eMedicine Specialties > Pediatrics: General Medicine > Oncology

Acute Myelocytic Leukemia

Author: Mark E Weinblatt, MD, Chief, Division of Pediatric Hematology/Oncology, Professor of Clinical Pediatrics, Department of Pediatrics, Winthrop University Hospital
Contributor Information and Disclosures

Updated: Jul 15, 2009

Introduction

Background

Acute myeloid leukemia (AML) consists of a group of malignant disorders characterized by the replacement of normal bone marrow with abnormal, primitive hematopoietic cells. If untreated, the disorder uniformly results in death, usually from infection or bleeding. Although the cure rate has improved, treatments are associated with notable morbidity and mortality.

Pathophysiology

Acute leukemia is believed to begin in a single somatic hematopoietic progenitor that transforms to a cell incapable of normal differentiation. Acute myeloid leukemia is a very heterogeneous disease from a molecular standpoint; oncogenic transformation into a leukemic stem cell may occur at different stages of normal hematopoietic cellular maturation, from the most primitive hematopoietic stem cell to later stages, including myeloid/monocytoid progenitor cells and promyelocytes. This determines which subtype of acute myeloid leukemia results, often with very different behavior and growth characteristics.

As opposed to acute lymphoblastic leukemia (ALL), acute myeloid leukemia is most commonly associated with the development of fusion genes resulting from chromosome translocations. Many translocations are characteristic of a particular subtype of acute leukemia and often convey additional prognostic information to the clinician. Although many patients have only a single cytogenetic abnormality, multiple genetic mutations are often required for the complete leukemic transformation.

Many of the leukemic cells no longer possess the normal property of apoptosis, or programmed cell death. As a result, they have a prolonged life span and are capable of unrestricted clonal proliferation. Because transformed cells lack normal regulatory and growth constraints, they have favorable competitive advantage over normal hematopoietic cells. The result is the accumulation of abnormal cells with qualitative defects. A major cause of morbidity and mortality is the deficiency of normally functioning mature hematopoietic cells rather than the number of malignant cells.

Splenomegaly due to leukemic infiltration further contributes to pancytopenia by sequestering and destroying circulating erythrocytes and platelets. As the disease progresses, signs and symptoms of anemia, thrombocytopenia, and neutropenia increase.

Leukemic cells may infiltrate other bodily tissues, causing many clinically significant complications including CNS involvement, pulmonary dysfunction, or skin and gingival infiltration.

Frequency

United States

Acute myeloid leukemia accounts for nearly 20% of about 3250 newly diagnosed cases of leukemia in children each year. Although 1 in every 3 newly diagnosed leukemias is acute myeloid leukemia, the ratio of acute myeloid leukemia to ALL rapidly decreases until adolescence.¹ During adolescence, the rate increases to account for nearly 50% of all new diagnoses of leukemia.

International

Although leukemia has been reported in children worldwide, the incidence rate widely varies. In the United States and other highly industrialized countries, acute myeloid leukemia accounts for about 15% of childhood leukemia. In other areas, such as Turkey, nearly one half of children diagnosed with leukemia have acute myeloid leukemia. Childhood leukemia (other than Burkitt type) is less common in Africa, but the ratio of acute myeloid leukemia to ALL is roughly 1:1. Likewise, the incidence of acute myeloid leukemia in Asia is significantly higher than more developed parts of the world, nearly equal to that of ALL as reported by Bhatia and Neglia.²

Mortality/Morbidity

The long-term survival rate for pediatric patients with acute myeloid leukemia is nearly 55%. Acute myeloid leukemia accounts for about 35% of childhood deaths from leukemia. Mortality is a consequence of resistant progressive disease or treatment-related toxicity.

Race

Minor geographic variations are observed in the incidences of the different subtypes of acute myeloid leukemia. However, ALL is more common in white children than in black children, whereas acute myeloid leukemia affects all races nearly equally. The incidence of one subtype, acute promyelocytic leukemia (APL), is slightly increased in the Hispanic pediatric population. Areas of the world where rates of acute myeloid leukemia are higher than average include Shanghai, New Zealand, and parts of Japan.

Sex

Male and female distributions are nearly equal at all ages.

Age

Acute myeloid leukemia is diagnosed in persons of all ages, ranging from the newborns to the elderly. In the first year of life, acute myeloid leukemia accounts for nearly one third of all newly diagnosed leukemias. For the rest of the first decade of life, ALL is more common than acute myeloid leukemia by a ratio of 4:1. The incidence of these diseases is roughly equal during adolescence, and the incidence of acute myeloid leukemia increases in adulthood.

Clinical

History

Symptoms of acute myeloid leukemia (AML) can be divided into those caused by a deficiency of normally functioning cells, those due to the proliferation and infiltration of the abnormal leukemic cell population, and constitutional symptoms.

• Symptoms due to a deficiency of normally functioning cells
  • Cytopenias
  • Anemia: This common finding is characterized by pallor, fatigue, tachycardia, and headache. The major pathophysiologic mechanism is related to decreased production in the infiltrated bone marrow. Bleeding, hemolysis, and sequestration and destruction in an enlarged spleen or liver may all contribute to anemia.
  • Hemorrhage due to thrombocytopenia: This is in part due to decreased production of megakaryocytes in the bone marrow. The most common findings are easy bruising, petechiae, epistaxis, gingival bleeding, and, sometimes, GI or CNS hemorrhage. The patient with disseminated intravascular coagulation might also have symptoms of hemorrhage or thrombosis, including painful swelling and sharp, colored demarcation of an extremity.
  • Fever: This is a common presenting complaint in patients with acute leukemia. In this context, fever should always be attributed to infection. Depending on the site of infection, symptoms may vary. Symptoms may be pulmonary (eg, cough, dyspnea, hypoxia, chest pain), as in patients with pneumonias; neurologic (eg, lethargy, emesis, headache), as in patients with meningitis; or other (eg, pain or changes in bladder and bowel function due to colitis or urinary tract infection).
• Symptoms due to the proliferation and infiltration of the abnormal leukemic cell mass and infiltrative disease
  • The most common extramedullary infiltration due to leukemic cells occurs in the reticuloendothelial system. This infiltration may manifest as adenopathy, hepatomegaly, or splenomegaly.
  • In rare cases, a mediastinal mass may cause symptoms of respiratory insufficiency or superior vena cava syndrome.
  • Abdominal masses may cause pain or obstruct the GI or urogenital tracts. Nodules of myeloblasts, called chloromas, can be found in the skin, CNS or any other organ.
  • Monoblastic leukemia is often associated with gingival hyperplasia and CNS infiltration.
    
    

    

    Gingival hyperplasia in a patient with monoblastic leukemia.

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    Gingival hyperplasia in a patient with monoblastic leukemia.

• Constitutional and miscellaneous symptoms
  • Fever: Unexplained persistent fevers are sometimes the only presenting symptom of patients with leukemia. Weight loss and cachexia are unusual findings in children with leukemia but not in adults. These effects can result from increased catabolic nutritional state combined with decreased caloric intake from anorexia.
  • Orthopedic symptoms: Bone pain is less common in patients with acute myelocytic leukemia than in patients with acute lymphoblastic leukemia (ALL). Its cause may be periosteal elevation due to leukemic cell infiltrates or bone infarctions. On occasion, weakened bony cortex permits pathologic fractures of the extremity, which result in pain and decreased mobility, or vertebral compression fractures after minimal trauma. Such compression fractures cause back pain and dysfunction of the lower extremity (eg, weakness, loss of bladder and bowel function).
  • CNS involvement
    • Although this is uncommon at initial diagnosis, it can appear at any time during follow-up and is associated with various findings.
    • The most common signs and symptoms are related to elevated intracranial pressure; they include headache, nausea and emesis, lethargy, irritability, and visual complaints.
    • Involvement of the cranial nerves, most often the facial nerve (resulting in Bell palsy) and the abducens nerve (resulting in esotropia), may appear as an isolated finding or in combination with other manifestations.
    • In addition to infiltration and proliferation of leukemic cells with mass effect, intracranial hemorrhage and CNS infections can cause similar devastating CNS complications.
    • Spinal lesions are rare. However, in acute myeloid leukemia, blast cells periodically form large aggregates called chloromas or granulocytic sarcomas that lead to epidural compression.
    • Extreme leukocytosis with WBC counts of more than 200 X 10⁹/L (>200,000 cells/μL) is often associated with hyperviscosity, intracerebral leukostasis, and intracerebral hemorrhage early in the course of the disease.
  • Ocular manifestations: In rare cases, leukemic cells infiltrate all parts of the eye. The retina and iris are the sites most commonly affected. Iritis often causes photophobia, pain, and increased lacrimation, whereas, retinal involvement is often accompanied by hemorrhage and can lead to a loss of vision.

Physical

• Pancytopenia
  • Pallor with tachycardia is observed to different degrees proportional to the severity of anemia. With severe anemia, patients may have lethargy, a heart murmur, and signs of congestive heart failure.
  • Bleeding manifestations are most commonly observed in the skin and include petechiae, purpuric lesions, and ecchymoses.
  • GI bleeding may indicate erosions or perforation.
  • Signs of infection include fever, gingivitis, hypotension, or respiratory distress, depending on the site of infection.
• Signs of leukemic infiltration and proliferation
  • Adenopathy, at times generalized, is less common in acute myeloid leukemia than in ALL.
  • Splenomegaly is sometimes massive, particularly in young children.
  • Pronounced organomegaly occasionally result in respiratory embarrassment in infants due to decreased diaphragmatic excursion.
  • CNS findings include lethargy, cranial nerve dysfunction (particularly esotropia and facial palsy), and papilledema.
  • Typhlitis can lead to acute pain in the lower quadrants that mimic signs of appendicitis.
  • Signs of perforation include hypotension, abdominal distension, and decreased bowel sounds. Clinical deterioration is rapid if the condition is not recognized.
  • Skin nodules are occasionally found in patients with acute myeloid leukemia. They are typically firm, raised, and often bluish-purple in color.

Causes

Although the cause of acute myeloid leukemia is unknown in most patients, several factors are associated with its development. Despite these correlations, most people exposed to the same factors do not develop leukemia. This pattern suggests that these factors trigger the malignant transformation of cells, perhaps due to the action of one or more oncogenes or tumor suppressor genes. Defects in DNA repair mechanisms also contribute to the development of acute myeloid leukemia.

• Radiation exposure
  • A great deal of evidence has implicated radiation in leukemogenesis in many patients, as evidenced in Japan after the atomic explosions at Hiroshima and Nagasaki. Although young children had the high risk of developing ALL, teens and adults were most likely to contract acute myeloid leukemia. Most of the leukemias arose within the first 5 years after exposure, although some developed as much as 15 years after exposure. 
  • Reports of increased risk of leukemia among patients who live near nuclear plants are under investigation, but data are lacking. Likewise, early reports that exposure to strong electromagnetic fields is a risk factor for acute leukemia have not been corroborated.
• Exposure to toxins and drugs
  • Exposure to toxic chemicals that cause damage to bone marrow, such as benzene and toluene used in the leather, shoe, and dry cleaning industries, is associated with leukemia in adults. Direct evidence of this effect in children has not been established. Exposure to pesticides has been noted to increase the risk of acute myeloid leukemia.
  • A compelling association has been observed after treatment with antineoplastic cytotoxic agents, particularly alkylating agents such as procarbazine, the nitrosoureas, cyclophosphamide, melphalan, and, most recently, the epipodophyllotoxins etoposide and teniposide. Patients receiving these agents to treat malignancies (eg, Hodgkin Disease) have a significantly increased risk of developing a preleukemic syndrome that ultimately transforms into overt acute myeloid leukemia, especially if the agents are administered with radiation therapy.
• Genetic factors and syndromes
  • Children with Down syndrome (trisomy 21) have a 15-fold increased risk of developing leukemia, most commonly acute megakaryoblastic leukemia, compared with the general population. The risk of megakaryoblastic leukemia in Down syndrome is approximately 400 times greater than the rest of the population. Children with Down syndrome who have transient myeloproliferative syndrome as neonates, a condition often indistinguishable from acute leukemia, also have a high risk of developing acute leukemia in subsequent years.
  • Patients with inherited disorders, such as Shwachman-Diamond syndrome, Bloom syndrome, or Diamond-Blackfan anemia, Fanconi anemia, dyskeratosis congenita, Kostmann syndrome, also have an elevated risk of developing leukemia. Although statistics vary, about 10% of patients with Fanconi anemia, 5-10% of patients with Shwachman-Diamond syndrome, and 1 in 6 patients with Bloom syndrome develop leukemia. The risk of acute myeloid leukemia in patients with dyskeratosis congenita is nearly 200 times the normal population. These syndromes share features of poor DNA repair that are believed to predispose affected individuals to leukemogenic stimuli. Children with neurofibromatosis type I also appear to be at increased risk for developing acute myeloid leukemia. 
  • Although most cases are diagnosed after a relatively brief duration of symptoms, some patients may present with myelodysplasia. This relatively indolent disorder is characterized by slowly progressive anemia or thrombocytopenia. This disorder can be present for many months or even years before it ultimately converts to acute myeloid leukemia.

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