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LEUKEMIAS
The leukemias are the most common malignant neoplasms in childhood, accounting for about 41% of all malignancies that occur in children younger than 15 yr of age. an annual incidence of 4.1 new cases per 100,000 children younger than 15 yr of age.
Acute lymphoblastic leukemia (ALL) accounts for about 77% of cases of childhood leukemia, Acute myelogenous leukemia (AML):11%, Chronic myelogenous leukemia (CML):2 3%, and Juvenile chronic myelogenous leukemia (JCML) for 1 2%. The remaining 7 9% of cases include a variety of acute and chronic leukemias that do not fit classic definitions for ALL, AML, CML, or JCML.
History
Means white blood in Greek Discovered by Dr. Alfred Velpeau in France, 1827 Named by pathologist Rudolf Virchow in Germany, 1845
DEFINITION
The leukemias may be defined as a group of malignant diseases in which genetic abnormalities in a hematopoietic cell give rise to a clonal proliferation of cells. The progeny of these cells have an increased rate of proliferation, a decreased rate of spontaneous apoptosis, or both. The result is a disruption of normal marrow function and, ultimately, marrow failure.
Etiology.
In virtually all cases, the etiology of ALL is unknown, although several genetic and environmental factors are associated with childhood leukemia.
GENETIC CONDITIONS: Down syndrome Severe combined Fanconi syndrome immune deficiency Bloom syndrome Ataxia-telangiectasia Paroxysmal nocturnal Diamond-Blackfan hemoglobinuria anemia Schwachman syndrome Li-Fraumeni syndrome Klinefelter syndrome Turner syndrome Neurofibromatosis
ENVIRONMENTAL FACTORS
Pathogenesis.
The classification of ALL depends on characterizing the malignant cells in the bone marrow to determine the morphology. phenotypic characteristics as measured by cell membrane markers, and cytogenetic and molecular genetic features. Morphology alone is usually adequate to establish a diagnosis.
ALL
Stage 1- Normal
Stage 2- Symptoms
Stage 3- Diagnosis
Pictures Of Blood
Platelet White Cell Red Cell White Cell Red Cell Platelet Blasts
Classification
Acute leukemia can be classified based on
morphologic characteristics, cytochemical features, immunologic characteristics and cytogenetic and molecular characteristics.
FAB
CYTOLOGIC FEATURES
CLASSIFICATION L1(80-85%)
OF L2(15%)
ALL L3(1-2%)
Cell Size
Heterogeneous
Variable
Variable
Prominent
Light microscopy, cytochemistry, immunophenotyping, and cytogenetics are necessary studies to characterize leukemic subtypes.
Uncommon ALL subtypes: 1. B-cell ALL with L1 morphology: ALL patients have been described with lymphoblasts having L1 morphology but displaying B-cell ALL immunophenotype. The blast cells are TdT+ in some cases. L3 lymphoblasts generally express immunoglobulin on their cell surface, whereas L1 do not.
2. Transitional pre-B ALL: This is characterized by: a. Blasts cells that may express cytoplasmic and surface heavy chains but not Ig or light chains, indicating that these cells are in transition between pre- B and B stages of differentiation b. Blast cells that lack FAB L3 morphology or chromosomal translocations associated with Bcell ALL c. Very good clinical outcome.
Immunology The putative immunologic classification and cellular characteristics of B-lineage ALL and T-cell ALL are shown in slide13 A panel of antibodies is used to establish the diagnosis of leukemia and to distinguish among the immunologic subclones. The panel should include at least one marker that is highly lineage specific, for example,
CD19 for B lineage, CD7 for T lineage, and CD13 or CD33 for myeloid cells.
In addition, the use of cytoplasmic CD79a for early pre-B-cell lineage, cytoplasmic CD3 for T lineage, and cytoplasmic myeloperoxidase for myeloid cells can be helpful in differentiating unclear immunophenotypes.
Immunophenotype Distribution of Acute Lymphoblastic Leukemia Pre-B-cell accounts for 80% of ALL cases and is subdivided on the basis of cytoplasmic immunoglobulin into transitional pre-B or common ALL antigen (CALLA positive). Mature B-cell type accounts for 1 2% of ALL cases. These have surface immunoglobulin positivity and are treated as Burkitt lymphoma. The prognosis has improved and is now similar to other subtypes of high-risk ALL.
T-cell type accounts for 15 20% of ALL cases. This subtype is associated with:
Older age at presentation High initial WBC count Presence of extramedullary disease
Poor prognosis
Specific cytogenetic abnormalities have been shown to have prognostic significance (slide31)
Specific cytogenetic abnormalities have been shown to have prognostic significance (slide31)
Clinical Manifestations.
The initial presentation of ALL is usually nonspecific: Anorexia, fatigue, and irritability are often present. Intermittent, low-grade fever. Bone or joint pain, particularly in the lower extremities, may be present. Signs and symptoms of bone marrow failure:pallor, fatigue, bruising, or epistaxis.
The proliferative nature of the disease may be manifested as: lymphadenopathy, splenomegaly, or hepatomegaly. There may be exquisite tenderness on bone palpation or objective evidence of joint swelling and effusion.
Rarely, patients show signs of increased intracranial pressure that indicate leukemic involvement of the central nervous system (CNS): papilledema, retinal hemorrhages, and cranial nerve palsies.
1 to 2% of patients present initially with pancytopenia and may be erroneously diagnosed as having aplastic anemia or bone marrow failure and ultimately develop acute leukemia. In these cases the illness is characterized by:
Pancytopenia or single cytopenia Hypocellular bone marrow No hepatosplenomegaly Diagnosis of leukemia 1 9 months after onset of symptoms.
Splenomegaly Hepatomegaly.
Signs and symptoms of parenchymal involvement (e.g., focal neurologic signs such as hemiparesis, cranial nerve palsies, convulsions, cerebellar involvement ataxia, dysmetria, hypotonia, hyperflexia). Hypothalamic syndrome (polyphagia with excessive weight gain, hirsutism,and behavioral disturbances).
Diabetes insipidus (posterior pituitary involvement). Chloromas of the spinal cord (very infrequent in ALL) may present with back pain, leg pain, numbness, weakness, Brown Squard syndrome, and bladder and bowel sphincter problems.
CNS hemorrhage complication that occurs more frequently in patients with AML than in those with ALL. It is caused by: a. Leukostasis in cerebral blood vessels, leading to leukothrombi, infarcts, and hemorrhage b. Thrombocytopenia and coagulopathy, contributing to CNS hemorrhage.
4. Risk factors for the development of testicular involvement: a. T-cell ALL b. Leukocytosis at diagnosis (>20,000/mm3) c. Presence of a mediastinal mass d. Moderate to severe hepatosplenomegaly and lymphadenopathy e. Thrombocytopenia (<30,000/mm3).
Renal Involvement 1. Occasionally may present with hematuria, hypertension, and renal failure. 2. Evaluated in many patients by ultrasonography; more common in T-cell ALL or mature B-cell ALL.
Gastrointestinal Involvement 1. The gastrointestinal (GI) tract is frequently involved in ALL. The most common manifestation is bleeding. 2. Leukemic infiltrates in the GI tract are usually clinically silent until terminal stages when necrotizing enteropathy might occur. The most common site for this is the cecum, giving rise to a syndrome known as typhlitis
Bone and Joint Involvement Bone pain is one of the initial symptoms in 25% of patients. It may result from direct leukemic infiltration of the periosteum, bone infarction, or expansion of marrow cavity by leukemic cells.
Radiologic changes seen most frequently include: 1. Osteolytic lesions involving medullary cavity and cortex 2. Transverse metaphyseal radiolucent bands 3. Transverse metaphyseal lines of increased density (growth arrest lines) 4. Subperiosteal new bone formation.
Cardiac Involvement One half to two thirds of patients have demonstrated cardiac involvement at autopsy, although symptomatic heart disease occurs in less than 5% of cases. Pathologic findings include leukemic infiltrates and hemorrhage of the myocardium or the pericardium. Lung Involvement This may be due to leukemic infiltrates or hemorrhage.
Diagnosis.
Laboratory Studies
Blood count: a. Hemoglobin: Moderate to marked reduction. Normocytic; normochromic red cell morphology. Low hemoglobin indicates longer duration of leukemia; higher hemoglobin indicates a more rapidly proliferating leukemia. b. White blood cell (WBC) count: Low, normal, or increased. c. Blood smear: Blasts. Very few to none (in patients with leukopenia). When the
WBC count 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. d. Thrombocytopenia: 92% of patients have platelet counts below normal. Serious hemorrhage (GI or intracranial) occurs at platelet counts less than 25,000/mm3.
Bone marrow: Bone marrow is usually replaced by 80 100% blasts. Megakaryocytes are usually absent. 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, a relatively undifferentiated cell with diffusely distributed nuclear chromatin, one or more nucleoli, and basophilic cytoplasm.
Special bone marrow studies, which help in detailed cell classification, include the following: a. Histochemistry b. Immunophenotyping c. Cytogenetics.
Chest radiograph: Mediastinal mass in T-cell leukemia. Blood chemistry: Electrolytes, blood urea, uric acid, liver function tests,immunoglobulin levels.
Cerebrospinal fluid: Chemistry and cells. Cerebrospinal fluid findings for the diagnosis of CNS leukemia require: a. Presence of more than 5 WBCs/mm3 b. Identification of blast cells on cytocentrifuge examination.
CNS involvement in leukemia is classified as follows: CNS 1 <5 WBCs/mm3, no blasts on cytocentrifuge slide CNS 2 <5 WBCs/mm3, blasts on cytocentrifuge slide CNS 3 >5 WBCs/mm3, blasts on cytocentrifuge slide
If a lumbar puncture is traumatic in a patient with peripheral blasts, the following formula can be helpful in defining the presence of CNS leukemia.CNS disease is present if: CSF WBC/CSF RBC is greater than Blood WBC/Blood RBC
Coagulation profile: Decreased coagulation factors that frequently occur with AML are hypofibrinogenemia, factors V, IX, and X. Cardiac function: Electrocardiogram (ECG) and echocardiogram. Infectious disease profile: Varicella antibody titer, cytomegalovirus (CMV) antibody titer, herpes simplex antibody, hepatitis antibody screening. Immunologic screening: Serum for immunoglobulin levels, C3 and C4.
DIFFERENTIAL DIAGNOSIS.
Acute lymphoblastic leukemia must be differentiated from acute myelogenous leukemia (AML). Other malignant diseases that may invade the bone marrow and cause marrow failure such as
Neuroblastoma, Rhabdomyosarcoma, Ewing's sarcoma, Retinoblastoma.
aplastic anemia and myelofibrosis. Failure of a single cell line, as in transient erythroblastic anemia. congenital or acquired neutropenia, sometimes produces a clinical picture that is difficult to distinguish from ALL and that may require bone marrow examination.
Infectious mononucleosis in patients with acute onset of fever and lymphadenopathy. Rheumatoid arthritis in patients with fever and joint swelling.(systemic onset)
Prognostic Factors
Patients who are between ages 1 and 9 with an initial WBC <50,000/mm3 (standard risk), which includes two thirds of pre-B ALL patients, have a 4-year event-free survival of 80%. The remaining patients (high risk) have a 4year event-free survival of 65%.
Factors that should be included in risk classification are: Age: Patients under 1 year of age and greater than 10 years of age have a worse prognosis than children >1 years and <10 years of age. Infants under 1 year of age have the worst prognosis.
White cell count: Children with the highest WBC tend to have a poor prognosis. Immunophenotype: Early pre-B-cell ALL has the best prognosis. Mature T-cell ALL has a worse survival due to its association with older age and higher WBC at diagnosis. Mature B-cell ALL previously had a poor prognosis with early relapses and CNS involvement but recent aggressive therapies have improved prognosis.
DNA index >1.16 hyperdiploid ALL with greater than 50 chromosomes has been associated with good outcome due to increased apoptosis and increased sensitivity to chemotherapeutic agents.
Cytogenetics: The combinations of trisomies of chromosomes 4, 10, and 17 have been associated with a very low risk of treatment failure and good outcome. Translocations involving the MLL rearrangement on 11q23 have been associated with a worse prognosis. The Philadelphia chromosome t(9;22)(q34;q11) ALL is the most difficult translocation to treat and has a bad prognosis. Hypodiploid ALL is also associated with a poor prognosis.
CNS disease: The presence of CNS disease at diagnosis is an adverse prognostic factor despite intensification of therapy with CNS irradiation and additional intrathecal therapy.
Early response to induction therapy: Patients who are not in remission at the end of induction therapy have a very poor prognosis. Bone marrow results on day 7 and day 14 of induction therapy have also been used to estimate response to therapy.
In future clinical trials the presence of minimal residual disease at day 28 of induction therapy will be used in addition to day 7 and day 14 bone marrow blasts percentages in determining rapid early response and subsequent therapy.
Reference
Lanzkowsky_Manual of Pediatric Hematology and Oncology 4th ed Pediatric Hematology (Third Edition)
Treatment.
The single most important prognostic factor in ALL is the treatment: without effective therapy the disease is fatal. The choice of treatment of ALL is based on the estimated clinical risk of relapse in the patient, which varies widely among the subtypes of ALL.
Three of the most important predictive factors are the Age of the patient at the time of diagnosis, The initial leukocyte count, and The speed of response to treatment (i.e., how rapidly the blast cells can be cleared from the marrow or peripheral blood.
Different study groups use various factors to define risk. Patients considered to be at higher risk are
Older than 10 yr of age or who have an initial leukocyte count of more than 50,000/L.
the initial therapy is designed to eradicate the leukemic cells from the bone marrow and is known as REMISSION INDUCTION.
Therapy is usually given for 4 wk and consists of vincristine weekly, a corticosteroid such as dexamethasone or prednisone, and either repeated doses of native L-asparaginase or a single dose of a long-acting asparaginase preparation.
Intrathecal cytarabine or methotrexate, or both, may also be given. Patients at higher risk also receive daunomycin at weekly intervals. With this approach, 98% of patients are in remission.
REMISSION: defined by less than 5% blasts in the marrow and a return of neutrophil and platelet counts to near-normal levels after 4 5 wk of treatment. Intrathecal chemotherapy is usually given at the time of diagnosis and once more during induction.
The second phase of treatment focuses on CNS therapyin an effort to prevent later CNS relapses. Intrathecal chemotherapy is given repeatedly by lumbar puncture in conjunction with intensive systemic chemotherapy. The likelihood of later CNS relapse is thereby reduced to less than 5%.
maintenance phase:patients are given daily mercaptopurine and weekly methotrexate, usually with intermittent doses of vincristine and a corticosteroid. lasts for 2 3 yr, depending on the protocol used.
A small number of patients with particularly poor prognostic features, principally those with the t(9;22) translocation known as the Philadelphia chromosome, may undergo bone marrow transplantation during the first remission.
Relapse occurs in the bone marrow in 15 20% of patients with ALL. Intensive chemotherapy with agents not previously used in the patient followed by allogeneic stem cell transplantation can result in long-term survival for a few patients with bone marrow relapse.
Patients with relapse in the CNS. The diagnosis is confirmed most readily by demonstrating the presence of leukemic cells in the CSF . The treatment includes intrathecal medication and craniospinal irradiation. Systemic chemotherapy must also be used because these patients are at high risk for subsequent bone marrow relapse.
Testicular relapse occurs in 1 2% of boys with ALL, usually after completion of therapy. S/S:painless swelling of one or both testes. The diagnosis is confirmed by biopsy of the affected testis. Treatment includes systemic chemotherapy and local irradiation. The survival rate of these patients is good.
Reference
Lanzkowsky_Manual of Pediatric Hematology and Oncology 4th ed Pediatric Hematology (Third Edition)