Leukemia in Children

Persistent bone pain, limp, back pain, fever, headache, and symptoms of anemia and thrombocytopenia are common ways that pediatric leukemia presents. Many of these symptoms can be seen in common childhood illnesses, so a high index of suspicion in patients with persistent symptoms is required to make the diagnosis. The prognosis for these children is excellent, especially in acute lymphoblastic leukemia, but survivors of childhood leukemia need to be followed closely for long-term toxicities.After completing this article, readers should be able to:Leukemia is the most common malignancy of childhood, accounting for 30% of cases of childhood cancer. Although there are some associations between environmental or host factors, most leukemia diagnoses in children are sporadic. There are 3 main subtypes of leukemia: acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML). ALL is the most common subtype, accounting for approximately 80% of cases. CML is the least common, and this review touches on this subtype only briefly. There are many subgroups within ALL and AML. These subgroups have variable biological features, prognoses, and treatment regimens. Children generally present with symptoms related to cytopenias or leukemic infiltration of the bone marrow. Other organs, such as the spleen, liver, testes, and central nervous system (CNS), can also be involved. With modern, risk-adapted therapy, most children are cured of their disease. Despite these successes, relapse continues to be a problem. However, we have entered an exciting time of targeted and immunologic therapy that is revolutionizing the treatment of these challenging patients. There are late effects of treatment, and these need to be recognized by the general pediatrician, with an understanding that these late effects are different among the many subtypes of leukemia.Childhood cancer is very rare, with approximately 14,000 cases diagnosed in children younger than 18 years in the United States annually. For perspective, there are 80,000 cases of prostate cancer diagnosed each year, which is only the fifth most common cancer in adults. In children, hematologic malignancies predominate, accounting for approximately one-third of all cases of childhood cancer. Cancer remains the most common cause of disease-related death in children. The incidence of ALL is approximately 30 cases per 1 million persons. This incidence varies among different ethnic groups. ALL is more common in white individuals compared with black individuals, with Hispanic people having the highest risk. (1)Precursor B-cell ALL is much more common than T-cell disease, accounting for approximately 80% of cases of ALL. AML accounts for 18% of cases of childhood leukemia, and CML is very rare and tends to occur in adolescents. Outside of exposure to ionizing radiation, there are very few environmental factors that have shown a strong link with childhood leukemia. Monozygotic twins have a 10% to 15% concordance rate for ALL. The cause of ALL is most likely multifactorial, involving genetic, immunologic, and infectious factors that need further study. (2)Patients with Down syndrome are at 15 times increased risk of developing leukemia compared with the general population. This risk is increased for both ALL and AML. (3) This is especially true in children with trisomy 21, who had transient myeloproliferative disorder as infants. In this population the risk of developing AML is 16% at a median age of 441 days. (4) Transient myeloproliferative disorder is characterized by peripheral blasts and hepatosplenomegaly in the newborn with trisomy 21. Most cases resolve spontaneously, but some require treatment with low-dose chemotherapy. Interestingly, patients with Down syndrome who develop AML have a favorable outcome compared with those without Down syndrome. Other syndromes, such as Fanconi anemia, Bloom syndrome, Klinefelter syndrome, and neurofibromatosis, are also associated with leukemia.The most common presenting symptoms of leukemia result from the clonal proliferation of leukemic blasts in the bone marrow, preventing normal production of red blood cells, platelets, and neutrophils. The degree of anemia, thrombocytopenia, and neutropenia is highly variable. A significant anemia can cause pallor, fatigue, dyspnea on exertion, headache, dizziness, and near syncope. Although the thrombocytopenia can be severe, most patients with leukemia do not present with bleeding. Many patients can have bruising and petechiae, but serious bleeding is rare. Fevers are very common in patients with leukemia and should be part of the differential diagnosis of fever of unknown origin. Despite sometimes severe neutropenia, infection or sepsis at diagnosis is uncommon.Children with leukemia have bone marrow that has been replaced with leukemic blasts. This expansion of the bone marrow cavity very commonly causes bone pain, limp, or refusal to walk. Back pain is also found, and a complete blood cell (CBC) count with a differential count should be considered as part of the evaluation of this complaint, along with close interval follow-up until the cause of the back pain is discovered. Patients with bone pain are frequently referred to orthopedics, where a diagnosis of leukemia is sometimes made when magnetic resonance imaging shows diffuse increased signal intensity in the bone marrow.Leukemia can infiltrate other organs outside of the bone marrow, leading to lymphadenopathy, hepatomegaly, splenomegaly, and kidney lesions. The most impressive splenomegaly is seen with CML. The acute leukemias have variable spleen and liver size. Despite the hepatomegaly, liver dysfunction is uncommon. Testicular disease occurs in approximately 2% of children with ALL. (5) This presents with a painless testicular mass or uniformly enlarged testes. CNS leukemia can be seen in both ALL and AML but is more common in the former. T-cell ALL has the highest risk of CNS disease. This can manifest itself as headache, seizure, visual changes, cranial nerve abnormalities, and change in mental status. CNS disease can also be asymptomatic.The different types of leukemia tend to exhibit certain features in their clinical presentation. Infantile ALL, defined as leukemia presenting before 1 year of age, tends to present with very high white blood cell (WBC) counts. When an adolescent male presents with a high WBC count and an anterior mediastinal mass, T-cell ALL should be considered. These patients frequently can have difficulty breathing, especially in the supine position. This can be a medical emergency, and airway management can be difficult. CML can have extremely high WBC or platelet counts, with massive splenomegaly. Acute promyelocytic leukemia, a rare subtype of AML, is strongly associated with bleeding, CNS hemorrhage, and disseminated intravascular coagulation (DIC) at diagnosis. Chloromas are extramedullary collections of leukemic blasts that can occur anywhere in the body, more often in soft tissues and the CNS. They tend to occur more often in AML with monocytic differentiation. Children with trisomy 21 and AML tend to present with isolated thrombocytopenia, many times after a history of transient myeloproliferative disorder.It is very important for a pediatrician to understand the proper interpretation of a CBC count with differential count. It is easy to think of a CBC count as a measure of bone marrow function. The marrow produces red blood cells, neutrophils, and platelets. A cytopenia reflects poor marrow function or peripheral destruction of the involved cell. Most patients with leukemia have more than 1 cell line affected at diagnosis. If patients have isolated neutropenia, anemia, or thrombocytopenia, then an appropriate differential diagnosis should be formulated for the individual cytopenia. When more than 1 cell line is affected, the diagnosis of leukemia should be more strongly considered. Diagnoses that can be commonly confused with leukemia include viral suppression, drug-induced cytopenia, immune thrombocytopenic purpura, autoimmune hemolytic anemia or neutropenia, Evan syndrome, transient erythroblastopenia of childhood, aplastic anemia, splenic sequestration, and juvenile idiopathic rheumatoid arthritis.A bone marrow aspirate is necessary to definitively diagnose leukemia. The diagnosis can also be made from peripheral blood if a sufficient number of blasts are present. This can be helpful in cases where the WBC count is high and making a diagnosis quickly is advantageous. Both morphologic analysis and flow cytometry are used to evaluate the bone marrow. Morphologic analysis evaluates the marrow and leukemic blasts under the microscope (Fig 1). Flow cytometry uses immunophenotypic characteristics to differentiate between the different types of leukemia. ALL and AML can sometimes be differentiated using morphologic features alone, where T- and B-cell ALL look identical under the microscope. The different leukemias have distinctive immunophenotypic markers that can be found using flow cytometry. This modality is required for accurate diagnosis. (6) CML has very distinctive characteristics and can be diagnosed using morphologic analysis alone. It is characterized by a proliferation of normal hematopoietic progenitor cells seen in the peripheral blood. All patients with acute leukemia require a lumbar puncture with cerebrospinal fluid sampling to rule out CNS disease. If neurologic symptoms, severe headache, or cranial nerve palsies are present at diagnosis, magnetic resonance imaging may also be necessary. A thorough testicular physical examination should be performed in all male patients.Hyperleukocytosis can be seen in any patient with leukemia and is generally defined as a WBC count of greater than 100,000/μL (>100×109/L). This is more common in those with AML, T-cell ALL, and infantile leukemia. The large number of blasts can cause leukostasis, which precipitates decreased tissue perfusion. This is a medical emergency causing neurologic and pulmonary sequelae. Patients with AML have more problems with leukostasis, at lower WBC counts, because AML blasts are larger and stickier. Those with ALL generally only develop signs of leukostasis with extremely high WBC counts.Signs and symptoms of leukostasis include the following: neurologic—headache, confusion, lethargy, dizziness, blurry vision, ataxia, papilledema, retinal hemorrhage, and CNS hemorrhage; respiratory—tachypnea, hypoxia, infiltrates on chest radiography, respiratory failure, and acute respiratory distress syndrome; vascular—peripheral vascular occlusion and thrombosis; and coagulation—DIC, abnormal tests of coagulation with elevated prothrombin and partial thromboplastin times with a decreased fibrinogen level.These patients are also at risk for tumor lysis syndrome, defined as hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia. Tumor lysis syndrome usually develops after therapy is started but can occur at initial presentation. It is caused by the intracellular contents of malignant cells being spilled into the circulation. This can overwhelm the kidney’s ability to process the released nucleic acids, potassium, and phosphorus. Without prompt intervention this can lead to cardiac arrhythmias and renal failure. The management of hyperleukocytosis includes the following:The use of leukapheresis has fallen out of favor in patients with hyperleukocytosis. This therapy requires central line access, significant planning with the blood bank, and resources, all delaying definitive therapy. Leukapheresis is also of questionable benefit in these patients and carries its own risks. (7) Therefore, induction chemotherapy should be started as soon as possible. If delayed, cytoreduction can be achieved with hydroxyurea or corticosteroids, the latter being used only with a known diagnosis of ALL. Leukapheresis is reserved for patients who have persistent or worsening symptoms of leukostasis despite appropriate attempts at cytoreduction.T-cell ALL is commonly associated with an anterior mediastinal mass. This mass can be very large and cause significant symptoms, including dyspnea on exertion, shortness of breath, tachypnea, orthopnea, and stridor. Patients with significant respiratory compromise require admission to the ICU and prompt initiation of leukemia-directed therapy. Reduction in size of the mass can be achieved with the use of corticosteroids alone, and responses are usually prompt, avoiding the need for intubation. Induction therapy should be started after definitive diagnosis is made.Acute promyelocytic leukemia is a very rare subtype of AML that is associated with severe coagulopathy. Patients can present with DIC, bleeding, and thrombosis. Prompt diagnosis is necessary and can be done preliminarily using morphologic analysis alone (Fig 1). Left untreated, patients can develop pulmonary or cerebrovascular catastrophic bleeding. 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