INTRODUCTION
LEARNING OBJECTIVES
After studying this chapter you should know:
The major categories of hematologic malignancies.
The types of tests that are used to diagnose hematologic malignancies.
The importance of clonality as a defining feature of these diseases.
Just as studies of hematopoiesis have been at the forefront of stem cell biology, rapid advances in our understanding of the pathogenesis of hematopoietic and lymphoid tumors have brought us to the dawn of a new molecular era of cancer diagnosis and therapy. Remarkably, in the not-too-far distant future it will become possible to routinely sequence the entire genome of blood cancers, providing us with a detailed view of the genetic changes that underlie these tumors. These advances will undoubtedly revolutionize how we diagnose and treat patients with these diseases and other cancers as well.
This accelerating rate of progress is exhilarating for workers in the field, but it creates challenges for students who are trying to grasp the basics (and authors who are trying to help them do so!). With this in mind, this chapter and the following one are meant to serve as a primer for students new to these fascinating and clinically important diseases. Here, we provide an overview of the classification and diagnosis of hematologic malignancies. In Chapters 20, 21, 22, 23, 24 we delve into the pathogenesis of these malignancies, emphasizing molecular insights that have already impacted the diagnosis and treatment. In these chapters we provide a more detailed look at the pathophysiology, clinical features, and treatment of the major types of hematologic malignancy, which include some of the most common cancers of children and adults.
NOMENCLATURE OF HEMATOLOGIC MALIGNANCIES
The names and descriptive terms used for the various hematologic malignancies reflect their origin and usual clinical behavior. Tumors composed of cells of the myeloid series (granulocytes, red cells, platelets, and their progenitors) are referred to as myeloid, myelogenous, or myeloproliferative, whereas tumors composed of lymphocytes or their progenitors are variously termed lymphoid, lymphocytic, lymphoblastic, or lymphoproliferative. Leukemia (literally, white blood) is applied to neoplasms that typically involve the bone marrow and the peripheral blood, whereas lymphoma is used to describe lymphoid tumors that commonly present as masses within lymph nodes or other soft tissues. Some lymphomas are named based on the resemblance of the tumor cells to a normal counterpart; for example, the malignant B cells of follicular lymphoma closely resemble the normal cells found within the B-cell follicles (also commonly referred to as germinal centers) of lymph nodes. Other descriptors relate to the natural history of the disease in question. Acute leukemias, if untreated, are lethal within weeks to several months, whereas chronic leukemias may be compatible with survival for many years without treatment.
CLASSIFICATION OF HEMATOLOGIC MALIGNANCIES
Classification systems are meant to provide a common language for the diagnosis and treatment of specific disease entities. As recently as 20 years ago, few areas of medicine were as contentious and confused as the classification of hematologic malignancies. Diagnoses were then based largely on clinical features and the morphologic appearance of tumor cells, criteria that are inadequate for classifying the diversity of hematologic malignancies that we now recognize molecularly.
In 1994, this picture began to change with the advent of classification that subdivided lymphoid tumors into distinct entities based on clinical features, microscopic appearance, and objective markers, including lineage-specific proteins and tumor-specific genetic aberrations. This proved so successful that the same approach was subsequently extended to myeloid neoplasms. There is now wide acceptance of a classification system, shown in Table 19-1, that sorts hematologic neoplasms based on their lineage and presumed cell of origin. The “cell of origin” concept is particularly important in the classification of lymphoid neoplasms, many of which are composed of cells that appear to be the malignant counterparts of some normal stage of B or T lymphocyte differentiation.
| Myeloid neoplasms | |
| Subtype | Putative cell of origin |
Acute myeloid leukemia (AML) AML with recurrent genetic aberrations AML without recurrent genetic aberrations AML following cytotoxic therapy | Early myeloid progenitor |
Chronic myeloproliferative disorders Chronic myelogenous leukemia Polycythemia vera Essential thrombocythemia Chronic eosinophilic leukemia Primary myelofibrosis | Hematopoietic stem cell or early myeloid progenitor |
| Myelodysplastic syndromes | Early myeloid progenitor |
| Lymphoid neoplasms | |
| Immature B-cell and T-cell tumors | |
B-cell acute lymphoblastic leukemia/lymphoma T-cell acute lymphoblastic leukemia/lymphoma | Early B-cell progenitor Early T-cell progenitor |
| Mature B-cell tumors | |
Chronic lymphocytic leukemia/small lymphocytic lymphoma Mantle cell lymphoma Follicular lymphoma Burkitt lymphoma Diffuse large B-cell lymphoma | Post-germinal center B cell Naïve B cell Germinal center B cell Germinal center B cell Germinal center or post-germinal center B cell |
| Plasma cell tumors and related entities | |
Multiple myeloma Lymphoplasmacytic lymphoma | Post-germinal center B cell Mature B-cell |
| Mature T-cell and natural killer cell tumors | Mature T-cell or natural killer cell |
| Hodgkin lymphoma | Germinal center or post-germinal center B cell |
The neoplasms recognized in the World Health Organization classification of hematologic malignancies fall into five broad clinicopathologic categories, each containing a number of entities:
Acute leukemias are tumors in which early myeloid or lymphoid progenitors (blasts) accumulate in the bone marrow and to varying degrees spill into the peripheral blood and infiltrate other tissues. They are believed to arise from early myeloid or lymphoid progenitors. Leukemic blasts are so primitive as to be nonfunctional and tend to displace or suppress the production of normal hematopoietic elements in the marrow. As a result, most patients present with symptoms related to pancytopenia.
Chronic myeloproliferative disorders are tumors that arise in the bone marrow and most commonly lead to the increased production of one or more types of mature myeloid cells. They may arise from early myeloid progenitors or hematopoietic stem cells. Most symptoms initially stem from the hyperproliferation of bone marrow progenitors and increased numbers of red cells, granulocytes, and/or platelets in the peripheral blood and the spleen.
Myelodysplastic syndromes are a poorly understood, heterogeneous group of myeloid tumors in which the maturation of bone marrow progenitors is abnormal (dysplastic) and ineffective. The cell of origin is believed to be an early myeloid progenitor. Patients present with symptoms related to one or more cytopenias and follow a highly variable course.
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