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The leukemias are malignant neoplastic proliferations of hematopoietic cells in the bone marrow. In most cases, the neoplastic cells are also present in increased numbers in the peripheral blood. See Acronyms.
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The number of new cases of leukemia in the United States is about 25,000 per year, with 15,000–20,000 deaths. Death rates have fallen because of increasing effectiveness of treatment.
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Acute leukemias account for 50–60% of all leukemias, with acute myeloblastic leukemia (AML) slightly more common than acute lymphoblastic leukemia (ALL).
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ALL occurs predominantly in young children (peak age incidence 3–4 years) (Figure 26-2). AML can occur at any age but is most common in young adults (peak 15–20 years).
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Chronic leukemias account for 40–50% of leukemias, with chronic lymphocytic leukemia (CLL) slightly more common than chronic myelocytic leukemia (CML).
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CLL occurs mainly in patients over the age of 60 years.
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CML occurs at all ages, with a peak incidence in the age group from 40 to 50 years (Figure 26-2).
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The cause of most kinds of leukemia is unknown.
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Viruses are known to cause animal leukemias and are highly suspect in humans. A retrovirus (human T lymphotropic virus type I; HTLV-I) has been identified as the causative agent in one type of acute T lymphocytic leukemia first described in Japan, while a related virus, human T lymphotropic virus type II (HTLV-II), has been linked to hairy cell leukemia. However, no causal agent has been identified for most cases of human leukemia.
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Exposure to radiation resulted in an increased incidence of leukemia in the first generation of radiologists and among survivors of the Hiroshima and Nagasaki bombs. Fetuses who have been exposed to radiation in utero and patients who have received radiation in the treatment of ankylosing spondylitis and Hodgkin's disease have an increased incidence of leukemia.
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The same cytotoxic drugs used in treatment of leukemia and other cancers produce an increased incidence of leukemia. In addition, arsenic, benzene, phenylbutazone, and chloramphenicol have been implicated in some cases.
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Marrow aplasia due to any cause appears to be associated with an increased incidence of subsequent leukemia, as do the refractory anemias.
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Immune deficiency states are associated with an increased incidence of leukemia, suggesting that immunologic surveillance is important in preventing the emergence of neoplastic hematopoietic cells.
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Chromosomal abnormalities are present in a high proportion of patients with leukemia (Table 26-10). The first reported was the association of the Philadelphia chromosome (a small chromosome 22 resulting from the reciprocal translocation of genetic material from chromosome 22 to chromosome 9) with chronic myelocytic leukemia. Also interesting is the increased incidence (20 times normal) of leukemia in patients with Down syndrome (trisomy 21). Chromosome fragility syndromes (Bloom's syndrome, Fanconi's anemia) also carry a high risk of acute leukemia.
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Leukemias are classified in several ways:
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According to Onset and Clinical Course
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This was the earliest approach because the identity of the cells involved was not known. It still has clinical merit.
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Acute leukemias have a sudden onset with a rapidly progressive course leading to death within months, if untreated. They are usually characterized by primitive cells (blasts) that are morphologically poorly differentiated.
Chronic leukemias have an insidious onset and a slow clinical course, with patients often surviving several years even if untreated. Chronic leukemias are usually characterized by more mature (well-differentiated) type cells.
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According to the Peripheral Blood Picture
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Leukemic, characterized by elevation of the white blood cell count and numerous leukemic cells. This is the common form.
Subleukemic, in which the total white count is normal or low but recognizable leukemic cells are present in the peripheral blood.
Aleukemic, where the total white count is normal or low and no recognizable leukemic cells are present in the peripheral blood. This is rare, but it may occur early in the disease.
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According to Cell Type
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Classification by cell type becomes more complex as new criteria evolve for cell recognition (Table 26-11, Figure 26-3).
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Lymphocytic leukemias are neoplasms of lymphocytes. Their close relationship to certain of the lymphomas is considered in Chapter 29: The Lymphoid System: II. Malignant Lymphomas.
ALL is characterized by the presence in the bone marrow and peripheral blood of uniform large cells that resemble the proliferating lymphoblast of fetal development (Chapter 4: The Immune Response). Acute lymphoblastic leukemia is further classified by its morphologic features (French-American-British (FAB)—system; Table 26-12) or by its immunologic or genetic features (Figure 26-3; see also Tables 26-14, 29-5, and 29-7).
CLL is characterized by the proliferation of small mature lymphocytes that resemble the resting small lymphocytes of the peripheral blood. In 95% of cases, the lymphocytes are B cells; in the rest, they are T cells.
When lymphocytic leukemia involves lymph nodes, it has the appearance of malignant lymphoma (Chapter 29: The Lymphoid System: II. Malignant Lymphomas). ALL in lymph nodes is identical to lymphoblastic lymphoma (B, T, or nonmarking type—formerly classified within the broader category of poorly differentiated lymphocytic lymphoma). CLL in lymph nodes is identical to small lymphocytic lymphoma (B or T type—formerly termed well-differentiated lymphocytic lymphoma).
In each case, this phenomenon represents part of the spectrum of a single disease process, lymphoma-leukemia. This concept is discussed further in Chapter 29: The Lymphoid System: II. Malignant Lymphomas.
Myeloid (granulocytic) leukemias are characterized by the proliferation of cells of the granulocyte series, usually neutrophils, although concomitant proliferation of eosinophils and basophils is not uncommon.
AML is characterized by proliferation of myeloblasts. Myeloblasts are difficult to differentiate morphologically from lymphoblasts except (1) when they contain Auer rods, which are purple, crystalline cytoplasmic inclusions; (2) when they show some show maturation into promyelocytes, in which coarse granules are seen in the cytoplasm; and (3) when cytochemical or immunologic markers are used (Tables 26-13, 26-14; see also Table 29-5). AML is further classified (FAB system M1, M2, M3, M4) by its morphologic features. (Note that the FAB classification of AML includes monocytic leukemia [M5], erythroleukemia [M6], and megakaryoblastic leukemia [M7], which others consider separately.)
Chronic myelocytic leukemia is characterized by proliferation of cells of the granulocyte series that have matured beyond the myeloblast stage. Less than 5% of cells in the marrow are myeloblasts. When a patient with chronic myelocytic leukemia has a bone marrow containing more than 5% myeloblasts, that patient is defined as being in the accelerated or blast phase of the disease.
Monocytic leukemia–Traditionally, two forms were distinguished: acute monocytic (Schilling type) and acute myelomonocytic (Naegeli type). Both are now included under acute myeloblastic leukemia in the FAB classification, in recognition of the known common origin with granulocytes. There is no well-defined chronic form of monocytic or myelomonocytic leukemia, although some myeloproliferative disorders do show monocytic proliferation.
Acute monocytic (monoblastic) leukemia (FAB–M5) is characterized by proliferation of monoblasts. These can be reliably distinguished from other blasts only with the use of cytochemical markers (Table 26-13).
Acute myelomonocytic leukemia (FAB—M4) is characterized by blasts that have the characteristics of myeloblasts and monoblasts, both morphologically and in cytochemical studies.
Other types–Erythroleukemia (Di Guglielmo's disease), plasma cell leukemia, eosinophilic leukemia, and megakaryocytic leukemia (Figure 26-3) are all rare.
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Acute leukemia is characterized by an acute clinical onset and rapid progression of disease. Patients usually present with evidence of a decrease in one or more of the normal hematopoietic elements because the bone marrow is overrun by the leukemic cells. Anemia, often severe and rapidly developing, causes pallor and hypoxic symptoms. Thrombocytopenia may produce abnormal bleeding or purpura. Neutropenia results in infections, fever, and ulceration of mucous membranes. Patients with acute promyelocytic leukemia (M3) frequently present with disseminated intravascular coagulation due to the coagulant properties of the cytoplasmic granules.
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Enlargement of lymph nodes is common in ALL and acute monocytic leukemia but usually absent in AML. Involvement of tissue other than lymph nodes occurs rarely in all types of acute leukemia. Rarely, a local tissue mass (chloroma or granulocytic sarcoma) may be the first manifestation of AML. Similarly, tissue masses may occur in acute monocytic leukemia.
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Chronic leukemias usually have an insidious onset and a slow rate of progression. Most patients present with slowly developing anemia and enlargement of organs infiltrated by leukemia cells.
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Generalized lymph node enlargement is present in CLL; histologic features of affected nodes are indistinguishable from those of small-cell (well-differentiated) lymphocytic lymphoma (Chapter 29: The Lymphoid System: II. Malignant Lymphomas). Splenomegaly—often massive—and hepatomegaly are usually obvious at presentation in all chronic leukemias. Patients may also manifest nodular masses in the skin, liver, heart, and kidneys.
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Massive splenomegaly and hepatomegaly are common presenting complaints in patients with CML. Pain in the left lower chest is evidence of splenic infarction due to vascular occlusion by aggregates of granulocytes.
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Acute leukemias are characterized by the proliferation of primitive cells (blasts) that mature little, if at all. In both AML and ALL, the peripheral blood usually shows an increased total white cell count with increased numbers of blasts (Figure 26-5B). Rarely, the total white count is not increased, although the diagnosis may be made by the finding of blasts in the peripheral blood smear. Extremely rarely, no blasts are seen in the peripheral blood (aleukemic leukemia).
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Rarely, marked lymphocytosis as seen in whooping cough or a viral infection may mimic ALL. Infectious mononucleosis, in which there are activated atypical lymphocytes in the blood, may cause considerable diagnostic difficulty (Table 26-3).
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The bone marrow is abnormal in all cases of acute leukemia because it is the primary site of the disease. Involvement is diffuse. The bone marrow is hypercellular, with proliferation of the cell type involved at the expense of the normal hematopoietic elements (Figure 26-6). Diagnosis of the type of acute leukemia and subclassification according to the FAB system depends on identification of the cell type.
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In AML, the primitive myeloblasts may not show any maturation (in the M1 subtype in the FAB classification), or show minimal maturation into promyelocytes and myelocytes (M2 subtype). Acute promyelocytic leukemia (M3 subtype) is characterized by a predominance of promyelocytes. Separation from ALL and distinction of the different AML subtypes (M1–M7) is by subtle cytologic features plus cytochemical (Table 26-13), cytogenetic (Table 26-10), and immunologic markers (Tables 26-14 and 29-5). CD34 (stem cell) is expressed strongly in M1–M3, while CD13 and CD33 are positive in M1–M7.
In ALL, there is proliferation of lymphoblasts (Figure 26-5B). While these may be difficult to differentiate from myeloblasts on morphologic grounds, the use of cytochemical (Table 26-13) and immunologic stains (Tables 26-14 and 29-5) permits accurate diagnosis. ALL is considered in more detail in Chapter 29: The Lymphoid System: II. Malignant Lymphomas along with the related lymphomas (Table 29-7).
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Chronic leukemias are characterized by the presence of very high peripheral white blood cell counts. Morphologically, the cells are mature. The peripheral blood picture is diagnostic of chronic leukemia in most cases (Figure 26-5). Rarely, a leukemoid reaction (severe neutrophil leukocytosis in response to an acute inflammatory process) may be difficult to distinguish from CML (Table 26-5). The bone marrow is always abnormal, showing diffuse hypercellularity.
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In CML, the dominant cells in the peripheral blood and bone marrow are myelocytes, metamyelocytes, and granulocytes. The granulocytes are usually neutrophils, but it is not uncommon to find increased numbers of basophils and eosinophils. Very rarely, the eosinophils are the dominant cells (eosinophilic leukemia). In the bone marrow, general myeloproliferation is present, involving not only the granulocyte series but also erythroid cells and megakaryocytes. Myelofibrosis (Chapter 25: Blood: II. Hemolytic Anemias; Polycythemia) may complicate CML. The Philadelphia chromosome (Chapter 19: Neoplasia: III. Biologic & Clinical Effects of Neoplasms) is present in all of these cell lineages and remains detectable even after remission of the CML. The chronic phase of CML persists for 1–10 years (median, 3 years), following which there is an accelerated phase that eventually (80% of cases) enters blast crisis. In most cases, the process then resembles AML (M2 or M4). Less often (15% of cases), it resembles ALL (usually pre-B ALL, occasionally T ALL) with the corresponding antigenic markers. Acceleration typically is accompanied by further cytogenetic changes, including extra copies of the Ph1 chromosome.
In CLL, the neoplastic cells resemble resting small lymphocytes morphologically (Figure 26-5A) but can be shown to be monoclonal. The bone marrow is infiltrated by similar cells, but normal hematopoietic elements remain until an advanced stage of the disease. CLL is considered in Chapter 29: The Lymphoid System: II. Malignant Lymphomas.
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Treatment & Prognosis
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Combination chemotherapy, using several anticancer agents simultaneously in various combinations, has improved the prognosis of patients with acute leukemias dramatically. Common ALL in children is now considered to be a curable disease in many cases (70% 5-year survival rate). The rate of cure in other types of ALL (T and B cell, 10% 5-year survival rates), AML, and acute monocytic leukemia (both with 5-year survival rates near zero) is much worse. However, chemotherapy does increase the duration of survival in comparison with nontreated cases.
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Paradoxically, treatment has little effect on the survival rate of chronic leukemias. Many of these patients survive many years after diagnosis of disease without treatment, and their overall course and outcome does not seem to be altered by therapy.
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Recently, acute leukemias have been treated more aggressively with the intention of destroying all the hematopoietic cells in the marrow, including leukemic cells, followed by rescue of the patient by bone marrow transplantation (see Chapter 10: Nutritional Diseases). The transplant consists either of matched heterologous marrow or of autologous marrow taken prior to therapy and purged of leukemic cells by in vitro treatment with monoclonal antibodies.
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Hemorrhage and infection are major causes of death of patients with leukemia, occurring as a direct effect of the leukemia or as a complication of cytotoxic therapy or failed transplantation.