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Hematologic Malignancies
Hematologic Malignancies Introduction
The hematologic malignancies are a diverse group of disorders that are frequently considered together because they consist of clonal expansions of hematopoietic cells. The cell of origin of many of the hematologic malignancies is known. The stage of differentiation of the transformed cell essentially determines the phenotype of the disorder. Before considering the types of hematologic malignancies, we review the normal differentiation pathway of hematopoietic cells.
Hematologic Malignancies
Introduction
Acute Leukemias
¬Classification
¬Treatment
¬Future Directions
Myelodysplasia
¬Pathogenesis
¬Classification
¬Treatment
¬Future Directions
Myeloproliferative Disorders
¬Chronic Myelogenous Leukemia
¬Polycythemia Vera
¬Essential Thrombocythemia
¬Myeloid Metaplasia with Myelofibrosis (MMMF)
Lymphoproliferative Disorders
¬Chronic Lymphocytic Leukemia
¬Hairy Cell Leukemia
¬Plasma Cell Dyscrasias
¬Monoclonal Gammopathy of Uncertain Significance
¬Multiple Myeloma
¬Waldenstrom's Macroglobulinemia
¬Amyloidosis
Malignant Lymphomas
¬Non-Hodgkin's Lymphomas
¬Hodgkin's Disease
Summary
References
Malignant Lymphomas
¬Non-Hodgkin's Lymphomas
¬Hodgkin's Disease
Summary
References
Figure 38.1 shows a version of the differentiation pathway from the lymphopoietic stem cell to the lymphoid lineages (T and B). There is also a stem cell (not shown) that matures to the myeloid lineages, giving rise to neutrophils, platelets, red cells, monocytes, eosinophils, and basophils. Steps of the differentiation pathway can be blocked, resulting in a clonal expansion of malignant cells. Thus, multiple myeloma represents as accumulation of the terminally differentiated B cell, whereas pre-B acute lymphocytic leukemia (ALL) represents a less differentiated B lymphocyte. Characteristic cell surface markers including the CD antigen system determine the immunophenotype of the malignant cell and assists in the diagnosis; this helps to differentiate morphologically similar entities. Thus, ALL can be differentiated from acute myelocytic leukemia (AML) by the presence of typical lymphoid cell-surface markers, such as CD10 and CD19. In many cases such distinctions have important therapeutic implications.
Hematologic malignancies disproportionately affect elderly patients. The disorders AML, chronic lymphocytic leukemia (CLL), and multiple myeloma all have characteristic patterns of increasing incidence with advancing age, such that the average age of onset of these diseases is 60 years of age or older. Additionally, other than with the acute leukemias, the clinical onset of hematologic malignancies is typically insidious, mimicking many other disease processes and frequently going unrecognized. As the name implies, many of the chronic malignancies can have an indolent or prolonged course. Elderly patients are frequently compromised from other comorbid diseases and in the past have not always ben-efited from interventions such as chemotherapy and radiotherapy because of the associated toxicities. More recently, we have made advances in tailoring therapy to the geriatric patient. More importantly, new approaches to treatment, such as immunotherapy and molecular- targeted therapy, have revolutionized our ability to successfully treat the elderly patient while avoiding significant toxicity.
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This section examines the acute leukemias (AML and ALL). Myelodysplastic syndromes that frequently evolve into leukemia are also considered. We discuss myeloproliferative disorders and lymphoproliferative disorders, including the lymphomas, the chronic leukemias, and the plasma cell dyscrasias. We emphasize new therapy developments that may impact responses and survival while offering less toxic and more tolerable treatment for the elderly patient.
Hematologic malignancies are cancers that affect blood, bone marrow, and lymph nodes. This classification includes various types of leukemia (acute lymphocytic [ALL], chronic lymphocytic [CLL], acute myeloid [AML], chronic myeloid [CML]), myeloma, and lymphoma (Hodgkin's and non-Hodgkin's [NHL]).
History
Although solid tumors such as breast malignancies were described and treated as early as 1500 BCE in ancient Egypt, the first description of a hematologic malignancy did not occur until 1832, following the introduction of an innovative achromatic microscope by Joseph Lister in 1830. Thomas Hodgkin, one of the most prominent pathologists of his time, used Lister's microscope to describe tissue abnormalities associated with an enlargement of lymphoid tissue, spleen, and liver. This form of lymphoma was later named for him by Samuel Wilks, who described the same disease 33 years later. Numerous physicians in the early 19th century had observed that some of their patients had abnormally high levels of white blood cells, leading them to call the associated condition weisses blut, or "white blood." The first definitive descriptions of leukemia came in 1844 from Rudolph Virchow, a German politician and physician with wide-ranging interests in cell biology, pathology, and anthropology. Myeloma was also first described in 1844, when Samuel Solly first documented the case of a patient with "mollities ossium" (soft bones). One year later, Henry Bence Jones found that the urine of a mollities ossium patient exhibited a peculiar thermal solubility caused by the presence of a protein that became known as Bence Jones protein. Ultimately, Bence Jones proteins were identified as free monoclonal immunoglobulin light chains. By 1900, J. H. Wright reported that myeloma tumors originated from plasma cells. Wright's patients may have been the first in whom X-rays demonstrated characteristic lytic lesions in the ribs.
Demographics of Hematologic Malignancies
Taken together, hematologic malignancies accounted for 9% of all newly diagnosed cancers in the United States last year.
As shown in the accompanying table, lymphomas (especially NHLs) are much more common than leukemias or myeloma.
With the exception of ALL and Hodgkin's lymphoma, these diseases tend to be associated with increasing age. This will be progressively more important with the rising average age of the U.S. population: the number of people who are >65 years old will double during the first third of the 21st century, as will the number of people >85 years old. In addition to having an increased incidence of hematologic cancers, older patients may have reduced tolerance for intensive therapy, underlining the importance of developing less toxic, targeted treatment approaches.
Hematologic Malignancies Summary
The hematologic malignancies are a diverse group of disorders that vary in clinical severity and response to treatment. Some are compatible with a long life expectancy, and others can produce a fulminant course rapidly leading to death. Treatment strategies generally result in significant morbidity, and for elderly patients with comorbid conditions, a careful analysis of options, including no treatment, is appropriate. Supportive care is improving, and elderly patients should benefit from improved understanding of the biology of many of these diseases. Molecularly targeted and immunologically targeted treatment may improve the ratio of benefit to toxicity for older patients.