Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children

INTRODUCTION — 

Acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL) is the most common childhood malignancy. The term ALL/LBL is used because the current system for diagnosis and classification does not distinguish between clinical presentations as leukemia or lymphoma; by convention, the term lymphoma is used when the disease is confined to a mass lesion with little or no blood and marrow involvement.

The clinical presentation, evaluation, diagnosis, and classification of ALL/LBL in children are reviewed here.

Risk group stratification and treatment of childhood ALL/LBL are discussed separately. (See "Prognostic factors and risk group stratification for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents" and "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)

EPIDEMIOLOGY — 

ALL/LBL accounts for approximately one-third of all childhood malignancies and is the most common form of cancer in children; ALL/LBL is five times more common in children than acute myeloid leukemia (AML) [1,2]. The distribution of ALL/LBL categories is B lineage (85 percent), T lineage (10 to 15 percent), and NK lineage (<1 percent).

Approximately 2500 to 3500 new cases of ALL/LBL are diagnosed in children each year in the United States, with an incidence of approximately 3.4 cases per 100,000 [1]. The incidence varies worldwide but this may be influenced, in part, by diagnostic and reporting differences [3]. In the United States, the incidence of ALL/LBL is higher in Latino and White individuals than in Black and Asian individuals [4,5]. The peak incidence of ALL/LBL occurs between ages two to five years, and it is more common among boys than girls [1,4,6,7].

The incidence of childhood leukemia appears to be increasing, as demonstrated by the following studies:

●In an analysis of the Surveillance, Epidemiology, and End Results (SEER) database, there was a steady increase in ALL/LBL incidence from 2000 to 2016, with an average annual increase in incidence of approximately 1 percent [5]. ALL/LBL accounted for one-quarter of childhood cancer cases in 2014-2016 [1,8].

●In a study that used data from 63 European population-based cancer registries of children diagnosed with cancer, the incidence of leukemia, including ALL/LBL, increased by an average of 1.4 percent per year from 1970 to 1999 [9].

●In a study from Great Britain, the incidence of leukemia (mostly ALL/LBL) steadily increased from 38 per million in the period from 1971 to 1975 to 46 per million in 1996 to 2000 [10].

More accurate reporting may also contribute to the apparent increase in the incidence of ALL/LBL. A study from Denmark, Finland, Norway, and Sweden reported that the incidence of childhood ALL/LBL remained stable at 3.3 cases per 100,000 in children <15 years old from 1983 to 2002 after an increase in incidence between 1975 and 1983 [6].

RISK FACTORS FOR ALL/LBL — 

The vast majority of cases of ALL/LBL have no known cause, but an increased incidence has been associated with certain environmental or genetic risk factors.

Large studies have reported modest increases of ALL/LBL in association with advanced paternal age and maternal fetal loss [11-13]. A Scandinavian case-control study of >1900 children with ALL/LBL reported that increased birth weight was associated with increased risk for ALL/LBL (odds ratio [OR] 1.26 per 1 kg increase in birth weight; 95% CI 1.13-1.41); however, children with leukemia did not weigh more at birth than their siblings [14]. Studies of the relationship between childhood leukemia and urban/rural status, population density, and other possible etiologic factors (eg, environmental exposures, abnormal immune response to common infections) have yielded inconsistent results [15-28].

In most cases, childhood ALL/LBL is not considered to be a familial disease. However, a Scandinavian study that included 3994 children with ALL/LBL identified 36 siblings who were subsequently diagnosed with ALL/LBL [29]. They reported that, compared with the general population, monozygotic twin siblings of children with ALL/LBL have a much higher risk of developing leukemia (standardized incidence ratio [SIR] 163; 95% CI 70-320), while singleton siblings are at only slightly increased risk (SIR 3; 95% CI 2-6). The high risk of ALL/LBL in monozygotic twin siblings of affected children stems from the spread of "pre-leukemic" clones from one twin to the second in utero [30]. However, not all monozygotic twins develop leukemia, and there is sometimes a long latency between leukemia development [31].

Certain genetic syndromes (eg, Down syndrome, neurofibromatosis type 1, Bloom syndrome, ataxia-telangiectasia) are associated with an increased risk for ALL/LBL [32,33]. In addition, germline mutations in PAX5, ETV6, and TP53 predispose to the development of ALL/LBL and large-scale genomic studies have noted that polymorphic variants of ARID5B, CDKN2A, and IKZF1 (the gene encoding Ikaros) are associated with an increased risk of leukemia (OR: 1.3-1.9) [34-38]. Rare examples of familial ALL/LBL syndromes are described separately. (See "Down syndrome: Clinical features and diagnosis", section on 'Acute lymphoblastic leukemia' and "Familial disorders of acute leukemia and myelodysplastic syndromes".)

PRESENTATION — 

The most common presenting findings associated with ALL/LBL are nonspecific and may be difficult to distinguish from ordinary, self-limited diseases of childhood. A meta-analysis that included >3000 children from 33 studies reported that more than half of children with childhood leukemia had at least one of the following five features on presentation: palpable liver, palpable spleen, pallor, fever, or bruising. A minority (6 percent) of children were asymptomatic at the time of diagnosis [39]. Evaluation of these clinical findings is described below. (See 'Clinical evaluation' below.)

Among the most common clinical findings at the time of presentation with ALL/LBL are:

●Hepatomegaly (64 percent) and/or splenomegaly (61 percent) are the most common clinical findings in association with childhood leukemia [39]. Organomegaly may manifest as anorexia, weight loss, abdominal distension or abdominal pain noted by a family member or clinician.

●Lymphadenopathy is present in nearly half of children with ALL/LBL [39].

●Fever is present in more than half of children at the time of diagnosis of ALL/LBL [39]. Fever may be caused by infection or may represent a constitutional symptom caused by the leukemia itself.

●Hematologic abnormalities are common presenting findings in childhood ALL/LBL. About half of children present with bleeding (eg, petechiae, purpura) and three-quarters have a platelet count <100,000/microL at diagnosis [40]. Manifestations of anemia (eg, pallor, fatigue) are reported in more than half of children [39]. The white blood cell (WBC) count may be low, normal, or high; WBC count is <10,000/microL in one-half of patients at presentation and >50,000/microL in 20 percent.

●Musculoskeletal pain is a presenting symptom in 43 percent of cases of ALL/LBL [39]. Young children with bone pain may present with a limp or refusal to bear weight [40].

Less common manifestations of ALL/LBL in children include:

●Headache is uncommon (<5 percent of cases), but leukemia involving the central nervous system can present with headache, vomiting, lethargy, nuchal rigidity, and, rarely, cranial nerve abnormalities [41-43].

●Testicular enlargement is rare (<1 percent), but painless unilateral testicular enlargement can be a presenting sign of ALL/LBL. Notably, testicular involvement is present in up to 10 percent of boys with relapsed leukemia [44].

●A mediastinal mass, which is most often associated with T-ALL/LBL, can cause superior vena cava (SVC) syndrome, which may manifest as pain, dysphagia, dyspnea, or swelling of the neck, face, and upper limbs due to obstruction the SVC. Respiratory distress may result from a mass compressing the trachea. (See "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma", section on 'Clinical presentation'.)

CLINICAL EVALUATION

When to suspect ALL/LBL — ALL/LBL should be suspected in a child with persistent unexplained pallor, fever, bleeding/bruising, bone pain, hepatosplenomegaly, and/or lymphadenopathy. In some cases, less common findings (eg, testicular swelling, neurologic findings, or evidence of tracheal obstruction or superior vena cava syndrome) may be the sole manifestation. A high degree of suspicion is required because the most common findings are nonspecific and may be difficult to distinguish from ordinary, self-limited diseases of childhood. Young children may be unable to effectively describe their symptoms. (See 'Presentation' above.)

Children who are suspected of having leukemia, based on presentation and initial laboratory evaluation, should be referred promptly to a pediatric cancer specialist or pediatric cancer center for evaluation, diagnosis, and management.

History and physical examination — Clinical findings that may be detected by history or physical examination include (see 'Presentation' above):

●Hepatosplenomegaly – Organomegaly may be detected by physical examination or the child or a family member may report anorexia, weight loss, abdominal distension or abdominal pain. Evaluation of the child with unexplained splenomegaly, including imaging and laboratory studies, is presented separately. (See "Approach to the child with an enlarged spleen", section on 'Evaluation'.)

●Lymphadenopathy – Persistent or progressive lymphadenopathy that does not respond to antibiotic therapy should be evaluated for ALL/LBL. Typical lymphadenopathy associated with ALL/LBL is nontender, firm, rubbery, and matted. A lymph node is generally considered enlarged when it is >10 mm, except for the following nodes that are considered abnormal: epitrochlear (>5 mm), inguinal (>15 mm), and cervical (>20 mm). Evaluation and diagnostic studies of lymphadenopathy is described separately. (See "Overview of common presenting signs and symptoms of childhood cancer", section on 'Lymphadenopathy'.)

●Fever – Recurrent fevers, failure to respond to seemingly appropriate treatment, drenching sweats, or unexplained weight loss should prompt evaluation for underlying leukemia. Fever may be caused by infection or may be a constitutional symptom caused by the leukemia itself. Assessment of a child with unexplained fever or other constitutional symptoms that may be attributable to leukemia is described separately. (See "Overview of common presenting signs and symptoms of childhood cancer", section on 'Constitutional symptoms'.)

●Hematologic findings – Pallor, persistent fatigue, unusual bleeding/bruising, or petechial rash are common manifestations of ALL/LBL in children. Evaluation of children with anemia or thrombocytopenia is described separately. (See "Approach to the child with anemia", section on 'Evaluation' and "Approach to the child with unexplained thrombocytopenia", section on 'Diagnostic evaluation'.)

●Musculoskeletal pain – Bone pain is common as a presenting symptom, but young children may instead present with a limp or refusal to bear weight. Joint pain caused by ALL/LBL may be mistaken for rheumatologic pain. Diagnostic evaluation in children and features that may distinguish leukemia-associated musculoskeletal pain from other causes are discussed separately. (See "Overview of common presenting signs and symptoms of childhood cancer", section on 'Bone and joint pain'.)

●Neurologic findings – Leukemia involving the central nervous system can present with symptoms related to increased intracranial pressure, including headache, vomiting, lethargy, and/or nuchal rigidity [41]. Rarely, leukemia can present with cranial nerve abnormalities [42,43]. Neurologic findings from the history and physical examination should be evaluated promptly by imaging and/or lumbar puncture (LP). As described below, all children who are diagnosed with ALL/LBL must have a diagnostic/therapeutic LP at the time that treatment is initiated, regardless of whether neurologic abnormalities are found. (See 'Lumbar puncture/neurologic evaluation' below.)

●Testicular enlargement – A patient with a persistent, painless, solid testicular mass should be referred to a pediatric cancer center or a pediatric cancer specialist after evaluation by ultrasound. (See "Causes of painless scrotal swelling in children and adolescents", section on 'Testicular cancer'.)

●Respiratory distress – Tachypnea, inspiratory stridor, wheezing, suprasternal/supraclavicular retractions, prolonged inspiratory phase, drooling, or other findings that suggest upper airway obstruction should be evaluated and managed, as discussed separately. (See "Emergency evaluation of acute upper airway obstruction in children".)

●Swelling of face, neck, or upper extremities – A large anterior mediastinal mass (typically associated with T-lineage ALL/LBL) may manifest as swelling of the neck, face, and upper limbs, or with pain, dysphagia, or dyspnea. (See "Malignancy-related superior vena cava syndrome", section on 'Clinical features'.)

LABORATORY EVALUATION

Laboratory studies — Laboratory evaluation for ALL/LBL includes a complete blood count (CBC) and differential, review of the peripheral smear, and bone marrow examination. When lymphadenopathy is a prominent component of the clinical presentation, the evaluation may begin with the sampling of a suspicious lymph node. An excisional or needle core biopsy is preferable to a fine needle aspirate because these approaches allow for evaluation of nodal architecture and provide sufficient material for a thorough pathologic work-up. (See "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach", section on 'Lymph node biopsy'.)

Morphology — Morphology of cells from peripheral blood, bone marrow, or other tissues may be variable, but visualization of characteristic morphology on a blood smear (picture 1) and bone marrow specimen (picture 2) is required for the diagnosis of ALL/LBL, as described below. (See 'Diagnosis' below.)

Lymphoblasts of ALL/LBL can be morphologically indistinguishable from atypical cells seen in a variety of other disorders. Features that distinguish ALL/LBL from other malignant and nonmalignant conditions are discussed below. (See 'Differential diagnosis' below.)

Cytochemistry — Cytochemical studies have some value in evaluating suspected cases of leukemia but are not performed at all centers and are not required to diagnose ALL/LBL. Cytochemical stains have been largely replaced by flow cytometry and cytogenetics (see below). Examples of cytochemical findings associated with ALL/LBL include:

●Periodic acid-Schiff (PAS) – Lymphoblasts may contain coarse ("chunky") PAS-positive granules, a finding present in only a subset of cases; this staining pattern is due to the presence of glycogen, which may also be present in some blasts of myeloid origin (particularly erythroblasts)

●Nonspecific esterase (NSE) – Staining is usually absent, but weak multifocal punctate or Golgi region staining may be seen

●Myeloperoxidase (MPO) – By definition, MPO staining is negative in ALL/LBL, since peroxidase is considered a lineage-defining myeloid marker

Flow cytometry/immunohistochemistry — Flow cytometry and/or immunohistochemistry is an important component of evaluation for suspected ALL/LBL, and it may be used to characterize the immunophenotype of lymphoblasts from peripheral blood, bone marrow, lymph nodes, or other tissue (eg, pleural fluid).

Immunophenotypic characterization should include:

●Lymphoid antigens – B cell (eg, CD19, CD20, CD22, CD79a, PAX5), T cell (eg, CD1a, CD3, CD4, CD5, CD7, CD8), NK cell (eg, CD56), and markers of immature lymphoid cells (CD10, terminal deoxyribonucleotide transferase [TdT]).

Markers of intermediate (CD10) and late (CD20) stages of pre-B cell maturation are variably expressed, depending on the stage of maturation arrest of the B lymphoblasts. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma", section on 'Evaluation and diagnosis'.)

T lymphoblasts are usually also positive for CD2, CD5, and CD7, and variable combinations of CD1a, CD4, CD8, and CD10 may be expressed, depending on the stage of maturation arrest. (See "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma", section on 'Evaluation and diagnosis'.)

●Myeloid antigens (eg, CD13, CD33, CD11b, CD64)

●Maturation antigens (eg, CD34, CD117, HLA-DR)

Aspects of the immunophenotype that are required for diagnosis and classification of ALL/LBL are described below. (See 'Diagnosis' below and 'Classification' below.)

Cytogenetic/molecular features — Cytogenetic and molecular features are not required for diagnosis, but they are essential criteria for World Health Organization classification of ALL/LBL [45]. (See 'Classification' below.)

Chromosome banding techniques and fluorescence in situ hybridization (FISH) are used to characterize cytogenetic features, while a variety of molecular techniques are used for mutation analysis and gene expression studies [46,47]. (See "General aspects of cytogenetic analysis in hematologic malignancies", section on 'Examination of tumor specimens' and "Tools for genetics and genomics: Gene expression profiling" and "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

Rearrangement of immunoglobulin and T cell receptor genes in ALL/LBL is not a reliable method for distinguishing between B and T cell lineages because rearrangement is variable and not lineage-specific. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma", section on 'Cytogenetic/Molecular analysis'.)

DIAGNOSIS — 

The diagnosis of ALL/LBL requires characteristic morphology and a diagnostic immunophenotype of cells from peripheral blood, bone marrow, lymph node, and/or other involved tissue:

●Morphology may vary from small cells with scant cytoplasm, condensed nuclear chromatin, and indistinct nucleoli (picture 1) to larger cells with moderate amounts of cytoplasm, dispersed chromatin, and multiple nucleoli; coarse azurophilic cytoplasmic granules may be present, but Auer rods are absent [45]. The appearance of lymphoblasts in biopsy specimens is relatively uniform (picture 2), but the cells may include round, oval, indented, or convoluted nuclei, finely dispersed chromatin, and nucleoli that can range from inconspicuous to prominent.

Features that distinguish ALL/LBL from other disorders are described below. (See 'Differential diagnosis' below.)

●Diagnostic immunophenotype of ALL/LBL requires confirmation of lymphoid lineage and exclusion of myeloid lineage by flow cytometry and/or cytochemistry [45].

Lymphoblast lineage is defined as one of the following (see 'Flow cytometry/immunohistochemistry' above):

•B-lineage lymphoblasts are almost always positive for the B cell markers CD19, cytoplasmic CD79a, and cytoplasmic CD22; although none of the B cell markers by itself is specific for B-lineage ALL/LBL, their positivity in combination or high-intensity expression strongly supports the diagnosis. Most cases are also positive for terminal deoxynucleotidyl transferase (TdT).

B lymphoblasts are negative for CD3 (T cell antigen) and negative for myeloperoxidase (MPO); however, in some cases, expression of certain myeloid antigens (eg, CD13, CD15, CD33) does not exclude a diagnosis of ALL/LBL, as described separately. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma", section on 'Evaluation and diagnosis'.)

•T-lineage lymphoblasts, which are positive for cytoplasmic or surface CD3, usually express CD5 and CD7 and are negative for B cell antigens and MPO. Expression of markers of immaturity (eg, CD1a, TdT) and detection of CD4/CD8 double positivity or double negativity are other helpful diagnostic findings.

•Other: Criteria for diagnosis of NK-ALL/LBL and early T cell precursor ALL/LBL are controversial and/or evolving [45].

Although there is no consensus regarding a minimal proportion of lymphoblasts in bone marrow, the diagnosis of B-ALL/LBL should be made cautiously and only when supported by additional pathologic findings when there are <20 percent lymphoblasts [45].

DIFFERENTIAL DIAGNOSIS — 

The presenting signs and symptoms of ALL/LBL are often nonspecific and morphology alone is not diagnostic, so it is important to consider a wide range of malignant and nonmalignant conditions in the differential diagnosis.

Malignant disorders

Burkitt lymphoma — Burkitt lymphoma (BL) is a highly aggressive B cell non-Hodgkin lymphoma that can present with a rapidly growing tumor mass (eg, jaw or abdominal mass) and/or as a leukemia.

BL can have substantial clinical and morphologic overlap with ALL/LBL. The histology of BL typically reveals highly proliferative monomorphic medium-sized cells with basophilic cytoplasm (often with a "starry sky" appearance) (picture 3) that are generally larger than ALL/LBL lymphoblasts. The diagnosis of BL is based on morphology, immunophenotype, and cytogenetic/molecular features, and it is distinguished from ALL/LBL by the characteristic mature germinal center B cell immunophenotype, as discussed separately. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma", section on 'Diagnosis'.)

Other acute leukemias — ALL/LBL lymphoblasts may be difficult to distinguish morphologically from other forms of acute leukemia, particularly those that are minimally differentiated:

●Acute myeloid leukemia (AML) – Myeloblasts of AML are typically immature cells with large nuclei, prominent nucleoli, and a variable amount of pale blue cytoplasm (sometimes with faint granulation and/or Auer rods). AML cells generally stain for myeloperoxidase (MPO) or lysozyme and are typically negative for B and T cell antigens and TdT; however, some cases of AML express antigens associated with stem cells or lymphoid lineages (eg, CD19 is commonly expressed in AML with RUNX1::RUNXT1 fusion). Other aspects of the diagnosis of AML are presented separately. (See "Acute myeloid leukemia: Clinical manifestations, pathologic features, and diagnosis".)

●Acute undifferentiated leukemia (AUL) – AUL blast cells are morphologically bland and generally indistinguishable from those of B-ALL/LBL. These entities are distinguished by immunophenotype; AUL blasts do not express lineage-specific antigens by flow cytometry or immunohistochemistry, whereas ALL/LBL blasts express B- or T-lymphoid antigens. (See "Mixed phenotype acute leukemia".)

●Mixed phenotype acute leukemia (MPAL) – Diagnosis of MPAL requires demonstration of both myeloid- and lymphoid-defining markers by flow cytometry and/or immunohistochemistry. (See "Mixed phenotype acute leukemia".)

Chronic myeloid leukemia (CML) — CML is typically manifested as an expanded population of myeloid cells at various stages of differentiation with the characteristic t(9;22) (Philadelphia chromosome) with BCR::ABL1 rearrangement that may be accompanied by splenomegaly and/or constitutional symptoms. However, about 10 percent of CML in blast phase may have a dominant population of lymphoblasts. CML in lymphoid blast crisis can be distinguished from ALL/LBL by detection of t(9;22) or BCR::ABL1 in myeloid cells. (See "Chronic myeloid leukemia: Pathogenesis, clinical manifestations, and diagnosis".)

Myeloid/lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2 — These rare neoplasms often present with lymphadenopathy due to proliferation of T-lineage (or less commonly, B-lineage) lymphoblasts that are morphologically and immunophenotypically indistinguishable from conventional LBL [45]. The characteristic gene rearrangements are also present in myeloid cells as well as the lymphoblasts, and these disorders should be suspected if examination of the blood reveals leukocytosis and eosinophilia. They are diagnosed based on identification of one of the pathogenic gene rearrangements (listed above), typically by fluorescence in situ hybridization (FISH). (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'HES variants'.)

Aplastic anemia — Aplastic anemia (AA) may present in children as pancytopenia with reticulocytopenia (frequently <10,000/microL) and profoundly hypocellular bone marrow with a decrease in all hematopoietic elements. In contrast to ALL/LBL, there is no infiltrate of malignant cells in AA; instead, the marrow space is largely composed of fat cells and marrow stroma.

Small round blue cell tumors — In children, small round blue cell tumors, including Ewing sarcoma (ES) and peripheral primitive neuroectodermal tumor (PNET) may superficially resemble B-ALL/LBL morphologically, but these disorders usually present as masses and are distinguished from B-ALL/LBL by the absence of B-lymphoid markers and the presence of certain characteristic cytogenetic/molecular findings (eg, t(11;22)(q24;q12), EWSR1::FLI1 rearrangement). Diagnosis and differential diagnosis of such tumors are discussed separately. (See "Epidemiology, pathology, and molecular genetics of Ewing sarcoma", section on 'Histologic features'.)

Nonmalignant disorders — The presenting signs and symptoms of ALL/LBL are nonspecific, and certain nonmalignant disorders may resemble ALL/LBL clinically and/or exhibit lymphocytes that may resemble lymphoblasts.

The following disorders may be included in the differential diagnosis in children:

●Immune thrombocytopenia (ITP) is associated with isolated thrombocytopenia that can resemble ALL/LBL clinically. The diagnosis of ITP in a healthy-appearing child with a typical presentation (ie, sudden onset of a petechial rash or bruising with isolated thrombocytopenia) is straightforward. Thrombocytopenia in ITP, especially in the context of an otherwise normal complete blood count, is typically more severe than in ALL/LBL. In contrast, thrombocytopenia in ALL/LBL is almost always associated with other clinical and laboratory findings (eg, fever, bone pain, weight loss, hepatosplenomegaly, lymphadenopathy, leukocytosis, anemia, peripheral blood lymphoblasts). When the diagnosis is uncertain, bone marrow examination and/or flow cytometry will distinguish ALL/LBL from ITP. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on 'Diagnosis'.)

●Infectious disease and other causes of lymphocytosis and/or aberrant lymphocytes include:

•Human immunodeficiency virus (HIV)

•Infectious mononucleosis

•Pertussis

•Osteomyelitis

•Tuberculosis

•Heavy metal toxicity

•Thymoma

•Autoimmune diseases (including juvenile rheumatoid arthritis in children)

Distinguishing these disorders from ALL/LBL in children is discussed separately. (See "Approach to the child with lymphocytosis or lymphocytopenia", section on 'Causes of reactive lymphocytosis'.)

CLASSIFICATION — 

ALL/LBL is classified according to cytogenetic features and immunophenotype.

Techniques used for classification include flow cytometry, chromosome banding techniques, fluorescence in situ hybridization (FISH), mutation analysis, and gene expression studies (in selected cases).

B-ALL/LBL — All cases of B-ALL/LBL should be classified because of different prognoses and/or distinctive treatment requirements.

The International Consensus Classification (ICC) and the World Health Organization 5^th edition (WHO5) apply similar labels and criteria for ALL/LBL subtypes [48,49].

Classification of B-ALL/LBL by the ICC [48] follows:

●B-ALL/LBL, not otherwise specified (NOS)

●B-ALL/LBL with recurrent genetic abnormalities:

•B-ALL with t(9;22)(q34.1;q11.2)/BCR::ABL1 (with lymphoid-only involvement or with multilineage involvement)

•B-ALL with t(v;11q23.3)/KMT2A rearranged

•B-ALL with t(12;21)(p13.2;q22.1)/ETV6::RUNX1

•B-ALL, hyperdiploid

•B-ALL, low hypodiploid

•B-ALL, near haploid

•B-ALL with t(5;14)(q31.1;q32.3)/IL3::IGH

•B-ALL with t(1;19)(q23.3;p13.3)/TCF3::PBX1

•B-ALL, BCR::ABL1-like, ABL-1 class rearranged

•B-ALL, BCR::ABL1-like, JAK-STAT activated

•B-ALL, BCR::ABL1-like, NOS

•B-ALL with iAMP21

•B-ALL with MYC rearrangement

•B-ALL with DUX4 rearrangement

•B-ALL with MEF2D rearrangement

•B-ALL with ZNF384(362) rearrangement

•B-ALL with NUTM1 rearrangement

•B-ALL with HLF rearrangement

•B-ALL with UBTF::ATXN7L3/PAN3,CDX2 ("CDX2/UBTF")

•B-ALL with mutated IKZF1 N159Y

•B-ALL with mutated PAX5 P80R

Provisional B-ALL entities include B-ALL, ETV6::RUNX1-like; B-ALL, with PAX5 alteration; B-ALL, with mutated ZEB2 (p.H1038R)/IGH::CEBPE; B-ALL, ZNF384 rearranged-like; B-ALL, KMT2A rearranged-like.

Details of criteria for classification of B-ALL/LBL are provided separately. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma".)

T-ALL/LBL — Immunophenotype is used to classify T-ALL/LBL and related entities.

Classification of B-ALL/LBL by the ICC [48] follows:

●T-ALL, NOS

●Early T cell precursor ALL with BCL11B rearrangement

●Early T cell precursor ALL, NOS

Additional features that distinguish categories of T-ALL/LBL are provided separately. (See "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma", section on 'Pathologic features'.)

PRETREATMENT EVALUATION — 

In addition to the studies that are required to establish the diagnosis of ALL/LBL, the following tests should be performed in advance of treatment.

Laboratory tests — Laboratory studies to evaluate potential complications of ALL/LBL (eg, coagulation abnormalities, liver or kidney dysfunction, metabolic abnormalities, tumor lysis syndrome) include:

●Coagulation profile – Prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen

●Chemistries – Electrolytes, renal and liver function tests, calcium, phosphate, lactate dehydrogenase (LDH), uric acid

Lumbar puncture/neurologic evaluation — All children who are diagnosed with ALL/LBL must undergo a lumbar puncture (LP) prior to beginning therapy to evaluate potential leukemic involvement of the central nervous system (CNS) and concomitantly administer the first dose of intrathecal therapy, as described separately. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Central nervous system evaluation and management'.)

Results from the LP are categorized as one of the following, which are used for determining the schedule of CNS prophylaxis:

●CNS-1 – No lymphoblasts in cerebrospinal fluid (CSF) regardless of the white blood cell count

●CNS-2 – <5 white blood cells (WBC)/microL in CSF with the presence of lymphoblasts

●CNS-3 – ≥5 WBC/microL in CSF with the presence of lymphoblasts

Neurologic findings from the history and physical exam should be evaluated promptly by imaging (eg, magnetic resonance imaging [MRI] or computed tomography [CT]) and/or urgent LP. Selection of the imaging modality is described separately. (See "Clinical manifestations and diagnosis of central nervous system tumors in children", section on 'Neuroimaging'.)

Performance of a diagnostic LP in a child and the evaluation of CSF are discussed separately. (See "Lumbar puncture in children" and "Cerebrospinal fluid: Physiology, composition, and findings in disease states", section on 'Composition of the CSF'.)

Other pretreatment tests — Other studies that should be performed before the initiation of treatment for ALL/LBL include the following:

●Infection evaluation

•Screen for active infections if the child is febrile, and initiate empiric treatment, as appropriate (see "Management of children with non-chemotherapy-induced neutropenia and fever")

•Some experts also include baseline viral titers in all children, including cytomegalovirus, Epstein-Barr virus, HIV, and hepatitis B virus

●Cardiac evaluation – Echocardiogram or cardiac scan should be performed to assess cardiac function in anticipation of treatment that includes an anthracycline.

●Human leukocyte antigen (HLA) typing – Some experts perform HLA typing in the event that hematopoietic cell transplantation is required for later management. This can be performed later in therapy since there are many children who will not need a transplant.

●CT of chest – For patients who are diagnosed with T-ALL/LBL, a CT scan of the chest, with contrast if possible, should be performed to evaluate the presence of a mediastinal mass. (See "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma", section on 'Clinical presentation'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute lymphoblastic leukemia".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Leukemia in children (The Basics)")

SUMMARY

●Definition – Acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL) refers to malignancies of precursor lymphoid cells. It is called ALL/LBL because leukemia and lymphoma are overlapping clinical presentations of the same disease (table 1).

●Epidemiology – ALL/LBL is the most common cancer in children, with peak incidence at two to five years of age. (See 'Epidemiology' above.)

●Causes – Most cases have no identifiable environmental or genetic cause. Incidence is increased in Down syndrome and other constitutional genetic disorders. (See 'Risk factors for ALL/LBL' above.)

●Presentation – Most children present with nonspecific symptoms that are difficult to distinguish from ordinary, self-limited diseases of childhood. Children usually present with persistent pallor, fever, bleeding/bruising, bone pain, hepatosplenomegaly, or lymphadenopathy. Less common findings include testicular swelling, tracheal obstruction, superior vena cava syndrome, or neurologic findings. (See 'Presentation' above.)

●When to suspect ALL/LBL – ALL/LBL should be suspected in children with the clinical findings described above or unexplained lymphocytosis, cytopenias, or circulating blasts. Such children should be referred promptly to a pediatric cancer specialist or pediatric cancer center for evaluation, diagnosis, and management. (See 'When to suspect ALL/LBL' above.)

●Evaluation

•Clinical – History and physical examination for disease-related findings (See 'History and physical examination' above.)

•Laboratory – Includes a complete blood count (CBC)/differential and review of blood smear for circulating lymphoblasts (picture 1). (See 'Laboratory studies' above.)

•Bone marrow – Bone marrow aspirate and biopsy are analyzed by microscopy, immunophenotyping by flow cytometry, cytogenetics, and molecular studies. This is best done at a pediatric cancer center or by a pediatric cancer specialist.

•Other tissues – Diagnosis can also be based on:

-Blood – Diagnosis requires adequate circulating lymphoblasts (eg, ≥1000 cells/microL).

-Lymph node – If LBL is the predominant/exclusive presentation, the diagnosis can be established from a lymph node or other lymphoid tissue. BM should also be examined, if possible, to rule out involvement of both sites.

●Diagnosis – Diagnosis of ALL/LBL generally requires ≥20 percent lymphoblasts in BM (picture 2), with an immunophenotype that confirms the lymphoid lineage and excludes a myeloid lineage. Occasionally the diagnosis can be established with a compatible finding in blood or a lymph node. Malignant blasts may indicate B cell lineage (85 percent), T cell lineage (10 to 15 percent), or NK cell lineage (<1 percent). (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of ALL/LBL is broad because the clinical presentation is often nonspecific and lymphoblast morphology is not diagnostic. The differential diagnosis of children with unexplained cytopenias, lymphadenopathy, or circulating aberrant lymphoid cells/blasts includes viral infections, aplastic anemia, other cancers, and other hematologic malignancies, including Burkitt lymphoma and acute myeloid leukemia. (See 'Differential diagnosis' above.)

●Classification – ALL/LBL is classified by immunophenotype and cytogenetic features. Some subtypes of ALL/LBL have characteristic clinical features and/or require distinctive management.

Broadly, ALL/LBL is categorized according to:

•B lineage (see 'B-ALL/LBL' above)

•T lineage (see 'T-ALL/LBL' above)