Acute Leukemia
Acute leukemia comprises about half of all leukemias. Acute lymphocytic leukemia (ALL) and acute nonlymphocytic leukemia (ANLL) are about equal in overall occurrence, but differ considerably in age groups. About 80%-90% of acute leukemia in childhood is ALL, and about 85%-90% in adults is ANLL (most commonly acute myelogenous leukemia and myelomonocytic leukemia). Peak incidence in childhood is 3-10 years, whereas it is most common in adults after age 50. About 50% of childhood ALL cases occur between ages 3 and 7, whereas the age incidence of ANLL is more evenly distributed. Childhood ALL and ANLL occur predominantly (>80%) in whites. About 5% have central nervous system (CNS) involvement at the time of diagnosis, and the CNS is eventually involved in about 50% unless prophylactic therapy is given.
Acute leukemia usually has more than 25% blasts in the peripheral blood and by FAB criteria must have more than 30% blasts in the bone marrow. Sometimes the peripheral blood has fewer than 25%, especially if there is a leukopenia or if the patient has monocytic leukemia. The peripheral blood WBC count typically is mildly to moderately elevated (15,000-50,000/mm3; 15-50 Ч 109/L). However, nearly one half of the patients either have WBC counts within the WBC reference range or have leukopenia. Also, about 10% have WBC counts more than 100,000/mm3 (100 Ч 109/L). Anemia is present in about 90% of patients and is generally of moderate to severe degree. If not present initially, it develops later. Thrombocytopenia is reported in 80%-85% of patients (range, 72%-90%); about 40% have a platelet count of 50,000/mm3 or less. Childhood acute leukemia may be associated with meningeal involvement in as many as 50% of patients.
Lymphadenopathy, usually of mild degree, is present in about 50% of patients, and splenomegaly, also usually minimal or mild, is reported in about 65% (range, 50%-76%). Generally speaking, enlargement of visceral organs is related to the duration of leukemia, so that the chronic leukemias are usually much more likely than the acute leukemias to be associated with marked organomegaly or with adenopathy. A significant number of patients with acute leukemia develop ulcerative lesions in the oral mucous membranes or gums and occasionally elsewhere, as in the gastrointestinal (GI) tract. Hemorrhagic phenomena (petechiae or localized small hemorrhages) are frequent, due to thrombocytopenia. Superimposed infection is common and is probably the most frequent cause of death.
French-American-British (FAB) classification of acute leukemias
In 1976 a group of French, American, and British hematologists proposed a system for classification of acute leukemia based primarily on morphologic and cytochemical criteria. The FAB classification has been widely adopted as the basis for standardization of diagnosis and comparing results of therapy (Table 7-1). During this time there have been several minor modifications. The classification can be applied only before initial therapy is begun. There are two categories, acute lymphocytic leukemia (ALL, FAB prefix L) and acute non-lymphocytic leukemia (ANLL, FAB prefix M). The latter includes myelocytic, myelomonocytic, monocytic, erythroid, and megakaryocytic leukemia subcategories. The panel stated that great caution was required before diagnosing leukemia in hypocellular bone marrow aspirates. It is worth noting that using morphologic study alone, even experts reached complete agreement only in about 80% of cases submitted for diagnosis.
Table 7-1 French-American-British (FAB) classification of acute leukemia (modified)
Cytochemical stains
The FAB group found that cytochemical stains were extremely helpful in categorizing some cases of acute leukemia, especially those that are relatively undifferentiated. Results of the Sudan black B stain are usually positive in myelocytic and myelomonocytic leukemia but negative in lymphocytic or other types of monocytic leukemia. The myeloperoxidase stain gives results similar to Sudan black B but is more technique dependent and thus less reliable in many laboratories. Nonspecific esterase stains are used to diagnose the monocytic leukemias. Results of alpha-naphthylbutyrate esterase are positive only in monocytic cells, whereas NASD-acetate esterase is positive in both myeloid and monocytic cells but is inhibited by fluoride in monocytic but not in myeloid cells. In a few cases none of the special stains produce diagnostic results. In categories not supposed to display special stain reaction, up to 3% reactive cells is permitted.
Terminal deoxynucleotidyl transferase (TdT) enzyme reaction is normally present (positive reaction) only in lymphocytes, predominately in nuclei of thymus-derived cells (T-lymphocytes) and a few bone marrow lymphocytes. It is usually not present in B-lymphocytes or B-lymphocytic malignancies (e.g., CLL, well or poorly differentiated lymphocytic lymphoma, or myeloma. However, one very early B-cell malignancy called Pre-B-cell ALL is TdT positive. TdT enzyme activity is present in 90% or more (88%-95%) of ALL patients, comprised mostly of T-cell and non-B, non-T phenotypes. The equivalent malignant lymphoma category (T-cell/lymphoblastic lymphoma) is also TdT positive. Therefore, TdT positivity has been used to differentiate ALL from ANLL. However, there are exceptions; FAB L3 ( B-cell ALL) and the equivalent malignant lymphoma (Burkitt’s lymphoma) are usually TdT negative. About 5%-10% of AML are reported to be TdT positive. About one third of patients in the blast crisis of CML may have a positive TdT reaction, even some who have the Philadelphia chromosome.
Chromosome studies
A considerable number of leukemia patients have chromosome abnormalities; and some leukemia subgroups have one particular abnormality that occurs more frequently than all others. In some cases the chromosome abnormality is diagnostic of an acute leukemia subgroup and in some cases it gives prognostic information. The most well-known examples is the Philadelphia chromosome abnormality of CML.
FAB phenotype in ANLL
In adults, approximately 80% of acute leukemia cases are the ANLL type. Of the adult ANLL cases, almost 30% each are FAB-M1, M2, or M4. About 5% are FAB-M3, known as acute progranulocytic leukemia. This category, especially the so-called hypergranular variant, is associated with an unusually high incidence of coagulation disorders, particularly disseminated intravascular coagulation (DIC). In childhood, about 20% of the acute leukemias is ANLL; roughly 60% of these are M4 and about 25% are M1 or M2.
FAB phenotype in ALL
About 20% of adult acute leukemia is ALL; of these patients, about 65% are FAB-L2. About 80% of children with acute leukemia have ALL, and about 15% have the nonlymphocytic form. About 80% of childhood ALL cases are the FAB-L1 type. About 2% of childhood cases and less than that of adult cases are FAB-L3. Morphologically, FAB-L3 leukemia resembles the malignant lymphoma known as Burkitt’s lymphoma and currently has the worst prognosis of the ALL categories.
Immunologic classification of acute lymphocytic leukemia
Both ALL and the non-Hodgkin’s malignant lymphomas have been classified according to the immunologic type of lymphocyte involved (see Table 37-7 and Table 7-4). Acute lymphocytic leukemia has been subdivided by immunologic techniques into three categories: B-cell, T-cell, and non-B, non-T (most of these are actually Pre-Pre-B or Pre-B-lymphocytes). Immature B-cell ALL displays surface immunoglobulin production and comprises about 2% (range 1%-5%) of ALL cases. Morphology is usually FAB-L3 and resembles Burkitt’s lymphoma. T-cell ALL demonstrates a positive spontaneous E rosette test. Two categories of T-cell ALL have been reported; the “idiopathic” type and the “endemic” type. The idiopathic type is derived from Pre-T- cells or early (subcapsular) T-cells and comprises about 20% (10%-28%) of ALL in the United States. It tends to occur in later childhood or in adolescents and has male predominance. Approximately 75% have a mediastinal mass due to lymphadenopathy; this group resembles the type of malignant lymphoma called lymphoblastic in the Rappaport classification. The endemic type is most frequent in Japan and the Caribbean islands and is apparently caused by human T-cell leukemia virus-I (HTLV-I) retrovirus infection. This type is more frequent in adults, has about equal male-female incidence, does not have a high incidence of prominent mediastinal lymphadenopathy, has leukemic cells with convoluted nuclei, and has a relatively high incidence of skin involvement and also of hypercalcemia (about 25% of cases, but ranging up to 70% in some series). Pre–pre-B and Pre-B ALL (formerly called non-T, non-B ALL) comprises about 70%–80% of ALL patients; these patients have blasts that do not possess surface immunoglobulins and have a negative E rosette test result. However, most have immunologic or DNA probe evidence of early B-cell lineage. These can be further subdivided into four groups. About 75%-80% (range, 65%-90%) of these patients, constituting about 65% (range, 50%-76%) of all ALL cases, have blasts with a surface antigen that reacts with antibody prepared against non-B, non-T lymphocytes (common ALL antigen or CALLA). This group is often designated “common” ALL. Another subset of about 10%-20% (constituting about 10%-15% of all ALL cases) demonstrate intracytoplasmic immunoglobulin production but not surface (membrane) immunoglobulin and are said to have pre-B-cell ALL. A few patients have blasts that react with antisera to T-lymphocyte surface antigens but that have negative B-cell test results. These patients are said to have pre-T-cell ALL. Finally, there are a few patients with blasts that do not react with any of the tests mentioned. These patients are said to have null cell ALL.
Table 7-4 Clinical staging of the malignant lymphomas*
Monocytic leukemia
Monocytic leukemia has the clinical and laboratory aspects of acute leukemia and is included in the FAB classification of acute leukemia as categories M4 and M5. In monocytic leukemia, however, the number of actual blasts may be low in both the peripheral blood and bone marrow. Instead of blasts there are cells resembling monocytes. In FAB category M4 the cells have a monocytic nucleus but cytoplasm containing granules resembling those found in granulocytes rather than those of monocytes (myelomonocytic leukemia, originally known as monocytic leukemia of Naegeli). In FAB category M5 the cells have both nucleus and cytoplasm resembling a monocyte (“pure” monocytic leukemia, originally known as monocytic leukemia of Schilling). Diagnosis of M5 requires 80% or more of the nonerythroid nucleated cells in the bone marrow to be monocytes, promonocytes, or monoblasts. There are two FAB subdivisions: 5A, in which more than 80% of the marrow monocytic cells are monoblasts, and 5B, in which less than 80% of the marrow monocytic cells are monoblasts.
Myelomonocytic leukemia is by far the most frequent type of monocytic leukemia. It actually is a form of myelogenous leukemia in which the leukemic cells have cytoplasmic features of the more differentiated myeloid line and nuclear characteristics of the more primitive histiocytic precursors of the myeloid cells. There may be accompanying myeloid cells that are nonmonocytic, less immature forms; if so, this helps suggest the diagnosis. Sometimes the monocytic cells are indistinguishable from those of pure monocytic leukemia (Schilling type), but eventually some of them develop myeloid cytoplasmic features. If Auer rods are found, this establishes the myeloid derivation of the cells. According to the revised FAB criteria, if there is peripheral blood absolute monocytosis, M4 can be diagnosed if more than 20% of the bone marrow nucleated cells are monocytic. Cytochemical tests for monocytes may be needed. If peripheral blood monocytes are not increased, more than 20% of the bone marrow nucleated cells must be monocytic either confirmed by cytochemical stains or by elevated serum lysozyme (an enzyme associated with histiocytes or monocytes).
Diseases accompanied by peripheral blood monocytosis sometimes raise the question of monocytic leukemia. Bone marrow aspiration provides the differentiation. The most common of these diseases are subacute bacterial endocarditis, typhoid fever, and tuberculosis.
Erythroleukemia
Erythroleukemia (FAB M6) was formerly known as Di Guglielmo’s syndrome. Some considered Di Guglielmo’s a single entity (erythroleukemia) and others included at least two categories: erythroleukemia and a syndrome comprising one or more disorders now included in myelodysplasia (discussed later). Erythroleukemia constitutes about 8% (range, 3.3%-13%) of acute leukemia cases. Sixty-five percent to 71% of patients are male. The mean age at diagnosis is in the forties and fifties, but patients from age 2-85 have been reported. Splenomegaly is reported in 18%-23% of patients, hepatomegaly in 0%-18%, and lymphadenopathy in 2%-43%. Various cytogenetic abnormalities have been found in about 60% of cases. At the time of diagnosis, all patients have anemia, most often moderate or severe, either normocytic or macrocytic. Leukopenia is reported in 25%-86% of cases, and thrombocytopenia is found in about 75%. Occasionally a monocytosis may be present in patients.
The disease is reported to progress in three bone marrow stages: (1) an erythroproliferative phase with abnormalities largely confined to the erythroid line, (2) a mixed erythroid-myeloid dysplastic phase, and (3) a transition to ANLL. Therefore, in erythroleukemia there is abnormality in both the RBC and the myeloid precursors. The peripheral blood typically contains varying numbers of nucleated RBCs and immature granulocytes. In classic cases there are some peripheral blood myeloblasts and rubriblasts (pronormoblasts), but in some patients there are only a few nucleated RBCs, and rubriblasts are not seen. There may be increased numbers of monocytes. There is most often leukocytosis, but the WBC count may be normal or decreased. A normocytic (or slightly macrocytic) and normochromic anemia is present with considerable RBC anisocytosis and often with some oval macrocytes. The platelet count may be normal or decreased. The bone marrow shows overall increase in cellularity with hyperplasia of both the granulocytic and the erythroid series. The erythroid hyperplasia usually predominates, typically producing a reversal of the myeloid to erythroid (M/E) ratio (the normal M/E ratio is 3:1 or 2:1). The erythroid precursors are usually megaloblastic or, at least, megaloblastoid, are often bizarre in appearance, and may exhibit erythrophagocytosis (40%-50% of patients); frequently there are increased (>2%) numbers of multinucleated RBC precursors. Ringed sideroblasts are usually present. The FAB criteria for M6 diagnosis are nucleated RBCs comprising more than 50% of all marrow nucleated cells, and at least 30% of the nonerythrocytic nucleated cells must be blasts. In most patients the marrow picture eventually progresses to ANLL of the M1, M2, or M4 type.
Differential diagnosis of acute leukemia
Several diseases can simulate part of the clinical or laboratory picture of acute leukemia.
Infectious mononucleosis is frequently a problem because of the leukocytosis (or initial leukopenia) plus atypical lymphocytes. However, infectious mononucleosis is almost never associated with anemia and only rarely with thrombocytopenia. The bone marrow of infectious mononucleosis is normal and is not infiltrated by significant numbers of atypical lymphocytes. Results of the Paul-Bunnell test for heterophil antibodies (chapter 17) are positive with infectious mononucleosis but negative in leukemia.
Pancytopenia or other peripheral blood cytopenias (Chapter 6) may raise the question of possible acute leukemia, since acute leukemia may present in this way. Aplastic anemia is one of the more frequent causes for concern. The bone marrow, however, is usually hypoplastic, and the number of blasts is not significantly increased. Patients with agranulocytosis have leukopenia and often have mouth lesions, thereby clinically simulating monocytic leukemia, but do not have anemia or thrombocytopenia or increased number of blasts in their bone marrow.
Certain viral diseases, such as mumps, measles, and pertussis, are occasionally associated with considerably elevated WBC counts. There may be occasional atypical lymphocytes. There is no anemia or thrombocytopenia. A disease called infectious lymphocytosis occurs in children but is uncommon. WBC counts may be 40,000-90,000, with most WBCs being mature lymphocytes. This condition lasts only a few days. There are no abnormal cells and no anemia or thrombocytopenia, and the bone marrow is normal.
Overwhelming infection may cause immature cells and even a few blasts to appear in the peripheral blood of infants and young children, and sometimes other toxic bone marrow stimulation has the same effect. Anemia is frequent, and sometimes there is thrombocytopenia. Bone marrow aspirates may be hypercellular and show marked myeloid hyperplasia but do not usually contain the number of blasts found in leukemia. There are usually less than 5% blasts in the peripheral blood. They decrease in number and disappear when the underlying disease is treated.