versus less than 20 by cytogenetic analysis. In addition, the DNA probe is claimed to be 5%-10% more sensitive than cytogenetic analysis. At present, the bcr rearrangement assay is mostly available in reference laboratories or university medical centers.