eMedicine Specialties > Pediatrics: General Medicine > Oncology

Acute Lymphoblastic Leukemia: Differential Diagnoses & Workup

Author: Noriko Satake, MD, Assistant Professor, Department of Pediatrics, Section of Hematology/Oncology, University of California Davis School of Medicine, Davis Medical Center
Coauthor(s): Janet M Yoon, MD, Assistant Clinical Professor, Department of Pediatrics, Hematology/Oncology, University of California Davis Medical Center
Contributor Information and Disclosures

Updated: Aug 12, 2009

Differential Diagnoses

Other Problems to Be Considered

Aplastic anemia
Idiopathic thrombocytopenic purpura (ITP)

Workup

Laboratory Studies

The following studies are indicated in acute lymphoblastic leukemia (ALL):

• Basic laboratory tests
  • Upon initial evaluation, obtain a CBC count. A hematologist or hematopathologist must evaluate the peripheral smear for the presence and morphology of lymphoblasts. An elevated leukocyte count of more than 10 X 10⁹/L (>10 X 10³/µL) occurs in one half of patients with acute lymphoblastic leukemia. Neutropenia, anemia, and thrombocytopenia may be observed secondary to inhibition of normal hematopoiesis by leukemic infiltration. Rare cases of acute lymphoblastic leukemia may initially manifest with pancytopenia.
  • Various metabolic abnormalities may include increased serum levels of uric acid, potassium, phosphorus, and calcium, and lactate dehydrogenase (LDH). The degree of abnormality reflects the leukemic cell burden and destruction (lysis). Although not universally performed, coagulation studies can be helpful, including tests of the prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen level, and D-dimer level to assess for disseminated intravascular coagulation; these studies are particularly important in a child who is acutely toxic.
• Immunophenotyping
  • Complete morphologic, immunologic, and genetic examination of the leukemia cells necessary to establish the diagnosis of acute lymphoblastic leukemia.
  • An important advancement in the classification of acute lymphoblastic leukemia was the observation that malignant lymphoblasts share many of the features of normal lymphoid progenitors. Acute lymphoblastic leukemia cells rearrange their immunoglobulin and T-cell receptor (TCR) genes and express antigen receptor molecules in ways that correspond to such processes in normal developing B and T lymphocytes. However, leukemic lymphoblasts can also have aberrant gene expression with resultant phenotypes that differ from those of normal lymphocyte progenitors. Nevertheless, acute lymphoblastic leukemia can be broadly classified as B-lineage or T-lineage acute lymphoblastic leukemia.
  • The diagnosis of B-cell leukemia, which accounts for only about 3% of acute lymphoblastic leukemia cases, depends on the detection of surface immunoglobulin on leukemic blasts. Lymphoblasts with this phenotype have a distinctive morphology, with deeply basophilic cytoplasm containing prominent vacuoles. This morphologic pattern is designated L3 in the French-American-British (FAB) system (see Histologic Findings). Prominent clinical features include extramedullary lymphomatous masses in the abdomen or head and neck and frequently involve the CNS.
  • Approximately 80% of childhood acute lymphoblastic leukemia involves lymphoblasts with phenotypes that correspond to those of B-cell progenitors. These cases can be identified by their cell-surface expression of 2 or more B-lineage–associated antigens (ie, CD19, CD20, CD24, CD22, CD21, or CD79). Only CD79 is specific for B-lineage acute lymphoblastic leukemia. In addition, about one fourth of B-cell precursor cases express cytoplasmic immunoglobulin µ heavy-chain proteins and are designated pre–B-cell acute lymphoblastic leukemia. Cases related to B-cell precursors can be subclassified as early pre–B-cell, pre–B-cell, or transitional pre–B-cell cases. Although mature B-cell acute lymphoblastic leukemia should be differentiated from B-precursor cases, distinguishing the subtypes of B-precursor acute lymphoblastic leukemia is probably not clinically relevant.
  • T-cell acute lymphoblastic leukemia is identified by the expression of T-cell–associated surface antigens, of which cytoplasmic CD3 is specific. T-cell acute lymphoblastic leukemia cases can be classified by early, mid, or late thymocytes. Clinical features most closely associated with T-cell acute lymphoblastic leukemia are high blood leukocyte counts and CNS involvement. About one half of patients have a mediastinal mass at the time of diagnosis. The prognosis of patients with T-cell acute lymphoblastic leukemia has historically been worse than that of patients with B-lineage acute lymphoblastic leukemia. However, the outlook for patients with T-cell leukemia is improved to nearly that of precursor B-cell acute lymphoblastic leukemia when intensive chemotherapy is used.
• Cytogenetic and molecular diagnosis
  • In more than 90% of acute lymphoblastic leukemia cases, specific genetic alterations can be found in the leukemic blasts. These alterations include changes in chromosome number (ploidy) and structure; about half of all childhood acute lymphoblastic leukemia involves recurrent translocations.  Standard cytogenetic analysis is an essential tool in the workup of all patients with leukemia because the karyotype of the leukemic cells has important diagnostic, therapeutic, and prognostic implications. In addition, molecular techniques, including fluorescence in situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR), and Southern blot analysis help improve diagnostic accuracy. Molecular analysis can be used to identify translocations not detected on routine karyotype analysis and to distinguish lesions that appear cytogenetically identical but are molecularly different.
  • Common chromosomal abnormalities in acute lymphoblastic leukemia include t(9;22)(q34;q11) or BCR-ABL, t(1;19)(q23;p13) or E2A-PBX1, t(12;21)(p13;q22) or TEL-AML1, MLL rearrangements, hyperdiploidy (>50 chromosomes/cell), and hypodiploidy (<44 chromosomes/cell). In general, BCR-ABL, t(4;11) with MLL-AF4, and hypodiploidy confer a poor outcome, whereas hyperdiploidy, TEL-AML1, and trisomy 4, trisomy 10, and trisomy 17 are associated with favorable outcomes.
• Minimal residual disease: Although still experimental, molecular analysis promises to play a role in the diagnosis and treatment of acute lymphoblastic leukemia and in monitoring patients' responses to therapy. Studies of minimal residual disease (MRD) may be based on the detection of chimeric transcripts generated by fusion genes, the detection of clonal TCR or immunoglobulin heavy-chain (IgH) gene rearrangements, or the identification of a phenotype specific to the leukemic blasts. All studies using MRD techniques have shown significant correlations between end-of-induction leukemia burden and outcome.
• Risk assessment: Current risk assessment includes clinical features (age and WBC at diagnosis), biological characteristics of the leukemic blasts, response to the induction chemotherapy, and MRD burden. Current studies are ongoing to assess an optimal treatment for each leukemia group with different risks. Future goals include better understanding the molecular pathways leading to specific phenotypes, minimizing the risk of relapse by identifying subsets of patients requiring more intensive therapy, and minimizing the risk of toxicity for those patients highly likely to be cured with currently available therapies. 

Imaging Studies

• Chest radiography: Evaluate for a mediastinal mass. In general, no other imaging studies are required. However, if the physical examination reveals enlarged testes, perform ultrasonography to evaluate for testicular infiltration.
• Testicular ultrasonography: Perform testicular ultrasonography if the testes are enlarged upon physical examination.
• Renal ultrasonography: Some clinicians prefer to evaluate for leukemic kidney involvement to assess the risk of tumor lysis syndrome.
• Echocardiography and ECG: Obtain an echocardiogram and an ECG before anthracyclines are administered.

Procedures

• Bone marrow aspirate and biopsy: The results confirm the diagnosis of acute lymphoblastic leukemia. In addition, special stains (immunohistochemistry), immunophenotyping, cytogenetic analysis, and molecular analysis help in classifying each case.
• Lumbar puncture with cytospin morphologic analysis: These tests are performed before systemic chemotherapy is administered to assess for CNS involvement and to administer intrathecal chemotherapy.

Histologic Findings

According to the French-American-British (FAB) classification system, acute lymphoblastic leukemia is classified into 3 groups based on morphology.

• L1: Cells are usually small, with scant cytoplasm and inconspicuous nucleoli. L1 accounts for 85% of all cases of childhood acute lymphoblastic leukemia.
• L2: Cells are larger than in L1. The cells demonstrate considerable heterogeneity in size, with prominent nucleoli, and abundant cytoplasm. L2 accounts for 14% of all childhood ALL.
• L3: Cells are large and notable for their deep cytoplasmic basophilia. They frequently have prominent cytoplasmic vacuolation and are morphologically identical to Burkitt lymphoma cells. L3 accounts for 1% of childhood acute lymphoblastic leukemia cases.

Although the FAB system was used in the past, it is no longer useful (except for L3) because current standard diagnosis is based on immunophenotype and molecular techniques.

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