23: Disorders of White Blood Cells

Chapter 23

Disorders of White Blood Cells

Disorders of white blood cells (WBCs) in the dental patient can greatly influence clinical decision making as well as the specifics of care, because WBCs provide the primary defense against microbial infections and are critical for mounting an immune response (< ?xml:namespace prefix = "mbp" />Box 23-1). Defects in WBCs can manifest as delayed healing, infection, or mucosal ulceration and, in some cases, may be fatal. To ensure the health of the patient, the dentist should be able to detect WBC abnormalities through history, clinical examination, and screening laboratory tests and should provide prompt referral to a physician for diagnosis and treatment before invasive dental procedures are performed. Patients with known life-threatening disorders who are under medical care should not receive dental care until after the dentist has consulted with the patient’s physician.


Box 23-1 Classification and Features of White Blood Cell (WBC) Dyscrasias

Leukocytosis—increased number of circulating WBCs

Leukopenia—decreased number of circulating WBCs

Myeloproliferative disorders

    1. Acute myeloid leukemia—immature neoplastic malignancy of myeloid cells
    2. Chronic myeloid leukemia—mature neoplastic malignancy of myeloid cells

Lymphoproliferative disorders

    1. Acute lymphoblastic leukemia—immature neoplastic malignancy of lymphoid cells
    2. Chronic lymphocytic leukemia—mature neoplastic malignancy of lymphoid cells
    3. Lymphomas
       a Hodgkin lymphoma—malignant growth of B lymphocytes, primarily in lymph nodes
       b Non-Hodgkin lymphoma—B or T cell malignant neoplasms, many types and locations; most are of B cell lineage

         (1) Burkitt lymphoma—non-Hodgkin B cell lymphoma involving bone and lymph nodes
    4. Multiple myeloma—Overproduction of malignant plasma cells involving bone


Three groups of WBCs are found in the peripheral circulation: granulocytes, lymphocytes, and monocytes. Of the granulocyte population, 90% is composed of neutrophils; the remainder consists of eosinophils and basophils. Circulating lymphocytes are of three types: T lymphocytes (thymus mediated), B lymphocytes (bursa-derived), and natural killer (NK) cells. Lymphocytes are subdivided by the surface markers they exhibit and by the cytokines they produce.1,2

The primary function of neutrophils is to defend the body against certain infectious agents (primarily bacteria) through phagocytosis and enzymatic destruction. Eosinophils and basophils are involved in inflammatory allergic reactions and mediate these reactions through release of their cytoplasmic granules. Eosinophils also combat infection by parasites. T lymphocytes (T cells) are involved with the delayed, or cellular, immune reaction, whereas B lymphocytes (B cells) play an important role in the immediate, or humoral, immune system involving the production of plasma cells and immunoglobulins (IgA, IgD, IgE, IgG, and IgM). Monocytes have diverse functions that include phagocytosis, intracellular killing (especially of mycobacteria, fungi, and protozoa), and mediating of the immune and inflammatory response through the production of more than 100 substances, such as cytokines and growth factors, that increase the activity of lymphocytes. In addition, monocytes serve as antigen-presenting cells and migrate into tissues. In tissue, these antigen-presenting cells are known as dendritic cells (in lymph nodes) or Langerhans cells (in skin and mucosa). Monocytes in tissue that phagocytose microbes are known as macrophages.1,2

Most WBCs are produced primarily in the bone marrow (granulocytes and monocytes), and these cells form several “pools” in the marrow: (1) the mitotic pool, which consists of immature precursor cells; (2) a maturing pool, which consists of cells undergoing maturation; and (3) a storage pool of functional cells, which can be released as needed.

WBCs released by the bone marrow that circulate in the peripheral blood account for only 5% of the total WBC mass and form two pools of cells: a marginal one and a circulating one. Cells in the marginal pool adhere to vessel walls and are readily available. When infection threatens the body, the storage and marginal pools can be called on to help fight the invading organisms.

Growth-promoting substances called colony-stimulating factors (CSFs) are responsible for the growth of committed granulocyte-monocyte stem cells. The major function of CSFs is to amplify leukopoiesis rather than recruit new stem cells into the granulocyte-monocyte differentiation pathway. Thus, through the local release of CSFs, the bone marrow can increase the production of granulocytes and monocytes. This process occurs in response to infection.3

Lymphocytes localize primarily in three regions: lymph nodes, the spleen, and the mucosa-associated lymphoid tissue (MALT) lining the respiratory and gastrointestinal tracts. At these sites, microbial antigens are trapped and presented to B or T lymphocytes (cells). Antigens bind B cells through cell surface immunoglobulins, whereupon B cells are activated, proliferate, and produce large amounts of immunoglobulin to aid in opsonization. Antigens are presented to CD4+ (helper) T cells by major histocompatibility complex (MHC) class I molecules, and to CD8+ T cells by MHC class II molecules. CD4+ T cells activate B cells and macrophages by producing cytokines and through direct contact. CD8+ T cells kill virus-infected cells.

Leukocytosis and Leukopenia

The number of circulating WBCs normally ranges from 4400 to 11,000/µL in adults.4 The differential WBC count is an estimation of the percentage of each cell type per microliter of blood. A normal differential count consists of neutrophils, 50% to 60%; eosinophils, 1% to 3%; basophils, less than 1%; lymphocytes, 20% to 34%; and monocytes, 3% to 7%. The term leukocytosis is defined as an increase in the number of circulating WBCs (lymphocytes or granulocytes) to more than 11,000/µL, and leukopenia as a reduction in the number of circulating WBCs (usually to less than 4400/µL).

Many causes of leukocytosis are known. Exercise, pregnancy, and emotional stress can lead to increased numbers of WBCs in the peripheral circulation. Leukocytosis resulting from these causes is called physiologic leukocytosis. Pathologic leukocytosis can be caused by infection, neoplasia, or necrosis. Pyogenic infections induce a type of leukocytosis that is characterized by an increased number of neutrophils. If excessive numbers of immature neutrophils (stab cells) are released into the circulation in response to a bacterial infection, a shift to the left is said to have occurred. Tuberculosis, syphilis, and viral infections produce a type of leukocytosis that is characterized by increased numbers of lymphocytes. Protozoal infections often produce a type of leukocytosis that increases the numbers of monocytes. Allergies and parasitic infections caused by certain helminths increase the numbers of circulating eosinophils. Cellular necrosis increases the numbers of circulating neutrophils. Leukemia (cancer of the WBCs) is characterized by a great increase in the numbers of circulating immature leukocytes. Carcinoma of glandular tissues may cause an increase in the number of circulating neutrophils. Acute bleeding also can result in leukocytosis.2,4

Many causes of deficient numbers of leukocytes (less than 4400/µL) in the blood are evident. Leukopenia may occur in the early phase of leukemia and lymphoma as a result of bone marrow replacement through excessive proliferation of WBCs. Leukopenia also occurs during agranulocytosis (reduction of granulocytes) and pancytopenia (decreased WBCs and RBCs) that result from toxic effects of drugs and chemicals. Leukopenia is a common complication that results from the use of chemotherapeutic (anticancer) drugs.2,4

Cyclic Neutropenia

An important form of leukopenia involving the cyclic depression of circulating neutrophils is a disorder called cyclic neutropenia. It is associated with mutations located near the junction of exons 4 and 5 of the neutrophil elastase gene (ELA2).2 The estimated frequency of cyclic neutropenia is about 1 in 1 million.5 In this condition, patients have a periodic decrease (at least a 40% drop) in the number of neutrophils (about every 21 to 28 days). During the period in which few circulating neutrophils are present, the patient is susceptible to infection and oral manifestations (see under “Oral Complications and Manifestations” later on).2,6 Up to 10% of patients die from pneumonia, cellulitis, or peritonitis.2

Patients with leukocytosis or leukopenia may have bone marrow abnormalities that can cause thrombocytopenia. Examination of the patient’s bone marrow aspirate is important for making the final diagnosis. Infectious diseases that can cause leukocytosis and leukopenia are discussed in Chapters 7, 13, and 18.

Leukemia and Lymphoma

The remainder of this chapter focuses on leukemia and malignancies of lymphoid cells (lymphoma and multiple myeloma). Leukemia and lymphoma account for about 8% of all new malignancies each year in the United States, which amounts to approximately 117,080 cases per year.7,8 These patients become gravely ill if they are not properly identified and do not receive appropriate medical care. In addition, patients are usually immunosuppressed as a result of the disease itself or because of the treatment used to control it. Hence, they are prone to develop serious infection and often bleed easily because of thrombocytopenia. A dental practice that manages 2000 patients is predicted to have 1 to 3 patients with leukemia or a malignancy of lymphoid cells.


Leukemia is cancer of the WBCs that affects the bone marrow and circulating blood. It involves exponential proliferation of a clonal myeloid or lymphoid cell and occurs in both acute and chronic forms. Acute leukemia is a rapidly progressive disease that results from accumulation of immature, functionless WBCs in the marrow and blood. Chronic leukemias have a slower onset, which allows production of larger numbers of more mature (terminally differentiated), functional cells. This section focuses on four types of leukemia: (1) acute lymphocytic leukemia (ALL), (2) acute myelogenous leukemia (AML), (3) chronic lymphocytic leukemia (CLL), and (4) chronic myelogenous leukemia (CML).

Leukemia occurs in all races, at any age, at an incidence of 12.3 per 100,000.8 Approximately 43,050 new cases were diagnosed in 2010 in the United States.7,8 The incidence of leukemia has remained somewhat stable in the United States since about 1956.9 In general, the likelihood of dying from most types of leukemia, lymphoma, or myeloma decreased from 1998 to 2007.8 All types of leukemia are somewhat more common in men. In 2010 the incidence of acute leukemia was 9740 cases in men and 7920 cases in women and the incidence of chronic leukemia was 11,670 in men and 8190 in women.7,8 In 2010, more cases of chronic leukemia (19,860) were reported than acute leukemia (17,860).7

Leukemia is much more common in adults than in children, with more than half of all cases occurring after age 65 years. The most common types of leukemia in adults are acute myelogenous leukemia, with an estimated 12,330 new cases in 2010, and chronic lymphocytic leukemia, with some 14,990 new cases in 2010.7 Chronic myelogenous leukemia is estimated to affect about 4870 persons in 2010.7 The most common form of leukemia among people younger than 19 years of age is acute lymphocytic leukemia. It accounted for about 5330 cases in 2010.7 Other unclassified forms of leukemia account for the remaining 5530 cases.7

The cause of leukemia remains unknown. Increased risk is associated with large doses of ionizing radiation, certain chemicals (benzene), and infection with specific viruses (e.g., Epstein-Barr virus [EBV], human lymphotropic virus [HTLV]-1). Cigarette smoking and exposure to electromagnetic fields also have been proposed to be causative.811

Acute Myelogenous Leukemia


AML is a neoplasm of myeloid (immature) WBCs, which demonstrate uncontrolled proliferation in the bone marrow space and subsequently appear in the peripheral blood.


In 2010, AMLs accounted for 28.6% of all leukemias.7 AML is a disease of adults.11 Incidence increases with age and rises rapidly after the age of 50 years,11 reaching 22 per 100,000 by age 80. The mean age of persons with AML in the United States is 65 years.11


AML arises de novo in younger adults or secondarily in elderly persons as a consequence of myelodysplasia. Environmental factors such as tobacco smoke, benzene-containing products, chemotherapies for cancer, and radiation exposure appear to be risk factors.11 It is estimated that 10% to 20% of all cases of AML are now therapy-related.11 Genetic factors (e.g., translocation and rearrangement of chromosomes) may cause cytogenetic abnormalities that affect transcriptional cascades of myeloid precursor cells and uncontrolled proliferation of these cells. Certain genetic disorders increase the risk for AML including Down syndrome, Klinefelter’s syndrome, Fanconi’s anemia, and von Recklinghausen disease.11

Pathophysiology and Complications

AML has a sudden onset and leads to death in 1 to 3 months if left untreated.12 It involves increased numbers of immature myeloid WBCs in the bone marrow space and peripheral circulation (Figure 23-1). As a result, patients are susceptible to excessive bleeding, anemia, poor healing, and infection after surgical procedures.12 Hemorrhage and infection, frequent complications of chemotherapy, are the chief causes of death.


FIGURE 23-1 Acute myeloid leukemia. Peripheral blood smear shows many myeloid cells with large nuclei and azurophilic granules.

(From Hoffbrand AV, Pettit JE: Color atlas of clinical hematology, ed 4, London, 2010, Mosby. Courtesy Prof. J.M. Chessells.)

Clinical Presentation

Signs and Symptoms

AML produces a leukemic infiltration of marrow and organs that causes cytopenia and diverse nonspecific signs and symptoms, including fatigue, easy bruising, and bone pain. Many patients complain of flulike symptoms for 4 to 6 weeks before the diagnosis. Anemia and thrombocytopenia usually manifest as malaise, pallor, dyspnea on exertion, and bleeding and small hemorrhage (petechiae, ecchymoses) in the skin and mucous membranes (Figure 23-2, A).10,11 Because of granulocytopenia, at least one third of patients have recurrent infections (nonhealing wounds), oral ulcerations, and fever. Enlargement of the tonsils, lymph nodes, spleen, and gingiva (see Figure 23-2, B) occurs as a result of leukemic infiltration of these tissues.11 Infiltration of the central nervous system (CNS) occurs in about 35% of the cases of AML with increased eosinophils (the M4Eo variant).11 Most of these patients are asymptomatic, but some will present with meningeal signs and symptoms and symptoms associated with increased intracranial pressure.11 Skin lesions consisting of collections of leukemic cells termed leukemic cutis, granulocytic sarcomas, and chloromas may occur.10


FIGURE 23-2 A, Acute myeloid leukemia presenting as bleeding and ecchymosis of the tongue in a 14-year-old. B, Gingival leukemia infiltrate in a patient with acute myeloid leukemia.

Laboratory Findings

The diagnosis of leukemia is made through examination of peripheral blood and bone marrow stained with Wright-Giemsa. Cytochemical staining, immunophenotyping, and cytogenetic analyses are used to characterize the type and subtype, to allow for specific treatment approaches, and to detect residual disease after therapy is provided. Granulocytopenia and thrombocytopenia are common.

The diagnosis of AML is made when myeloblasts are found in the bone marrow or peripheral blood at a rate of at least 20%. Myeloblasts stain positive for myeloperoxidase and are immunotype-positive for several of the following markers: CD13, CD33, CD34, CD65, and CD117.13 The French-American-British (FAB) classification categorizes AML into eight subtypes (Table 23-1). The WHO classification describes four subtypes that differ in terms of genetic abnormalities, evolution, and response to therapy.10,11

TABLE 23-1 Classification of Acute Leukemias and Associated Clinical,* Cytologic, and Immunologic Abnormalities


Acute Lymphoid Leukemia


ALL is the result of uncontrolled monoclonal proliferation of immature lymphoid cells in the bone marrow and peripheral blood. These neoplastic cells may also expand in the lymph nodes, liver, spleen, or CNS.


In 2010 there were 5330 cases of ALL reported in the United States.7 It occurs at an incidence of 1.6 in 100,000 and typically occurs in children.14 ALL accounts for about 25% of all neoplasms in children and 80% of leukemias in children.15 A remarkable peak of incidence occurs in children who are 2 to 3 years old, with 75% of cases reported in this age group.16 Boys are affected slightly more often than girls. In adults the greatest number of cases occur in those older than 65 years.16


Although environmental, infectious, and genetic factors are considered likely causes of the disease, causal links for ALL have not been established. The disease is 18- to 20-fold more common in patients with Down syndrome (trisomy 21). Cytogenetic studies frequently display the Philadelphia chromosome [t(9;22)], a shortened chromosome 22, as a result of translocation of genes between the long arms of chromosomes 9 and 22. About 5% of children and 25% of adults with ALL have cytogenetics showing the Philadelphia chromosome. Patients with the Philadelphia chromosome have slightly lower complete remission rates and greatly reduced remission durations. Other chromosomal anomalies are also common.9,14

Pathophysiology and Complications

Similar to AML, ALL results in suppression of normal hematopoiesis, leaving patients susceptible to excessive bleeding, anemia, poor healing, and infection after surgical procedures have been performed.9,14 Treatment of children results in remission rates that exceed 90% and cure rates above 70%. In adults, long-term survival from ALL occurs at rates of only about 50% to 60%.9,14

Clinical Presentation

Signs and Symptoms

The clinical presentation of ALL can be acute or insidious. Presenting signs and symptoms relate to anemia, thrombocytopenia, fever, and neutropenia. Frequently, bone and joint pain have effects on walking. In one large study one third of the patients presented with infection or fever and one third with hemorrhagic episodes, and over half of the patients with enlargement of the liver, spleen, and lymph nodes.14 A higher propensity toward CNS disease occurs with ALL compared with AML. Patients may present with cranial nerve deficiencies.14

Laboratory Findings

ALL is diagnosed when massive replacement of the bone marrow space with leukemic blast cells is observed. Figure 23-3 shows a peripheral blood smear of ALL. A correspondingly high number of lymphoblasts are detected in the peripheral blood smear and levels of Hb, hematocrit, and platelets are depressed, reflecting large replacement of marrow by lymphoblasts. Immunotyping and flow cytometry is the preferred method of lineage assignment and assessment of cell maturation. Detection of a nuclear enzyme, terminal deoxynucleotidyl transferase (Tdt), along with (B cell) antigen (CD10, originally designated CALLA) and CD19, CD22, and HLA-DR, allows histologic classification of ALL.9,14


FIGURE 23-3 Peripheral blood smear of acute lymphoblastic leukemia.

(From Hoffbrand AV, Pettit JE: Color atlas of clinical hematology, ed 4, London, 2010, Mosby.)

According to the French-American-British Cooperative Group, three distinct subtypes are based on type and size of neoplastic lymphocytes: L1 (cells small and homogeneous), L2 (cells pleomorphic and often large), and L3 (cells homogeneous and of medium size with dispersed chromatin).9,14

Medical Management of Acute Leukemia

The ability to cure a patient of acute leukemia is related to tumor burden and the rapid elimination of malignant WBCs. Normal bone marrow consists of 0.3% to 5% blast cells. Patients with acute leukemia have 100-fold more (about a trillion) blast cells. Once effective chemotherapy has been given, the number of blast cells is reduced from trillions to billions, leukemic cells can no longer be detected, and the patient is said to be in remission. With a 5-day generation time for the remaining undetectable leukemic cell mass, 10 doublings in 50 days could restore the leukemic cell mass to a trillion cells, and the patient would again show signs and symptoms of leukemia. This would constitute a short remission with relapse.17

Chemotherapy for acute leukemia consists of three phases. The purpose of the first phase (induction) is to hit hard and induce a state of remission by killing tumor cells with cytotoxic agents. Agents used to treat the acute leukemias are shown in Table 23-2. The second phase (consolidation or intensification) focuses on consolidating the kill of remaining leukemic cells. During the third phase (complete remission), maintenance therapy is provided to prevent expansion of any remaining leukemic cell mass. The criteria for complete remission include the following: platelet count higher than 100,000/µL, neutrophil count greater than 1000/µL, and bone marrow specimen with less than 5% blasts.18 During induction and consolidation, myeloid growth factors (granulocyte colony-stimulating factor [G-CSF] and granulocyte-monocyte colony-stimulating factor [GM-CSF]) are administered at some institutes to shorten the duration of neutropenia and reduce the incidence of severe infection.

TABLE 23-2 Classes of Drugs Used to Treat Leukemia

Drug Class Chemotherapeutic Agents Mechanism of Action
Alkylating agents Busulfan, carmustine, cyclophosphamide, dacarbazine, lomustine nitrogen mustard Derivative: chlorambucil Produce alkyl radicals, causing cross-linking of DNA and inhibition of DNA synthesis in rapidly replicating tumor cells
Antibiotics Bleomycin, daunorubicin, doxorubicin, idarubicin, mitomycin C Disrupt cellular functions, such as RNA synthesis, or inhibit mitosis
Antimetabolites Folic acid analogues: methotrexate Disrupt enzymatic processes or nucleic acid synthesis
Purine analogues: cladribine, fludarabine, fluorouracil 6-mercaptopurine, thioguanine
Pyrimidine nucleoside analogues: arabinosyl cytosine (Ara-C, cytarabine)
Biologicals Interferon alfa Causes a direct antiproliferative effect on CML progenitor cells
Monoclonal antibody to CD20
Monoclonal antibody to CD52
All-trans retinoic acid (ATRA) [tretinoin] Binds antigen target on malignant lymphocyte
Induces differentiation and apoptosis of malignant promyelocytes in APML
Enzymes Asparaginase Inhibits synthesis of asparagines, which is required for protein synthesis in leukemic lymphoblasts
Mitotic inhibitors Vincristine, vinblastine Act as mitotic spindle inhibitors causing metaphase arrest
Etoposide Topoisomerase II inhibitor
Steroid Prednisone Hormone that has antiinflammatory and antilymphocytic properties
Newer agents

Arsenic trioxide

Gemtuzumab ozogamicin



Imatinib mesylate

Inorganic compound

Monoclonal antibody to CD33

Inhibits DNA methyltransferase

Purine nucleoside antimetabolite

Tyrosine kinase inhibitor

(inhibits signal transduction in cancer cells)

Agents in clinical trials

Farnesyltransferase inhibitors





Signal transduction inhibitor

Kinase inhibitor


Monoclonal antibody to CD20

Monoclonal antibody to CD23

APML, Acute promyelocytic leukemia; CML, Chronic myelogenous leukemia.

Patients are cured of leukemia when no leukemic cells remain. Long-term survival occurs when the leukemic cell mass is greatly reduced and is kept from increasing over a long period. In general, once a patient relapses, a second remission is more difficult to induce, and if it occurs, it will be of a shorter duration. Bone marrow transplantation (BMT) generally is reserved for patients younger than 45 years of age and for children and young adults who relapse when a suitable sibling match is available (allogeneic).9,14 The marrow transplant or, more recently, the peripheral blood stem cell transplant procedure is preceded by high-dose chemotherapy (including busulfan) and radiation therapy.

Treatment of patients with AML is shown in Table 23-3. In 1966 the median survival of adults with AML was 40 days.10 Today patients younger than 60 years have complete remission rates of 70% to 80% after induction therapy but overall survival rate is only 50% for those who go into complete remission and 30% overall.10 The prognosis of AML in adults who are 60 years or older is poorer. The remission rate for older patients is 52% for patients 60 to 69 years and only 26% for patients 70 years or older with long-term survival rates of only 5% to 10% (Table 23-4).9,10

TABLE 23-3 Medical Treatment for Leukemia and Lymphoma


TABLE 23-4 Clinical Factors in Acute and Chronic Leukemias


Treatment for ALL is shown in Table 23-3. The prognosis for children with ALL is very good, with cure now being attained in more than 70% of cases. The prognosis is worse in persons older than 30 years of age, with a blast count greater than 50,000/µL, with mature B cell ALL phenotype, multiorgan involvement, and chromosomal translocations t(9;22) and t(4;11). In these patients, remission can be achieved with chemotherapy; however, the duration of remission is short. The overall long-term survival (cure) rate for adults is less than 20%.19 Relapse can result in second remission in 75%, but less than 30% of these patients are cured.

Another concern related to treatment of patients with acute leukemia is that leukemic cells can migrate to areas in the body where chemotherapeutic agents cannot reach them. These areas are called sanctuaries, and they require special treatment. The most important sanctuary in patients with ALL is the CNS. Thus, patients with ALL are treated with systemic chemotherapy plus high-dose methotrexate intravenously and cytarabine or intrathecal methotrexate and radiation to the cranium plus high-dose systemic chemotherapy. Another important sanctuary (in males) is the testes.9,14,19

Oral Manifestations of Acute Leukemia

Leukemic patients are prone to develop gingival enlargement, ulceration, and oral infection. Localized or generalized gingival enlargement is caused by inflammation and infiltration of atypical and immature WBCs (see Figure 23-2). It occurs in up to 36% of those with acute leukemia (most frequently with the acute myelomonocytic types) and in about 10% of those with chronic leukemia.20 The gingiva is boggy and bleeds easily, and multiple tooth sites are typically affected. Generalized gingival enlargement is more common and is particularly prevalent when oral hygiene is poor and in patients who have AML (particularly the monocytic type [M5]; see Table 23-1). The combination of poor oral hygiene and gingival enlargement contributes to gingival bleeding and fetor oris. Gingival bleeding is exacerbated by the presence of thrombocytopenia. Plaque control measures, chlorhexidine, and chemotherapy promote resolution of the condition.

A localized mass of leukemic cells (in the gingiva or other sites) is specifically known as a granulocytic sarcoma or chloroma. These extramedullary tumors have been observed in the maxilla and the palate.5

Chronic Myelogenous Leukemia


Chronic myelogenous leukemia (CML) is a neoplasm of mature myeloid WBCs.


CML has an incidence of 1 to 1.5 cases per 100,000 population, with 4870 cases reported for 2010 in the United States.7,21 It accounts for 15% to 20% of all leukemias and is much less common than CLL in the United States.21 The median age at diagnosis is 67 years, and the incidence increases with age. CML occurs slightly more common in men than in women. CML causes 3% of childhood leukemias.21


The etiology is unknown, but radiation exposure increases risk for the disease. The genetic defect consists of translocation of the cellular oncogene ABL (Abelson leukemia virus gene) from chromosome 9 to the BCR (breakpoint cluster region) gene of chromosome 22 and a reciprocal translocation of part of BCR from chromosome 22 to the ABL gene in chromosome 9. A shortened chromosome 22, the Philadelphia (Ph) chromosome, results from the translocations and is evident in more than 90% of cases of CML.21 The Philadelphia chromosome also is present in ALL. Translocation contributes to increased tyrosine kinase activity and myeloid proliferation.21

Pathophysiology and Complications

CML progresses slowly through a chronic phase for 3 to 5 years and then moves on to an accelerated phase, followed by a blast phase (or crisis). More than 90% of the patients when first diagnosed are in the chronic phase of the disease. During the chronic phase of CML, leukemic cells are functional; thus, infection is not a major problem. However, once transformation to the blastic stage has occurred, the leukemic cells are immature and nonfunctional. As a result, anemia, thrombocytopenia, and infection become problems. In about 25% of patients with CML per year exhibit progression to the blast phase of the disease 6 to 12 months after diagnosis. The blast phase is characterized by 30% or more leukemic blast cells in the peripheral blood or marrow.21,22 More than 85% of patients with CML die in the blast phase, and patients without the Philadelphia chromosome have a worse prognosis. The overall prognosis for CML was poor, and survival from the time of diagnosis was about 3.5 years before tyrosine kinase inhibitor treatment with imatinib mesylate therapy was initiated.21,22 Patients treated in the chronic phase with imatinib obtain complete remission, and about 70% of the patients remain in remission after 5 years. Allogeneic transplantation is associated with 10-year survival rates of 70% or better for younger patients in the early chronic phase of the disease. Patients treated in the accelerated or blast phase of the disease have a much poorer prognosis.21,22

Clinical Presentation

Signs and Symptoms

In nearly 90% of patients, CML is diagnosed during the chronic phase. Up to half of these patients are asymptomatic, and diagnosis is based on their complete blood cell count. Common symptoms are fatigue, weakness, abdominal (upper left quadrant) pain, abdominal fullness, weight loss, night sweats due to anemia, an enlarged and painful spleen (splenomegaly), and altered hematopoiesis. Hyperviscosity of the blood may cause a stroke.21,22

Laboratory Findings

Patients are identified by marked elevation of their WBC count during routine examination (Figure 23-4). WBC count usually is above 50,000/µL at the time of diagnosis, and basophilia and eosinophilia are present. Cytogenetic analysis, a part of the standard diagnostic workup, reveals the Philadelphia chromosome in more than 90% of cases. Serum chemistry reveals elevated levels of lactate dehydrogenase (LDH) and low levels of leukocyte alkaline phosphatase. The bone marrow is markedly hypercellular.21,22


FIGURE 23-4 Chronic myeloid leukemia. Peripheral blood smear shows myeloblasts, promyelocytes, and segmented neutrophils.

(From Hoffbrand AV, Pettit JE: Color atlas of clinical hematology, ed 3, London, 2000, Mosby.)

Medical Management

Patients with CML were historically treated during the chronic phase with hydroxyurea or busulfan; this approach resulted in good symptom and blood count control, along with significant toxicity. Interferon-α or imatinib mesylate (Gleevec), an inhibitor of tyrosine kinase, is widely used today.21,22 Two second-generation tyrosine kinase inhibitors, dasatinib and nilotinib, are being used to overcome imatinib resistance (see Table 23-3).21,23 Stem cell transplantation has resulted in remission in more than 70% of patients at 10 years when treatment is provided before the accelerated or blastic phase.24 Stem cell transplants generally are recommended for younger patients who have an adequate human leukocyte antigen (HLA) match.

Oral Manifestations

Chronic forms of leukemia are less likely to demonstrate oral manifestations than are acute forms of leukemia. Generalized lymphadenopathy, pallor of the oral mucosa, and soft tissue infection may be present.

Chronic Lymphocytic Leukemia


Chronic lymphocytic leukemia (CLL) is a neoplasm of mature clonal CD5+ B lymphocytes.


CLL is the most common type of leukemia in adults. In 2010 there were 14,990 cases of CLL reported in the United States. The incidence rate is 4 to 5.3 cases per 100,000.25,26 The median age at diagnosis is about 72 years. CLL is very uncommon before the age of 45 and infrequent in patients under 65 years of age. The 5-year survival rate is 75.9%, with more than 95,123 patients living with CLL.26 It is more common in men than in women; however, 5-year and 10-year survival rates are higher for women. It is more common in Jewish people from Russian or Eastern European ancestry. This disease is rare in Asia and in children throughout the world.26


The etiology of CLL is unknown, and risk factors are more related to familial inheritance than to exposure to harmful environmental agents. Neoplastic B cells have various genetic aberrations, most commonly gene deletions (e.g., on chromosome 11, 12, or 17) that lead to loss of cell cycle control.22,26 The specific genetic defect dictates the course of the disease. Cytogenetic analysis shows the following abnormalities: 13q deletion (40-50%), 11q deletion (15-20%), trisomy 12 (15-20%), and 17p deletion (5-10%). In most cases, low levels of expression of monoclonal immunoglobulin are demonstrated on the cell surface, which includes CD19, CD20, CD21, CD23, CD24/>

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