The lymphomas, chronic lymphocytic leukemias, and plasma cell neoplasms are a group of entities that have in common an origin from mature lymphoid cells. However, in other respects, these tumors are remarkably varied in terms of their clinical presentation, behavior, molecular pathogenesis, treatment, and outcome. Historically, these tumors have been grouped according to their typical presentation and their clinical aggressiveness. This remains a useful way to think about these tumors, with the important caveat that even within a particular diagnostic category there is a range of clinical presentations and courses. In recognition of this, the current World Health Organization (WHO) classification of lymphoid neoplasms largely relies on objective pathologic and molecular features to establish specific diagnoses.

Tumors referred to as lymphomas most commonly present as a mass within lymph nodes or other secondary lymphoid tissues but also may arise in and affect the function of virtually any organ in the body. Lymphocytic leukemias, by definition, involve the bone marrow and peripheral blood at presentation but also commonly cause lymphadenopathy and splenomegaly. As was discussed in Chapter 19, these distinctions are not absolute; virtually all tumors referred to as lymphomas present on occasion with marrow and blood involvement, and leukemias sometimes present as lymphomatous masses. Lymphomas and lymphocytic leukemias also share a propensity to cause immune dysregulation, which gives rise to:

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  B symptoms (fever, night sweats, and weight loss).

  
  
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  Immunosuppression and susceptibility to infection.

  
  
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  Breakdown of immune tolerance, often leading to production of autoantibodies, particularly against red cells or platelets, and other manifestations of autoimmunity.

Plasma cell tumors have their own distinctive set of signs and symptoms, which are related to destructive bone lesions, kidney failure, and the deleterious effects of complete or partial immunoglobulins secreted by the tumor cells.

The complexity of neoplastic disorders of mature lymphocytes and plasma cells is daunting, rivaling (and reflecting) the complexity of the immune system itself. The most recent WHO classification of lymphoid neoplasms lists over 50 different types, many of which have fascinating biologic and clinical features but are too rare to merit discussion here. Instead, we will focus primarily on the more common tumors (listed in Table 22-1). This handful of neoplasms, which includes several non-Hodgkin lymphomas, chronic lymphocytic leukemia, Hodgkin lymphoma, and plasma cell neoplasms and related disorders, encompasses over 90% of human lymphoid tumors. A few uncommon disorders of exceptional pathogenic interest also will be mentioned.

In this chapter, we present a brief overview of the pathogenesis of lymphoid neoplasms that is relevant to many of the most common subtypes and then discuss the most common forms of non-Hodgkin lymphoma and chronic lymphocytic leukemia in detail. The uncommon T-cell tumors will be mentioned only briefly, and the very rare natural killer (NK) cell tumors (<1% of all lymphoid neoplasms) will not be covered. Hodgkin lymphomas and plasma cell neoplasms are discussed in subsequent chapters.

It is notable that all of the neoplasms listed in Table 22-1, except for a small subset of chronic lymphocytic leukemias, are derived from B lymphocytes that have passed through germinal centers. In contrast, tumors derived from T cells and NK cells are rare, collectively comprising no more than about 10% of lymphoid neoplasms. Thus, relative to T cells or NK cells, germinal center B cells are unusually prone to give rise to lymphoid neoplasms.

The susceptibility of germinal center B cells to transformation is likely related to their inherent genomic instability. Early stages of B- and T-cell development are similar; pre-B cells rearrange their immunoglobulin genes in the bone marrow, emerging as mature naïve B cells expressing immunoglobulin M (IgM), whereas pre-T cells rearrange their T-cell receptor genes in the thymus, emerging as naïve T cells expressing T-cell receptors. Once naïve B and T cells are activated by antigen, however, their paths diverge. Although activated T cells continue to express the same T-cell receptors that they were “born” with, activated B cells migrate into germinal centers and further diversify their immunoglobulin genes through somatic hypermutation and class switching.

Germinal centers are oblong structures found in lymph nodes and the spleen that contain a meshwork of antigen-presenting dendritic cells, small numbers of helper T cells, and scattered phagocytic macrophages (Fig. 22-1). Here, antigen-stimulated B cells begin to divide rapidly and turn on the expression of activation-induced cytosine deaminase, an enzyme that converts cytosine residues in DNA to uracil residues and is required for both somatic hypermutation and class switching (Fig. 22-2). Somatic hypermutation and class switching are essential elements of an effective humoral immune response but are both error prone. Many genes besides the immunoglobulin locus undergo hypermutation in germinal center B cells, although at a lower rate. Similarly, certain chromosomal translocations found in B-cell neoplasms appear to be mistakes that result, in part, from breaks in DNA that are induced during attempted class switching. Some genes, such as BCL-6, can be deregulated by either point mutations or chromosomal translocations (Fig. 22-2). Thus, the germinal center reaction is a double-edged sword, permitting effective humoral immunity but also placing germinal center B cells at high risk for mutations that can lead to malignant transformation.

Several viruses and a few bacterial infections have been established as cofactors in the development of specific lymphoid malignancies. The clearest associations are with the following agents:

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  Epstein-Barr virus (EBV).

  
  
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  Human herpesvirus-8 (HHV-8, also known as Kaposi sarcoma herpesvirus [KSHV]).

  
  
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  Human T-cell lymphotropic virus (HTLV-1).

  
  
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  Human immunodeficiency virus (HIV).

  
  
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  Helicobacter pylori.

EBV is a gamma herpes virus that plays an important etiologic role in several forms of non-Hodgkin lymphoma and Hodgkin lymphoma. Most humans are infected with EBV during their lives, usually in childhood or adolescence. Mature B cells express a receptor for EBV called CD21 on their cell surfaces that permits the virus to enter the cell. Once internalized, EBV produces a number of viral proteins that immortalize B cells and cause them to proliferate in an uncontrolled fashion. In healthy people, T cells mount an immune response to viral antigens displayed on the surface of infected B cells. Cytokines produced by these T cells are responsible for the clinical syndrome known as infectious mononucleosis (Chapter 18). The host T-cell response kills most infected B cells, but a small number of cells turn off the expression of most viral proteins and escape immune destruction, creating a long-lived pool of latently infected B cells. If such cells are activated at some later time by antigen, they may again turn on the expression of EBV proteins that lead to B-cell transformation.

EBV contributes to the development of lymphoid neoplasms in several ways. The best understood is in the context of T-cell immunodeficiency, such as occurs following bone marrow transplantation or in patients treated with high doses of immunosuppressive drugs (eg, organ transplant recipients). If T-cell immunity falls below a certain threshold, lurking EBV-infected B cells may become activated and begin to proliferate in an uncontrolled fashion, giving rise to tumors that may occur in virtually any tissue. These EBV-positive tumors often can be brought under control by lowering the dose of immunosuppressive drugs (although at the risk of organ rejection or graft-versus-host disease, depending on the clinical setting) and by treatment with rituximab, an antibody specific for the B-cell antigen CD20. Other EBV-positive lymphoid tumors include subsets of Burkitt lymphoma, diffuse large B-cell lymphomas (particularly in the elderly), Hodgkin lymphoma, and rare T-cell and NK-cell tumors. The precise role of EBV in these lymphomas is less clear-cut, but molecular analyses have consistently shown that the EBV genomes within the tumor cells are monoclonal, meaning that all of these tumors originate from a single EBV-infected cell, a finding that is taken as strong evidence of a direct pathogenic role for the virus.

HHV-8, another human herpesvirus, is strongly associated with primary effusion lymphoma, a rare, aggressive, B-cell lymphoma that arises within chronic effusions, typically in the pleural or peritoneal spaces. Defective immunity sets the stage for these tumors, which are largely confined to HIV-infected patients and the elderly. Many (but not all) of these tumors are co-infected with EBV, a unique example of two transforming viruses collaborating to cause a human cancer. HHV-8 is also the cause of Kaposi sarcoma, another tumor largely confined to immunosuppressed individuals.

HTLV-1 is the only retrovirus directly associated with a human cancer, a rare tumor called adult T-cell leukemia/lymphoma. HTLV-1 is endemic in southeast Japan, certain parts of the Caribbean, western Africa, and South America. The virus infects and persists in CD4-positive T cells as a provirus integrated in the host cell DNA. After an asymptomatic period that usually spans decades, a small fraction of infected individuals develop adult T-cell leukemia/lymphoma, an aggressive tumor of HTLV-1–infected CD4-positive T cells. The mechanism of T-cell transformation in the unfortunate few who develop tumors is not understood.

Although HIV also infects CD4-positive T cells, it is associated with a greatly heightened risk of B-cell lymphomas. Early in the course of HIV infection, T-cell dysregulation produces a marked hyperplasia of germinal center B cells, resulting in generalized lymphadenopathy. Untreated, late-stage HIV infection with severe T-cell immunodeficiency (AIDS) is associated with a high incidence of aggressive EBV-positive B-cell lymphomas, which usually occur in extranodal sites such as the brain. These late-stage EBV-positive tumors are mostly prevented by antiretroviral therapy, but even in the era of highly effective therapy, HIV-positive patients have an increased incidence of EBV-negative, B-cell lymphomas. It may be that the germinal center B cells that proliferate extensively in early HIV infection accumulate oncogenic mutations that increase the risk of lymphoma.

Helicobacter pylori is a bacterium that colonizes the mucous layer overlying the pyloric epithelium of the stomach. It induces both an acute and chronic immune response and is an important cause of peptic ulcer. It is also strongly associated with gastric extranodal marginal zone lymphoma, a type of B-cell lymphoma that appears to be caused by chronic inflammation. The process begins as a straightforward inflammatory reaction that produces a gastritis. With persistence of the process and occurrence of mutations that give certain responding B cells a growth or survival advantage, a clonal B-cell neoplasm arises. Initially, however, this B-cell clone remains dependent on T helper cells that are specific for Helicobacter antigens. At this point, the tumor cannot grow beyond the stomach and, remarkably, often regresses completely if H. pylori is eliminated with antibiotics. Eventually, however, the tumor may acquire additional mutations that relieve the dependency on T-cell help; such tumors are refractory to antibiotic therapy and can spread to extragastric sites. Similar extranodal marginal zone lymphomas occur in tissues involved by chronic autoimmune reactions (such as the thyroid gland in Hashimoto thyroiditis and the salivary gland in Sjögren syndrome), further supporting the idea that long-standing immune stimulation can lead to certain lymphomas.

Although the infectious agents and unique features of germinal center B cells described earlier are important factors, the causes of lymphoid neoplasms remain incompletely understood. Occasional families have multiple afflicted members, suggesting the existence of genetic factors. Of concern, the incidence of lymphoma is increasing in the United States, particularly in the elderly, presumably due to currently unknown environmental factors.

We will now turn to the common forms of non-Hodgkin lymphomas and lymphocytic leukemia, beginning with the more indolent disorders.