Acute leukemia occurs when a progenitor cell undergoes malignant transformation within the bone marrow. Immature white blood cells called blast cells multiply and replace normal bone marrow with eventual invasion into the bloodstream. The first step of hematopoeisis involves differentiation into either lymphoid stem cells or myeloid stem cells. Lymphoid blast cells give rise to T- and B- lymphocytes. Myeloid stem cells give rise to monocytes, macrophages, erythrocytes, megakaryocytes (platelets), neutrophils, eosinophils, and basophils. Acute lymphoblastic leukemia (ALL) occurs when there is proliferation of lymphoid stem cells and acute myelogenous leukemia (AML) occurs when there is malignant proliferation of myeloid stem cells.
There are acute and chronic forms of both lymphoblastic and myelogenous leukemia. In this review, we will focus on acute leukemias as they comprise the vast majority of childhood leukemias.
Leukemia is the most common malignancy of childhood comprising 1/3 of all childhood cancers, 85% of which are cases of ALL. ALL is at least five times more common than AML in children.
The signs and symptoms of leukemia are resultant from bone marrow failure:
|Anemia||Fatigue, pallor, tachycardia|
|Neutropenia||Fever, infections, anorexia, oral sores|
|Thrombocytopenia||Excess bleeding (eg. Menorrhagia, epistaxis), bruising, petechiae|
|Leukostasis||Visual changes, headache|
|Major organ infiltration||Hepatosplenomegaly, early satiety, visual changes, papilledema, headache, painless testicular enlargement|
|Extramedullary leukemic spread||Lymphadenopathy, mediastinal mass (causing respiratory distress, tracheal compression)|
|High cell proliferation/death||Bone/joint pain, muscle weakness, constipation|
There are also some generalized symptoms that are seen in leukemia including generalized lymphadenopathy and constitutional symptoms. Constitutional symptoms include fever, anorexia, aches and pains, weight loss, and night sweats. In addition, generalized lymphadenopathy is present at diagnosis in up to 2/3 of children with ALL and in 1/3 of children with AML.
- CBC and differential, platelet count, reticulocytes, peripheral smear
- Liver and renal function, ALP (bone, liver), INR, PT, PTT, albumin
- Electrolytes, urea, creatinine
- Uric acid, phosphate, calcium, LDH (tumor lysis)
- Immunoglobulins, serology for VZV, CMV, EBC, HSV, hepatitis
- Staging: chest x-ray, lumbar puncture
- Bone marrow biopsy/aspirate, cytochemistry, flow cytometry, cytogenetics
Most acute leukemias arise de novo. However, there are some known predisposing factors:
- Family history of AML
- Down syndrome
- Fanconi’s anemia
- Ataxia telangiectasia
- Previous chemotherapy and/or radiation
- Benzene, petroleum, smoking, paint, pesticides
Genetic alterations such as translocations, additions, or deletions can result in leukemia via the inappropriate expression of specific oncogenes.
It is important to consider other disease processes that may result in either pancytopenia or leukocytosis. Also remember, at initial presentation you may only see a single cell line done such as only anemia or only thrombocytopenia. Always have leukemia on your differential.
- Acute leukemia
- Chronic leukemia
- Other malignancies with bone marrow involvement (e.g. neuroblastoma, rhabdomyosarcoma, etc)
- EBV, CMV, HIV, parvovirus B19 infection
- Chronic marrow infection
- Aplastic anemia
- Bone marrow replacement
- Acute leukemia
- Chronic leukemia
- Acute infection (eg. Infectious mononucleosis)
- Corticosteroid use
- Lithium carbonate
- Juvenile idiopathic arthritis
Bone marrow with more than 30% replacement by blast cells (normal <5%) is diagnostic of leukemia. Pancytopenia and blasts in the peripheral blood smear support the diagnosis.
|Morphologic Classification||L1: blast cells small, uniform, typical of childhood ALL, high nuclear to cytplasmic ratioL2: blast cells larger, heterogenous, lower nuclear to cytoplasmic ratioL3: vacuolated blasts, basophilic cytoplasm
Further categorized into B-cell or T-cell.
|M0 undifferentiatedM1 without maturationM2 with granulocytic maturation
M3 acute promyelocytic
M4 granulocytic and monocytic maturation
M5 monoblastic or monocytic
|Epidemiology||3-7 years old80% of childhood acute leukemia||15-40 years old20% of childhood acute leukemia|
|Treatment||Tumour lysis protocol:
Bone marrow transplantation (60-70% have long-term remission)
|Prognostic factors||Favorable (low risk):
Unfavorable (high risk):
||5 year survival:
Tumour Lysis Syndrome:
Tumour lysis syndrome is an oncologic emergency caused by massive tumour cell lysis that occurs most often after the initiation of cytotoxic therapy. It is characterized by hyperkalemia, hyperphosphatemia, hyperuricemia and hyper- or hypocalcemia. Risk factors for tumour lysis include large tumour burden and high tumour cell proliferation rate such as high grade lymphomas (e.g. Burkitts) and T cell leukemias. Principles of therapy involved monitoring these metabolic values extremely closely and trying to minimize the effects. Treatment and prevention of tumour lysis syndrome includes intravenous hyper-hydration, allopurinol and rasburicase to decrease uric acid production and urinary alkanization to decrease the likelihood of uric acid precipitation in the renal tubules.
Lymphomas on the other hand are solid tumors of lymphoid origin. They differ from leukemias only in that they do not originate from the bone marrow and are not characterized first by their presence in the circulation. They are the third most common pediatric malignancy, comprising 15% of all pediatric cancers. Lymphomas are divided into two main categories, Hodgkin’s disease (HD) and non-Hodgkin’s lymphomas. Hodgkin’s Disease is characterized by the presence of Reed-Sternberg cells which are thought to be the neoplastic components of the tumor. The absence of such cells characterizes non-Hodgkin’s lymphomas.
The lymphomas more often present with regional lymphadenopathy. In addition, constitutional signs including fever, anorexia, aches and pains, weight loss, and night sweats observed in the leukemias are less often seen in the lymphomas. Only 1/3 of children with Hodgkin’s lymphoma and 10% with non-Hodgkin lymphoma display them. It is important to ask about “B symptoms” which are comprised of fever, night sweats and weight loss, as the presence or absence of these symptoms has prognostic significance.
- Liver and renal function, ALP (bone, liver)
- Uric acid, phosphate, calcium, LDH (tumor lysis)
- ESR (active disease), ferritin, immunologic profile (T and B-cell counts, T-cell function, immunoglobulins)
- Staging: chest x-ray, chest/abdominal CT scan, gallium scan, bone scan, bone marrow biopsy, lumbar puncture
- Bone marrow biopsy/aspirate (bilateral to check for extent of disease)
- Tissue diagnosis: biopsy
|Presentation||Single non-tender lymphadenopathyContiguous spread||Multiple sites in peripheral nodesNoncontiguous spread|
|Epidemiology||1/100,000 per yearOlder children (15-34 years old)Boys>girls||1.5/100,000 per yearYounger children|
||Lymphoblastic lymphoma (30%):
Burkitt’s lymphoma (40-50%):
Large cell (20%):
|Staging||Stage I: single lymph node involvedStage II: 2+ lymphoid tissues on the same side of the diaphragm involvedStage III: LNs from both sides of the diaphragm involved
Stage IV: Disseminated involvement (one or more organs, excluding spleen)
Category A: asymptomatic
Category B: B-symptoms (fever, night sweats, weight loss >10%)
|Stage I: single lymph node involved outside of abdomen or mediastinumStage II: 2+ lymph nodes/intratranodal sites on same side of diaphragmStage III: lymph nodes on both sides of diaphragm involved, all primary intrathoracic, extensive intra-abdominal disease, or any paraspinal or epidural tumors
Stage IV: bone marrow or CNS disease
|Prognosis – cure rates||Stage IA/B, IIA: >90%Stage IIB, IIIA/B, IV: 80%||Stage I, II:
Stage III, IV:
|Treatment||Chemotherapy +/- radiation
In summary, leukemia and lymphomas are common in childhood and must always be on your differential when a child presents with fever, weight loss, fatigue, lymphadenopathy and bone pain as well as a variety of other symptoms. Consult pediatric oncology if you suspect a malignancy as rapid diagnosis and initiation of therapy is very important to improving outcomes in children.
Written by: Tram Nguyen
Edited by: Anne Marie Jekyll
3 responses to “Approach to Pediatric Leukemias and Lymphomas”
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