Porth's Essentials of Pathophysiology, 4e

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Disorders of White Blood Cells and Lymphoid Tissues

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a proto-oncogene that is the cellular homolog of the Abelson murine leukemic virus. The ABL gene is received at a specific site on 22q called the breakpoint cluster region (BCR). The resulting BCR–ABL fusion gene codes for a novel protein that allows affected cells to bypass the regulated signals controlling normal cell growth and differentiation, and instead undergo malig- nant transformation to become leukemic cells. The Philadelphia chromosome translocation is found in more than 90% of persons with chronic myelogenous leukemia and in some persons with acute leukemia. 7 The recent development of tyrosine kinase inhibitors (e.g., imatinib mesylate) has contributed to the targeted approach for treatment of leukemias that display the Philadelphia chromosome translocation. 19 Acute Leukemias The acute leukemias are cancers of the hematopoietic progenitor cells. They usually have a sudden and stormy onset with signs and symptoms related to depressed bone marrow function. 19–29 There are two main forms of acute leukemia: acute lymphocytic (lymphoblas- tic) leukemia (ALL) and acute myeloid (myelogenous) leukemia (AML). Acute lymphocytic (lymphoblastic) leukemia is the most common form of leukemia in chil- dren. It accounts for three of four cases of childhood cancer, with AML accounting for most of the remain- ing cases. 22,23 Acute myeloid (myelogenous) leukemia is mainly a disease of older adults, but it is also seen in children and young adults. 24,29 Acute lymphocytic (lymphoblastic) leukemia encom- passes a group of neoplasms composed of precursor B (pre-B) or T (pre-T) lymphocytes referred to as lympho- blasts (see Fig. 11-3). Most cases (about 85%) of ALL are of pre–B-cell origin. 4,7 Approximately 90% of per- sons with ALL have numeric and structural changes in the chromosomes of their leukemic cells. They include hyperploidy (i.e., more than 50 chromosomes), poly- ploidy (i.e., three or more sets of chromosomes), and chromosomal translocations and deletions. Many of these chromosomal aberrations serve to dysregulate the expression and function of transcription factors required for normal hematopoietic cell development. The AMLs are a diverse group of neoplasms affect- ing myeloid precursor cells in the bone marrow. 4,7 Most are associated with acquired genetic alterations that inhibit terminal myeloid differentiation. As a result, normal marrow elements are replaced by an accumu- lation of relatively undifferentiated blast cells. The result is suppression of the remaining progenitor cells and subsequent anemia, neutropenia, and thrombocy- topenia. Specific chromosomal abnormalities, includ- ing translocations, are seen in a large number of AMLs. One subtype of AML, acute promyelocytic leukemia, which represents 10% of adult cases of AML, is associ- ated with a (15;17) chromosomal translocation. 26 This translocation results in the fusion of the retinoic acid receptor α (RARA) gene on chromosome 17 with the promyelocytic leukemia (PML) gene on chromosome 15. This change in the retinoic acid receptor produces

a block in myeloid differentiation at the promyelocytic stage (see Fig. 11-3), probably by inhibiting the action of normal RARA receptors. This block can be overcome by pharmacologic preparations of retinoic acid (a vita- min A analog), causing the neoplastic promyelocytes to differentiate into neutrophils and die. Manifestations. Although ALL and AML are distinct disorders, they typically present with similar clinical features. Both are characterized by an abrupt onset of symptoms, including fatigue resulting from anemia; low-grade fever, night sweats, and weight loss due to the rapid proliferation and hypermetabolism of the leuke- mic cells; bleeding due to a decreased platelet count; and bone pain and tenderness due to bone marrow expan- sion. 20–26 Infection results from neutropenia, with the risk of infection rising steeply as the neutrophil count falls below 500 cells/ μ L. Generalized lymphadenopathy, splenomegaly, and hepatomegaly caused by infiltration of leukemic cells occur in all acute leukemias but are more common in ALL. In addition to the common manifestations of acute leukemia (i.e., fever, fatigue, weight loss, easy bruising), infiltration of malignant cells in the skin, gums, and other soft tissues is particularly common in the mono- cytic form of AML. The leukemic cells may also cross the blood–brain barrier and establish sanctuary in the CNS. Central nervous system involvement is more com- mon in ALL than AML, and is more common in children than adults. Signs and symptoms of CNS involvement include cranial nerve palsies, headache, nausea, vomit- ing, papilledema, and occasionally seizures and coma. Leukostasis is a condition inwhich the circulating blast count is markedly elevated (usually 100,000 cells/ μ L). The high number of circulating leukemic blasts increases blood viscosity and predisposes to the development of leukoblastic emboli with obstruction of small blood ves- sels in the pulmonary and cerebral circulations. Occlusion of the pulmonary vessels leads to vessel rupture and infil- tration of lung tissue, resulting in sudden shortness of breath and progressive dyspnea. Cerebral leukostasis leads to diffuse headache and lethargy, which can prog- ress to confusion and coma. Once identified, leukostasis requires immediate and effective treatment to lower the blast count rapidly. Initial treatment uses apheresis to remove excess blast cells, followed by chemotherapy to stop leukemic cell production in the bone marrow. 22 Hyperuricemia occurs as the result of increased pro- liferation or increased breakdown of purine nucleotides (i.e., one of the components of nucleic acids) secondary to leukemic cell death that results from chemotherapy. It may increase before and during treatment. Prophylactic therapy with allopurinol, a drug that inhibits uric acid synthesis, is routinely administered to prevent renal complications secondary to uric acid crystallization in the urine filtrate. Diagnosis and Treatment. A definitive diagnosis of acute leukemia is based on blood and bone marrow studies; it requires the demonstration of leukemic cells in the peripheral blood, bone marrow, or extramedullary