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) . The estimated frequency of cyclic neutropenia is about 1 in 1 million. In this condition, patients have a periodic decrease (at least a 40% drop) in the number of neutrophils (about every 21–28 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 ). Up to 10% of patients die from pneumonia, cellulitis, or peritonitis.

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 Chapter 7 , Chapter 13 , Chapter 18 .

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) . The estimated frequency of cyclic neutropenia is about 1 in 1 million. In this condition, patients have a periodic decrease (at least a 40% drop) in the number of neutrophils (about every 21–28 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 ). Up to 10% of patients die from pneumonia, cellulitis, or peritonitis.

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 Chapter 7 , Chapter 13 , Chapter 18 .

Leukemia

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, nonfunctional 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 myelogenous leukemia (AML), (2) acute lymphocytic leukemia (ALL), (3) chronic myelogenous leukemia (CML), and (4) chronic lymphocytic leukemia (CLL).

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.

Leukemia

In 2016, 60,140 people were expected to be diagnosed with leukemia. There are an estimated 354,422 people living with or in remission from leukemia in the United States. The overall 5-year relative survival rate for leukemia has more than quadrupled since 1960. From 2005 to 2011, the 5-year relative survival rates were 63.2% for CML, 84.8% for CLL, 26% for AML, and 70% for ALL. In 2016, 24,400 people were expected to die from leukemia (14,130 males and 10,270 females). From 2008 to 2012, leukemia was the fifth most common cause of cancer deaths in men and the sixth most common in women in the United States.

Definition

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

Epidemiology

Acute myelogenous leukemia occurs in about 19,950 persons in the United States annually and accounts for 28.6% of all leukemias. AML is a disease of adults. The incidence increases with age and rises rapidly after the age of 50 years, reaching 22 per 100,000 by age 80 years. The mean age of persons with AML in the United States is 65 years.

Etiology

Acute myelogenous leukemia arises de novo in younger adults or secondarily in older adults as a consequence of myelodysplasia. Myelodysplastic syndromes describe a diverse group of clonal disorders of hematopoietic stem or progenitor cells resulting in abnormal cellular differentiation that evolves into AML in 30% of cases. Environmental factors such as tobacco smoke, benzene-containing products, chemotherapies for cancer, and radiation exposure appear to be risk factors for AML. It is estimated that 10% to 20% of all cases of AML are now therapy related. 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 syndrome, Fanconi anemia, and von Recklinghausen disease.

Pathophysiology and Complications

Acute myelogenous leukemia has a sudden onset and leads to death in 1 to 3 months if left untreated. It involves increased numbers of immature myeloid WBCs in the bone marrow space and peripheral circulation ( Fig. 23.1 ). As a result, patients are susceptible to excessive bleeding, anemia, poor healing, and infection after surgical procedures. Hemorrhage and infection, frequent complications of chemotherapy, are the chief causes of death.

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 of Prof. J.M. Chessells.)

Clinical Presentation

Signs and Symptoms

Acute myelogenous leukemia produces a leukemic infiltration of marrow and organs that causes cytopenia and diverse non-specific signs and symptoms, including fatigue, easy bruising, and bone pain. Many patients complain of flu-like 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 ( Fig. 23.2, A ). 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 ( Fig. 23.2, B ) occurs as a result of leukemic infiltration of these tissues. Infiltration of the CNS occurs in about 35% of the cases of AML with increased eosinophils (the M4Eo variant). Most of these patients are asymptomatic, but some present with meningeal signs and symptoms and symptoms associated with increased intracranial pressure. Skin lesions, consisting of collections of leukemic cells termed leukemia cutis, granulocytic sarcomas, and chloromas, may occur.

A, Acute myeloid leukemia presenting as bleeding and ecchymosis of the tongue in a 14-year-old patient. 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. The French-American-British (FAB) classification categorizes AML into eight subtypes ( Table 23.1 ). The World Health Organization (WHO) classification describes several subtypes that differ in terms of genetic abnormalities, evolution, and response to therapy.

Definition

Acute lymphocytic leukemia 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.

Epidemiology

In 2016, 6590 cases of ALL were estimated to occur in the United States. ALL occurs at an incidence of 1.7 in 100,000 and typically occurs in children. It accounts for about 25% of all neoplasms in children and 80% of leukemias in children. A remarkable peak of incidence occurs in children who are 2 to 3 years old, and 57% of cases are reported in persons younger than age 20 years (median age at diagnosis, 15 years). Boys are affected slightly more often than girls. About 20% of cases occur after age 55 years.

Etiology

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.

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. 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 about 70%.

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; one third presented with hemorrhagic episodes; and more than half of the patients with enlargement of the liver, spleen, and lymph nodes. A higher propensity toward CNS disease occurs with ALL compared with AML. Patients may present with cranial nerve deficiencies.

Laboratory Findings

Acute lymphocytic leukemia is diagnosed when massive replacement of the bone marrow space with leukemic blast cells is observed. Fig. 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 hemoglobin, 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.

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).

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 (≈1 trillion) more blast cells. After 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 1 trillion cells, and the patient would again show signs and symptoms of leukemia. This would constitute a short remission with relapse.

Chemotherapy for acute leukemia consists of three phases. The purpose of the first phase (induction) is to aggressively 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. 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.

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, when 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). 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 time of adults with AML was 40 days. Today, patients younger than 60 years have complete remission rates of 70% to 80% after induction therapy, but the overall survival rate is only 50% for those who go into complete remission and 26.6% overall. 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 ).

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 and 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%. Relapse can result in second remission in 75%, but fewer 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 male patients) is the testes.

Oral Manifestations of Acute Leukemia

Patients with leukemia 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 Fig. 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. 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 is specifically known as a granulocytic sarcoma or chloroma. These extramedullary tumors have been observed in the hard tissues (maxilla, palate) and soft tissues (gingiva, tongue, oral mucosa) of the maxillofacial complex.