Acute Lymphoblastic Leukemia


Subtyptype and genetic abnormalities

Frequency (%)

Clinical implication

Estimated 5 years EFS (%)

B-lineage

 Hyperdiploidy >50

20–30

Excellent prognosis with antimetabolite-based therapy

85–95

 Hypodiploidy <44

1–2

Poor prognosis

30–40

 Trisomies 4 and 10

20–25

Excellent prognosis with antimetabolite-based therapy

85–90

 t(12;21)(p13;q22) ETV6-RUNX1 (formerly known as TELAML1)

15–25

Excellent prognosis with intensive asparaginase therapy

80–95

 t(9;22)(q34;q11.2) BCRABL1

2–4

Imatinib plus intensive chemotherapy improve early treatment outcome

80–90 at 3 years

 t(4;11) (q21;q23);MLL-AF4

1–2

Poor prognosis
 
 t(1;19)(q23;p13)TCF3PBX1

2–6

Increased incidence in blacks; excellent prognosis with high-dose methotrexate treatment; increased risk of CNS relapse in some studies

80–85

T-lineage

 MLL-ENL

2–4

Favorable prognosis

80–90


Cited from Pui [33]



Approximately 75 % of childhood ALL cases experience recurrent genetic abnormalities, including aneuploidy or structural chromosomal arrangements, detected by conventional karyotyping and fluorescence in situ hybridization (FISH), hence cytogenetic is important in diagnosis and as an indicator of response to therapy, thus playing a key role in risk stratification of patients for treatment [3739].

In B-lineage ALL, the alterations including: hyperdiploidy (>50 chromosomes) seen in 25–30 % and has a good prognosis. Recurrent translocations including t(12;21) (p13;q22), encoding for ETV6RUNX1 (TEL-AML1), which has a good prognosis, t(1;19) TCF3PBX1 (E2A-PBX1), t(9;22) BCRABL1 (Philadelphia chromosome), and rearrangement of MLL at 11q23 to a diverse range of fusion partners [38, 40].

T-lineage ALL is characterized by activating mutations of NOTCH1 and rearrangements of transcription factors TLX1 (HOX11), TLX3 (HOX11L2), LYL1, TAL1, and MLL [41]. The frequency of NOTCH1 activating mutations in T-cell leukemia provides a compelling rationale for the use of either inhibitors of the Notch pathway. T-lineage ALL is induced by the transformation of T-cell progenitors and mainly occurs in children and adolescents. Although treatment outcome in patients with T-ALL has improved in recent years, a significant number of patients remain at a high risk of relapse, and few individuals survive when relapse [42] (Fig. 43.1).

A314717_1_En_43_Fig1_HTML.gif


Fig. 43.1
Frequency of cytogenetic subtypes of pediatric ALL (Cited from Mullighan [38])

There are different subtypes of ALL based on morphological, immunological, cytogenetic, biochemical, and molecular genetic factors, and it may impact of the risk stratifications which have various responses to treatment.

The cause of childhood leukemia still remains unknown [3, 43].



43.3 Clinical Manifestation


Symptoms and clinical manifestations reflect of bone marrow infiltration by leukemic cells. Pallor, fever, muscle pain, bone pain, fatigue, bleeding (i.e. gum bleeding, epistaxis, ptechie, purpura, hematemesis and melena). The length of symptoms could be in weeks and occasionally several months. In physical examination organomegaly can be found [3, 44].

In complete blood count examination: Anemia, bicytopenia and often pancytopenia may be found.

Anemia: reflects of pressed erythropoiesis by young/immature leucocyte. Fever reflects infections due to low immunological status as peripheral blood dominated with young white blood cells (WBC), while WBC could be low, normal or high. Platelets: The platelets count usually low, and spontaneous bleeding can appear with platelet count 20,000–30,000/dL [3, 28, 45]. Summarized of clinical manifestations are listed in the Table 43.2.


Table 43.2
Clinical presentation of ALL
























The clinical presentation of ALL:

Sign of anemia

Lethargy, weariness, fatigue, rapid exhaustion, lack of appetite. Laboratory: normocytic, normochromic anemia

Signs of infections

Febrile illness. Laboratory: reduced of absolute neutrophil count

Signs of bleeding tendency

Purpura, mucosal bleeding, hematomas and bruising. Laboratory: thrombocytopenia, occasional coagulopathy

Signs of organ infiltration

Bone and join discomfort, hepatomegaly, generalized lymph node swelling, mediastinal mass and subsequent superior vena cava obstruction

Signs of systemic disease

Fever of unknown origin, weight loss, night sweats


Cited from Owen P. Smith and Ian M. Hann Clinical features and therapy of lymphoblastic leukemia


43.3.1 Clinical Manifestations/Involvement in Other Systems



43.3.1.1 Central Nervous System Manifestations


Involvement of central nervous system (CNS) leukemia is defined by the presence of lymphoblast in the cerebrospinal fluid. It is found in 1.2–10 % of children with newly diagnosed ALL. Leukemic blasts entering the CNS by hematogenous spread. CNS leukemia is more common in mature B cell, T-ALL and children with high WBC. Signs of CNS involvement:



  • Signs of increased intracranial pressure (headache, papilledema and lethargy)


  • Signs and symptoms of parenchymal involvement (e.g., focal neurologic signs such as hemiparesis, cranial nerve palsies, convulsions, cerebellar involvement – ataxia, dysmetria, hypotonia, hyperflexia)


  • Cranial nerve involvement: n. III, IV, VI and VII [28, 46, 47].


43.3.1.2 Cardiopulmonary Involvement


Leukemic involvement in the lungs and heart is rare. The manifestations could be: pericardial leukemic effusion and mediastinal mass, especially in T-ALL. Late cardiomyopathy is found after extensive treatment with anthracyclines [48].


43.3.1.3 Mediastinum


Mediastinal mass (thymus enlargement) due to leukemic infiltration, may cause life-threatening. Especially in T-ALL: superior vena cava syndrome.


43.3.1.4 Eye


Bleeding (retinal bleeding) caused by high white blood cell count and/or thrombocytopenia [28].


43.3.1.5 Musculoskeletal/Bone and Joint Manifestations


Involvement of musculoskeletal is characterized by severe pain, especially in lower extremities and sometimes unable/refusal to walk. This symptom occurred in 20–30 % of children with ALL. It may result of infiltration of leukemic cells to the bone or expansion of marrow cavity by leukemic cells. It may also appear swelling and tenderness due to leukemic infiltration [49, 50].


43.3.1.6 Urinary Tract (UT) Manifestations


Involvement of testicles is present mostly in boys. Testicular involvement is diagnosed if leukemic blasts found by testicular biopsy. It occurred only in boys with WBC >25,000/mm3, T-cell ALL, moderate to severe hepatosplenomegaly, lymphadenopathy and thrombocytopenia (<30,000/mm3). In girls, ovarian involvement occurs very rare [5153].


43.3.1.7 Gastro Intestinal Tract (GIT) Involvement


The commonest manifestation of leukemia in GIT is bleeding, as reflected by occult blood in the stool. GIT bleeding might also be caused by thrombocytopenia, disseminated intravascular coagulation (DIC) or infection. Neutropenic typhlitis or necrotizing enterocolitis diagnosed if right lower quadrant pain with tenderness, abdominal tension, vomiting and sepsis are found [46].


43.3.2 Radiology Changes






  • Metaphysis: transverse radiolucent lines


  • Subperiosteal new bone formation


  • Osteolytic lesion involving medullary cavity and cortex


43.4 Diagnostic and Classification


Diagnostic of ALL is based on clinical findings and some laboratory tests. Basic investigation required for diagnostic ALL are [5457]:


43.4.1 Blood Tests


Examination of complete blood count, differential blood count including morphology, lactate dehydrogenase (LDH), electrolytes, renal function tests, liver function tests, coagulation screening are necessary. Abnormal liver function test may be due to leukemic infiltration to the liver. Serum chemistry: Uric acid, potassium and calcium may be abnormal due to cell lysis as an impact of high WBC and chemotherapy. Serum lactate dehydrongenase usually high, and it may be has a prognostic value [5860]. Morphology of leukemic cells can be examined from peripheral blood smear and bone marrow smear, hence morphology of peripheral blood and BM smear is critical.

Red blood cell and Hemoglobin: Normocytic; normochromic red cell morphology. Low hemoglobin indicates longer duration of leukemia.

White blood cell (WBC) count can be low, normal, or increased.

Blood smear: lympholasts are detected in children with high WBC. Very few to none (in patients with leukopenia). When WBC is greater than 10,000/mm3, blasts are usually abundant. Eosinophilia is occasionally seen in children with ALL; 20 % of patients with AML have an increased number of basophils.

Platelet. Thrombocytopenia: 92 % of patients have platelet counts below normal. Serious hemorrhage (Gastro Intestinal tract or intracranial) occurs at platelet counts less than 25,000/mm3.


43.4.2 Bone Marrow Tests


Diagnostic tools may vary among countries. It depends on the ability of each country to provide. The Important thing is morphological examination both from peripheral blood and bone marrow. Bone-marrow aspiration done under sterile conditions is recommended for diagnosis of acute lymphoblastic leukemia because morphology of leukemic cells in bone marrow can be different from those in peripheral smear and 20 % of patients with acute lymphoblastic leukemia do not have circulating blast cells at diagnosis [61]. Site of aspiration is recommended in the posterior iliac region for children above 2 years of age, and for children under 2 years at tibia. Sternal aspiration is contraindicated in young children.


43.4.2.1 Morphology


Leukemia must be suspected when the bone marrow contains more than 5 % blasts. The hallmark of the diagnosis of acute leukemia is the blast cell (more than 25 %), a relatively undifferentiated cell with diffusely distributed nuclear chromatin, one or more nucleoli, and basophilic cytoplasm. Special bone marrow studies, will help in detailed classification, include the following: Cytochemistry, Immunophenotyping, Cytogenetic and DNA content [55]. Bone marrow smear stained with other May-Grünwald-Giemsa or Wright-Giemsa, and should be examined under a light microscope. It is important to examine the morphology to distinguish lymphoblast and myeloblast. Acute leukemia can be classified based on morphologic characteristics into lymphoblastic leukemia and myeloblastic leukemia (Table 43.3a) [44].


Table 43.3a
Lymphoblast and myeloblast characteristic































 
Lymphoblast

Myeloblast

Cell size

10–20 um

14–20 um

Cytoplasm

Blue, usually homogenous, sometimes with vacuoles

Blue-gray, granular, sometimes with Auer rods

Nucleus chromatin

Homogenous and or fine

Heterogeneous

Nucleoli

0–2, distinct

2–5 distinct “punched out”

Nucleus/cytoplasm ratio

High

Low

Cytochemical features is needed to sharpen the diagnosis [28]. Cytochemistry for myeloperoxidase and non-specific esterase should be done to exclude acute myeloid leukemia [62, 63]. To support diagnosis of ALL, cytochemistry such as periodic acid shift (PAS), peroxidase and Sudan-Black staining are recommended (Table 43.3b).


Table 43.3b
Cytochemistry characteristic of lymphoblast -myeloblast



























 
Lymphoblast

Myeloblast

PAS

++

−/+

Sudan black


+

Peroxidase


+

Esterase


+/−


43.4.2.2 FAB Classification


The French-American-British (FAB) Working Group Classification of ALL is based on morphologic and cytochemical features. Peripheral blood and bone marrow smears are stained (May-Grünwald-Giemsa method) and analyzed using light microscopy. Leukemic cells are characterized by a lack of differentiation, by a nucleus with diffuse chromatin structure, with one or more nucleoli, and by basophilic cytoplasm. This morphologic classification system categorizes lymphoblastic leukemias into three subtypes: L1, L2 or L3 (Table 43.4) [44].


Table 43.4
French-American-British (FAB) classification of lymphoblasts
















































 
L1

L2

L3

Cell size

Small

Variable

Large, heterogeneous

Nuclear shape

Regular, occasionally clefting

Irregular, clefting, indentation common

Regular, oval to round

Chromatin

Homogenous

Variable, heterogeneous

Finely stippled and homogeneous

Nucleoli

Not visible,

Often large, one or more present

Prominent, one or more

Cytoplasm

Scanty

Variable, often moderately abundant

Moderately abundant

Basophilic of cytoplasm

Very view

Variable, sometimes deep

Very deep

Cytoplasmic vacuolization

Variable

Variable

Often prominent


43.4.2.3 Immunophenotyping


Immunophenotyping of abnormal hematological cells using flow cytometry studies on peripheral blood or bone marrow samples improves both accuracy and reproducibility of classification of acute leukemias [6469]. It is very useful for the diagnosis, classification, cost-effective treatment and prognostic evaluation in patients with hematological malignancies [64, 7072]. Usually, ALL is classified into T-lineage, B-lineage, and B-cell (Burkitt’s) phenotypes. The World Health Organization (WHO) classification (Table43.5) divides ALL into two main groups only, i.e., B-lineage and T-lineage ALL, without further categorization [7376].


Table 43.5
WHO classification of acute leukemia









































Acute leukemias of ambiguous lineage

 Acute undifferentiated leukemia

 Mixed phenotype acute leukemia with t(9;22)(q34;q11.2); BCR-ABL1

 Mixed phenotype acute leukemia with t(v;11q23); MLL rearranged

 Mixed phenotype acute leukemia, B-myeloid, NOS

 Mixed phenotype acute leukemia, T-myeloid, NOS

Provisional entity: natural killer (NK) cell lymphoblastic leukemia/lymphoma

B lymphoblastic leukemia/lymphoma

 B lymphoblastic leukemia/lymphoma, NOS

 B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities

 B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2); BCR-ABL 1

 B lymphoblastic leukemia/lymphoma with t(v;11q23);MLL rearranged

 B lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22) TEL-AML1 (ETV6-RUNX1)

 B lymphoblastic leukemia/lymphoma with hyperdiploidy

 B lymphoblastic leukemia/lymphoma with hypodiploidy

 B lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32) IL3-IGH

 B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); TCF3-PBX1

T lymphoblastic leukemia/lymphoma

Classification of acute leukemia (B- or T-lineage ALL/AML) is based on reactivity patterns obtained with a panel of lineage-associated antibodies [7779]. Immunophenotyping is also essential for distinguishing between ALL and AML; errors in differentiating between these two types of acute leukemias can occur in up to 10 % of cases [8083]. Essential monoclonal antibodies for detecting acute leukemia are presented in Table 43.6.


Table 43.6
Monoclonal antibody panel for acute leukemia


















































 
B-linage

T-lineage

AML

Monoclonal antibody

CD10

CD2

CD13

CD19

Cytoplasmic CD3

CD33

CD20

CD5

CD117

CD22

CD7

Cytoplasmic MPO

CD34
   

Cytoplasmic CD79a
   

HLA-DR
   

IgM
   

TdT
   

The B-lineage phenotype ALL, positive for the following: B cell markers CD19, CD20, CD22, TdT, cytoplasmic CD79a, CD34 and CD10. It has been sub-classified according to maturation stage into: early pre B (pro-B), pre-B, transitional (or late) pre-B and (mature) B-ALL [64, 84]. In different regions, various incidences of B-lineage ALL have been reported. Burkitt’s leukemia displays an immunophenotype consisting of mature B cells [78].

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Mar 25, 2016 | Posted by in INTERVENTIONAL RADIOLOGY | Comments Off on Acute Lymphoblastic Leukemia
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