Approach

Acute lymphoblastic leukemia (ALL) commonly presents rapidly and aggressively in adults. It may mimic many other conditions, which often creates diagnostic confusion.

A definitive diagnosis can be made from a bone marrow aspiration and trephine biopsy. Leukemic lymphoblasts may circulate in the blood; if present in sufficient numbers, this may be used to defer bone marrow exam at presentation.

History

The appearance of signs and symptoms associated with cytopenias is often the initial cause for seeking medical attention by the patient. Most patients present within a few weeks of symptom onset.

Anemia typically manifests as fatigue, dyspnea, palpitations, and dizziness; thrombocytopenia presents with bleeding (e.g., epistaxis, menorrhagia) and easy bruising; neutropenia presents as recurrent infections, which may cause fever.

Lymph node involvement is common in ALL. Enlarged lymph nodes can be an initial presenting cause.

Abdominal and bone pain may be present due to infiltration of blast cells in the spleen and bone marrow, respectively.[47]

Historic factors suggestive of ALL include history of malignancy, family history of ALL, genetic disorder (e.g., trisomy 21, Klinefelter syndrome, Fanconi anemia, Bloom syndrome, ataxia-telangiectasia), treatment with chemotherapy, radiation exposure, and smoking.[1][2][3][11][12][13][14][19][30][32]​​[48]

Less common ALL presentations

These include eosinophilia, isolated renal failure, pulmonary nodules, bone marrow necrosis, pleural/pericardial effusion, superior vena cava obstruction, hypoglycemia, joint pain, mental status changes, headaches, chin numbness, and skin nodules.[1][8]

Physical examination

Findings may include pallor, ecchymoses, petechiae, lymphadenopathy, hepatosplenomegaly, mediastinal masses, abdominal masses, testicular enlargement (unilateral and painless), renal enlargement, and skin infiltrations (skin nodules).

Lymphadenopathy is classically generalized, and the enlarged nodes are painless and freely movable.[1][8] T-ALL more commonly causes mediastinal masses, whereas B-ALL more commonly causes abdominal masses. The findings of stridor, wheezing, pericardial effusion, and superior vena cava syndrome may be associated with mediastinal masses. Mature B-ALL (Burkitt lymphoma/leukemia) may initially present as a palpable large abdominal mass from a rapidly proliferating tumor.[30][48]

Testicular involvement occurs most commonly in children and adolescents with T-ALL.[49] Testicular examination should be carried out at diagnosis in all male patients. The testes can represent a sanctuary site that is relatively protected from the effects of systemic therapy via the blood-testis barrier.[49]

Neurologic assessment

Required to exclude central nervous system (CNS) involvement, which is a major complication of ALL. CNS involvement occurs in approximately 5% to 7% of patients at diagnosis; incidence is highest in patients with T-ALL (8%) and mature B-ALL (Burkitt lymphoma/leukemia, 13%).[50][51][52][53][54]

The meninges are the primary site of CNS disease.[55] Presenting features of CNS disease include focal neurologic signs, headache, papilledema, nuchal rigidity, and meningismus. Some patients may present with signs or symptoms of focal neurologic deficit (e.g., diplopia) due to isolated sites of CNS involvement on the cranial nerves (mainly the seventh, third, fourth, and sixth).[52]

Initial laboratory tests

Should include complete blood count with differential, peripheral blood smear, comprehensive metabolic panel (serum electrolytes; serum uric acid; serum lactate dehydrogenase [LDH]; renal function tests; liver function tests), coagulation profile (prothrombin time, partial thromboplastin time, fibrinogen, and D-dimers), blood type and antibody screening for eventual transfusion support, and viral antibody testing (including cytomegalovirus, hepatitis B and C, and HIV serologies).

Laboratory findings

Over 90% of patients have clinically evident hematologic abnormalities at the time of initial diagnosis. Normocytic normochromic anemia with low reticulocyte count is present in 80% of patients. Thrombocytopenia is very common, affecting 75% of patients.[1][2][8]​ Leukocytosis is found in 50% of patients. In 25% of these patients, white blood cell (WBC) count is >50,000/microliter. High WBC at presentation is associated with a poorer prognosis. Despite the elevation in WBC, many patients have severe neutropenia (absolute neutrophil count <500 cells/microliter), thus placing them at high risk for serious infections.[56] See Febrile neutropenia.

Leukemic lymphoblasts may be detected on peripheral blood smear. The presence of leukemic lymphoblasts ≥1000/microliter in the peripheral blood is sufficient to defer bone marrow exam at presentation.[57]

Hypercalcemia may occur due to bony infiltration or ectopic release of a parathyroid hormone-like substance.

Hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and elevated serum LDH may occur due to tumor lysis syndrome (TLS), particularly during treatment and if WBC count (tumor burden) is high. This can lead to cardiac arrhythmias, seizures, acute renal failure, and death, if untreated. TLS is an oncologic emergency. See Tumor lysis syndrome.

Evaluation of bone marrow

The diagnostic workup for ALL requires evaluation of bone marrow aspirate and trephine biopsy specimens (or peripheral blood if sufficient numbers of circulating lymphoblasts are present) using cytomorphology assessment, immunophenotyping, molecular studies, and cytogenetic analysis.[57][58]​ These investigations are important for risk stratification, treatment planning, and establishing a baseline for measurable residual disease (MRD) assessment during treatment.[57]

Hematopathology evaluation

Bone marrow aspiration specimens should be stained with Wright-Giemsa stain, and trephine biopsy specimens should be stained with hematoxylin and eosin. Biopsy specimens should also be stained with myeloperoxidase, which will be negative in patients with ALL.[59]​ A biopsy demonstrating bone marrow hypercellularity and infiltration by lymphoblasts is characteristic for ALL. There is a lack of consensus regarding the proportion of lymphoblasts in the bone marrow that is required to make a diagnosis of ALL; however, a threshold of ≥20% is generally advised.[57] The proportion of lymphoblasts in the bone marrow can help distinguish between ALL and lymphoblastic lymphoma. See Differential diagnosis. A defined number of lymphoblasts in the bone marrow (or peripheral blood) is not always required for the diagnosis of ALL (e.g., T-ALL can be diagnosed based on immunophenotyping). See Classification.

Immunophenotypic findings

Immunophenotyping (on bone marrow specimens, or peripheral blood if sufficient numbers of circulating lymphoblasts are present) using flow cytometry is required to assess cell surface markers to:[1][3][8]

  • determine lymphoid lineage (B-cell or T-cell);

  • define an aberrant phenotype for MRD assessment; and

  • detect clinically important cell surface antigens (e.g., CD20).

Leukemic cells typically exhibit markers of one cell type. Rarely, simultaneous expression of lymphoid and myeloid markers occurs in ALL, either as ALL with aberrant expression of myeloid antigens (My+ ALL) or true biphenotypic acute leukemia.

Molecular and cytogenetic evaluation

Molecular studies (e.g., reverse transcriptase polymerase chain reaction [RT-PCR]) and cytogenetic analysis (e.g., karyotyping, fluorescence in situ hybridization [FISH]) are required to detect genetic abnormalities (e.g., BCR::ABL1 fusion gene encoded by the Philadelphia chromosome; ETV6::RUNX1 [also known as TEL::AML1]; KMT2A rearrangement). Findings may be of prognostic and therapeutic significance.[58]

Next-generation sequencing assays can be used to detect certain gene fusions and mutations with prognostic significance (e.g., NOTCH1/FBXW7 mutation in T-ALL).[57][59] See Diagnostic criteria.

[Figure caption and citation for the preceding image starts]: Lymphoblasts in bone marrow smear from 3-year-old male with ALL (Wright-Giemsa stain)Image and description are from the AFIP Atlas of Tumor Pathology [Citation ends].com.bmj.content.model.Caption@2bee43ff

Baseline measurable residual disease (MRD) testing

It is important to establish a baseline for MRD testing based on immunophenotypic, molecular, and/or cytogenetic features of the leukemic cell. MRD testing enables depth and speed of remission to be assessed during treatment. It is prognostically important and can guide therapeutic decisions. The exact tests for MRD depend on the patient, and assays available to the treating center.

The preferred sample for MRD testing is the first small volume (of up to 3 mL) pull of the bone marrow aspirate and/or peripheral blood.[57]

Lumbar puncture

A lumbar puncture is required in all patients given the relatively high frequency of CNS involvement. Signs or symptoms of CNS involvement include focal neurologic deficits, headache, and meningismus. The procedure should only be performed once raised intracranial pressure has been ruled out.

Lumbar puncture should be carried out at a time consistent with the treatment protocol being used. Pediatric-inspired protocols typically include lumbar puncture at diagnostic workup. However, the National Comprehensive Cancer Network ALL Panel recommends the first lumbar puncture be performed concomitantly with initial intrathecal therapy to avoid seeding the CNS with circulating leukemic blasts, unless symptoms require a lumbar puncture to be performed earlier.[57]

Diagnostic lumbar puncture in adults: animated demonstration
Diagnostic lumbar puncture in adults: animated demonstration

How to perform a diagnostic lumbar puncture in adults. Includes a discussion of patient positioning, choice of needle, and measurement of opening and closing pressure.

Detection of lymphoblasts in the initial cerebrospinal fluid (CSF) sample by multiparameter flow cytometry can identify patients at high risk of CNS relapse.[66][67]

CNS involvement at diagnosis can be graded based on the presence of lymphoblasts, WBCs, and red blood cells (RBCs) in the CSF, using the Children’s Oncology Group classification.[68][69]​​​ Higher grade (i.e., increased lymphoblasts, WBCs, and RBCs [traumatic lumbar puncture] in the CSF) is associated with poorer outcomes. See Diagnostic criteria.

Imaging

Chest radiograph may be performed to identify a mediastinal mass, pleural effusion, or lower respiratory tract infection. Pleural effusions should be tapped and samples sent for cytology and immunophenotyping. A mediastinal biopsy should be avoided if possible, though this may be the primary site of involvement for some patients and in such cases is unavoidable.

CNS imaging (e.g., computed tomography [CT]/magnetic resonance imaging [MRI] brain) should be performed in patients with major neurologic signs and symptoms (e.g., lowered consciousness level, meningismus, or focal neurologic deficits) to identify meningeal involvement or CNS bleeding. Spinal cord and parenchymal brain involvement may occur, but is very rare.

CT thorax should be performed in the presence of a widened mediastinum on chest radiograph. CT thorax, abdomen, and pelvis should be performed if there is palpable lymphadenopathy or other evidence of extramedullary disease.

In males with an abnormal testicular exam or symptoms, scrotal ultrasound should be performed to characterize the nature of the abnormality and to establish a baseline prior to treatment initiation.[57]

Echocardiogram or multigated acquisition (MUGA) scan should be considered in all patients to assess cardiac function before initiating treatment.[57] Anthracyclines are used in most treatment regimens for ALL and are potentially cardiotoxic.[Figure caption and citation for the preceding image starts]: Chest x-ray of patient presenting with dyspnea, showing widened mediastinum and tracheal displacementFrom the personal collection of CR Kelsey [Citation ends].com.bmj.content.model.Caption@4c9e9cf8

Other investigations

The following tests may be carried out once a diagnosis of ALL is confirmed:[2][3][70]

  • Human leukocyte antigen (HLA)-typing

  • Thiopurine methyltransferase (TPMT) phenotyping

  • Nudix hydrolase 15 (NUDT15) phenotyping

HLA-typing is required to identify a suitable donor for stem cell transplantation and for obtaining HLA-matched platelets in the event of platelet alloimmunization during platelet transfusion.

TPMT and NUDT15 phenotyping help to guide dosing of mercaptopurine during maintenance therapy.[70]

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