Definition and Etiology
Non-Hodgkin’s lymphoma (NHL) and Hodgkin’s lymphoma (HL) are neoplasms arising from cells of the lymphoid lineage. T and B cells originate in the bone marrow, migrate to the thymus or peripheral lymphoid tissues respectively, and develop into highly specialized mediators of the adaptive immune response. Generating and maintaining this dynamic repertoire of cells is a complex error-prone process. Lymphoid cells are at various times susceptible to acquired genetic defects, direct viral infection, chronic stimulation by antigen, and effects of generalized host immunodeficiency—four dynamic factors involved in lymphomagenesis. The heterogeneity of lymphomas, reflecting the complexity of the human immune system, implies that a number of genetic and acquired risk factors play a role in pathogenesis.
Lymphomas are divided into two major groups, NHL and HL, based on a range of pathologic and clinical features. The incorporation of genetic and immunologic characteristics into lymphoma diagnosis is a recent advancement, proposed by the 1994 Revised European-American Classification of Lymphoid Neoplasms (REAL) classification divided lymphomas into B cell neoplasms, T cell neoplasms, and Hodgkin’s disease, with clinically relevant categories.1 It also served as the basis for the ensuing World Health Organization (WHO) classification of lymphoid neoplasms. The many WHO subtypes of NHL are made more manageable via grouping into indolent, aggressive, or highly aggressive categories based on their natural history (Box 1). HL encompasses two main categories: classic HL (with four further subgroups) and nodular lymphocyte-predominant HL. Classic HL includes nodular-sclerosis, mixed-cellularity, lymphocyte-rich, and lymphocyte-depleted subgroups. The WHO classification, though complex and continually evolving, establishes a common language for researchers and clinicians and is key to collaborative research aimed at curing lymphoma.
Box 1 Simplified World Health Organization Classification of Non-Hodgkin’s Lymphoma by Clinical Behavior
Indolent
B Cell
Follicular lymphoma (grades I and II)
Chronic lymphocytic leukemia / small lymphocytic lymphoma
Marginal zone: extranodal, mucosa-associated lymphoid tissue (MALT), nodal, splenic
Plasma cell myeloma
Plasmacytoma
Hairy cell leukemia
T Cell
Mycosis fungoides
Sézary syndrome
Aggressive
B Cell
Diffuse large B cell lymphoma and variants
Follicular lymphoma (grade III)
Mantle cell*
T Cell
Peripheral T cell
Anaplastic large cell
Highly Aggressive
Burkitt’s lymphoma
Precursor B/T lymphoblastic
*Mantle cell lymphoma may also behave in an indolent fashion.
Back to Top
Prevalence and Risk Factors
According to the National Cancer Institute and Centers for Disease Control and Prevention SEER database, lymphoma was diagnosed in about 74,340 people in the United States in 2008, giving an age-adjusted incidence rate of 22.2 per 100,000 per year.2 In general, NHL is increasing in incidence (especially diffuse large B cell lymphoma [DLBCL]), though mortality among those affected with NHL has decreased. HL is much less common than NHL, accounting for about one tenth of all lymphoma cases; its annual incidence is 2.8 per 100,000. The prevalence of lymphomas tends to be much higher than their incidence, given their natural history and availability of effective therapies. For example, the U.S. prevalence of HL was 156,000 (patients with HL or a history of HL) as of January 1, 2005.
As noted, risk factors for the development of lymphoma are not fully understood. Environmental associations with pesticides, agricultural chemicals, and hair dyes have been inconsistently identified. Reports of a protective effect of sun exposure in the development of lymphoma have been conflicting. On the other hand, known risk factors for lymphoma include systemic immunosuppression due to inherited conditions, HIV infection, or medications.
Back to Top
Pathophysiology and Natural History
The natural history of a given NHL is reflected in its conceptual grouping (e.g., indolent, aggressive, highly aggressive), although heterogeneity even within specific subtypes is observed. This heterogeneity is due to the broad spectrum of genetic changes, cell-signaling aberrations, and features of the tumor microenvironment that can affect the behavior of an individual lymphoma.
Although some population studies have found a higher risk of lymphoma in first-degree relatives of probands, defining the exact inherited genetic lesions has proved difficult.3 In contrast, genetic abnormalities acquired during early lymphocyte development have been clearly implicated in lymphomagenesis. The most noteworthy include chromosomal translocations during immunoglobulin (IG) gene rearrangement, a complex process that normally provides lymphocytes the diversity of antigen recognition needed for effective host defense. Expression of the viral gene products by host cell machinery contributes to the pathogenesis of HLs and lymphoproliferative disorders in immunosuppressed patients following organ transplant, the most well described being from infection with Epstein-Barr virus (EBV).
Infection by nonviral microbes can also lead to lymphoma, but not by direct infection of lymphocytes. Instead, chronic infection with organisms such as Helicobacter pylori is thought to lead to ongoing antigenic stimulation in lymphoid tissues, creating an environment ripe for selection of a malignant clone. Such stimulation can also follow immune attack on self-antigens, possibly explaining the link between some lymphomas and autoimmune conditions such as rheumatoid arthritis and systemic lupus erythematosis.
Inborn or acquired immunodeficiency is associated with a higher risk of lymphoma. Immunosuppression by HIV dramatically increases the risk for the development of lymphoma which can be reduced by anti-retroviral therapy. The interaction among these etiologic factors, and in particular the cellular interactions among immune and tumor cells (in the tumor microenvironment), are important topics of research in lymphoma pathogenesis and therapy.
Non-Hodgkin’s Lymphoma
Indolent Lymphomas
Follicular lymphoma (FL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) are the most common indolent lymphomas. Survival from diagnosis of indolent lymphoma is generally measured in years. Although radiation therapy can cure early-stage indolent lymphomas, advanced-stage disease is generally incurable. Despite initial chemosensitivity, such patients tend to face a continual pattern of relapse and treatment-related morbidity until death. Data from Stanford University published in 1984 showed that some asymptomatic patients with advanced FL had no decrement in survival following an initial watch-and-wait approach with spontaneous remission in a minority of cases.4
Based on these factors and the lack of curative therapy, treatment for FL was historically delayed until emergence of disease-related symptoms or organ compromise, and median survival was 8 to 10 years from diagnosis. However, newer treatment approaches using monoclonal antibodies with initial chemotherapy, and autologous stem cell transplantation for patients in relapse, may be prolonging survival and altering the natural history of FL. This has given rise to therapeutic optimism and prompted some to initiate treatment in some groups of patients with newly diagnosed lymphoma who may have been managed expectantly in the past.
In FL, the defining genetic lesion is the translocation between chromosomes 14 and 18 t(14;18), seen in the majority of cases (≥70%). As is typical for lymphomas, this translocation juxtaposes a regulatory sequence next to a normal, intact gene involved in cellular processes. (This contrasts with most leukemias, in which translocations—such as translocation 9;22 in chronic myelogenous leukemia—create a unique fusion gene and protein bearing unique oncogenic properties.) Translocation 14;18 places the BCL2 gene on chromosome 18 under the control of a key regulatory region (the IG heavy chain [IgH] enhancer sequence) on chromosome 14. This results in the overexpression of BCL2, a protein that renders cells resistant to programmed cell death (apoptosis). Affected cells are, in a sense, excessively durable: They defy the usual checks and balances controlling B lymphocyte growth, and they persist in the lymph node to face chronic antigenic stimulation and ongoing mutagenesis processes that can eventually bring about a malignant clone.
The fact that this translocation exists in a large fraction of healthy adults is evidence that further mutagenic events are crucial for lymphomagenesis. Other notable lesions in indolent lymphomas include t(11;14) in mantle cell lymphoma (causing increased cyclin D expression, and thus cell cycle progression), the deletion of chromosome 13q14 in CLL/SLL (a region containing suppressive micro-RNA that normally silences BCL2)5 and the t(11;18) in extranodal marginal zone lymphomas (producing a true fusion gene that also affects apoptosis) (Table 1). It should be noted that mantle cell lymphoma can behave in an indolent or aggressive manner, and current studies favor high-intensity induction chemotherapy for patients requiring treatment in an effort to improve poor outcomes.