Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is a malignant disease that evolves as a result of mutation of lymphoid precursor cells that have their origin in the marrow or thymus, at a particular stage of maturation. The immunophenotype reflects the antigen expression of the stage of differentiation of the dominant clone. The leukemic cells persistently accumulate in intrame-

dullary and extramedullary sites, constantly competing with normal hematopoietic cell production and function. This results in anemia, thrombocytopenia, and neutropenia, as well as an overpopulation of lym-phoblasts in the tissues such as liver, spleen, lymph nodes, meninges, and gonads.

Epidemiology

ALL is predominantly a disease of children, with highest incidence in children between the ages of 2 and 6. It accounts for 76% of all leukemias diagnosed in children younger than age 15.42 According to National Cancer Institute statistics, there is an increased incidence of ALL seen in all age groups in males compared to females of European or African descent.43 The exception is a slight female predominance in infancy.44 Although more uncommon in adults, ALL occurs in all ages, and rising incidence rates are seen with increasing age, with a second peak incidence in the elderly population.

The etiology of ALL is unknown in the vast majority of cases. Environmental agents, such as ionizing radiation and chemical mutagens, have been implicated, and there is evidence to suggest a genetic factor in some patients. Children with Down syndrome have an increased risk of leukemia, particularly precursor B lymphoblastic leukemia. There is a higher frequency of childhood ALL in industrialized countries compared with in developing countries. It has also been postulated that some cases of childhood leukemia stem from an adverse cellular response to common infections that occur at a later time than was typically experienced in past centuries.45,46 These "delayed" exposures are believed to increase the risk of genetic mutations in the lymphoid precursors, leading to the development of leukemia.

Clinical Features

Clinical presentation is variable; symptoms may be subtle and develop over months or they may be acute and quite severe. The presenting symptoms are directly related to the degree of bone marrow failure or extramedullary involvement (see Table 11.3). Symptoms that are seen in about half of the patients include fever that stems from the leukemic process itself (tumor burden) and from the neutropenia and pallor and fatigue that are caused by the anemia. Bleeding, purpura, and bone and joint pain are other common presenting complaints. Children often present with a limp or the inability to walk due to the pain caused by the leukemic infiltration of the periosteum (bone covering) or due to the actual bone itself causing osteoporosis or bone ero-

176 Part III • White Cell Disorders sion. Hepatosplenomegaly and lymphadenopathy may be prominent symptoms. Uncommon symptoms include cough, dyspnea, cyanosis, and syncope related to a bulky mediastinal mass that can compress blood vessels or the trachea.47

Classifications

The FAB classification defined three morphological subtypes—L1, L2, and L3—based on the appearance of the blasts that predominate. L1 lymphoblasts are small with scant cytoplasm, are uniform in size, and have indistinct nucleoli. L2 blasts are larger and more pleo-morphic, often containing abundant cytoplasm and prominent nucleoli (Table 11.9). Both LI and L2 blasts cannot be determined from morphology alone as they may be easily confused with myeloblasts seen in AML. L3 lymphoblasts are characterized by intensely basophilic cytoplasm that has many vacuoles. Because of the differences in prognosis based on immunophe-notype and cytogenetics, the WHO has recognized just two groups of acute lymphoblastic leukemias, precursor B-cell and precursor T-cell lymphoblastic leukemia/lymphoma.

Precursor B Lymphoblastic Leukemia/ Lymphoblastic Lymphoma

Precursor B lymphoblastic leukemia (B-ALL)/lym-phoblastic lymphoma (B-LBL) is a malignancy where B-lineage lymphoblasts predominate in the bone marrow (B lymphoblastic leukemia). Sometimes there is primary involvement of lymph nodes or extranodal sites (B lymphoblastic lymphoma). Greater than 25% of bone marrow cells must be identified as lymphoblasts to meet the WHO definition of acute lymphoblastic leukemia; however, the bone marrow aspirate typically consists of almost entirely lymphoblasts at diagnosis. When the leukemic process is limited to a mass lesion and 25% or fewer lymphoblasts are seen in the marrow, the designation lymphoma is used.19 B-ALL comprises approximately 85% of all childhood ALL, whereas B-LBL is a rare type of lymphoma and constitutes approximately 10% of lymphoblastic lymphoma cases.48 B-ALL may also develop in adults, and the prognosis is generally much poorer in adults.

The bone marrow and blood will manifest blasts in all cases of B-ALL. Extramedullary sites of hematopoiesis cause hepatosplenomegaly, and there is a predilection for CNS (meningeal leukemia), lymph nodes, and gonad involvement. Bone pain from marrow hyperplasia is also a frequent clinical symptom.

Laboratory Features

The WBC is variable in B-ALL—it may be markedly elevated, normal, or decreased. As with all other acute leukemias, anemia and thrombocytopenia are apparent at diagnosis. The blood and bone marrow contains lym-phoblasts with L1 or L2 morphology (Fig. 11.13). Coarse azurophilic granules may be present in the lym-phoblasts in up to 10% of cases. Lymphoblasts with pseudopod projections, termed "hand-mirror cells," are occasionally found. Although not as important as the immunophenotypic characterization, cytochemistries may be helpful until further studies can be performed to help separate the preliminary diagnosis of lymphoid from myeloid leukemia. The myeloid stains SBB and MPO will be negative or very weakly positive as compared to the intensely positive stain seen in myeloblasts. The NSE reaction is generally negative. By contrast, the PAS stain is positive in over 70% of ALL cases, with the nuclei often giving the appearance of being rimmed with a punctate PAS-positive string of beads.

Immunophenotype

As previously noted, the immunological classification should be performed in all cases as it allows for more

Table 11.9 O FAB Morphological Classification of Acute Lymphoblastic Leukemia

Feature L1 L2 L3

Cell size

Nuclear chromatin Nuclear shape

Nucleoli Cytoplasm

Small, regular Fine or condensed

Regular, cleft or indentation possible Indistinct Scant

Large, mixed sizes

Fine or condensed

Irregular, cleft or indentation more common

1 to 2, prominent

Large Fine

Regular, round or oval 1 to 2, prominent

Variable, often moderately abundant Deeply basophilic, vacuolated

Figure 11.13 Precursor B lymphoblastic leukemia.

precise diagnosis and important prognostic correlations. In order to define a particular population of lym-phoblasts in leukemia, evaluation of the results of a panel of antibodies used to distinguish the clusters of differentiation (CD) groups is done. Because no one surface marker is 100% specific, a panel is needed to establish the diagnosis and sort the leukemia into the appropriate subtype. To be able to interpret the CD information, it is important to have a basic understanding of lymphocyte ontogeny.

Each of the two lineages of lymphocytes (B and T cells) can be subclassified into several maturational stages by the expression of their surface antigens. Accordingly, ALLs are divided by immunophenotype, first into B- or T-cell lineages. In leukemia, the lym-phoblasts are "frozen" at a specific stage of maturation, and these blasts can then be further categorized by using CD markers into the particular stage of differentiation, that is, precursor B, pre-B, and mature B-ALL.

The lymphoblasts in B-ALL/LBL are uniformly TdT positive and HLA-DR positive. The flow cytometric immunophenotype in most cases is positive for CD 10, CD19, CD20, CD24, cytoplasmic CD22, and CD79a (Fig. 11.14).

Antigen Independent ^ ^ Antigen Dependent

Stem Cell

Early Pre-B Cell Pre-B Cell

B Cell

Plasma Cell

Immat.

B-Cell

Mat. B-Cell

Activtd B-Cell

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