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. The means for generating and maintaining this mobile, interactive, and highly plastic repertoire of cells are complex and prone to error. Lymphoid cells are at various times susceptible to genetic errors, direct viral infection, chronic stimulation by antigen, and effects of generalized host immunodeficiency—four dynamic factors involved in lymphomagenesis. However, it has proved difficult to identify consistent etiologic factors in families or populations. The heterogeneity of lymphomas, reflecting the complexity of the human immune system, implies that a number of genetic and acquired risk factors interact in their 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 (known as the REAL classification).¹ Dividing lymphomas into B cell neoplasms, T cell neoplasms, and Hodgkin’s disease, the REAL classification was validated and shown to be clinically relevant by subsequent studies. 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.

PREVALENCE AND RISK FACTORS

According to the National Cancer Institute and Centers for Disease Control and Prevention (CDC) 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), 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. On the other hand, known risk factors for lymphoma include systemic immunosuppression due to inherited conditions, HIV infection, or medications.

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. These include chromosomal translocations and the accidental mutation of bystander genes during immunoglobulin gene remodeling, a complex process providing lymphocytes the diversity needed for effective host defense. Expression of the virus’s genetic program by cell machinery (as occurs in chronic Epstein-Barr virus infection) contributes to the pathogenesis of HLs and lymphoproliferative disorders in immunosuppressed patients following organ transplant.

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. 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. However, although radiation therapy can cure early-stage indolent lymphomas, advanced-stage forms have classically been considered 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 follicular lymphoma had no decrement in survival following an initial watch-and-wait approach.⁴ Data from the same group have also shown a rate of spontaneous remission in up to 20% of patients with FL.

Based on these factors and the lack of curative therapy, treatment for follicular lymphoma 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 follicular lymphoma. 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 follicular lymphoma, the classic 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 immunoglobulin 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.

Table 1 Genetic Pathophysiology of Selected Indolent NHL Subtypes

Aggressive and Highly Aggressive lymphomas

Survival of patients with aggressive lymphomas is measured in months without treatment, and patients with untreated highly aggressive lymphomas can face even shorter survival (weeks). On the other hand, the curability of a number of these patients is well known, and survival rates are improving for many subtypes with modern treatment regimens. Given their tendency for rapid progression and the availability of effective chemotherapy, aggressive and highly aggressive lymphomas are treated immediately upon diagnosis and at times require urgent hospitalization and tumor lysis precautions.

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of aggressive lymphoma. About half of all patients with DLBCL achieve long-term disease-free survival after initial therapy, and relapses after more than 5 years are uncommon. Genetic errors involving BCL6 (a transcription factor), BCL2 (an antiapoptotic protein) and FAS (CD95, a TNF-family receptor), are often linked to the development and behavior of DLBCL.⁶ However, individual lesions fail to explain the pathologic and clinical heterogeneity of DLBCL. To investigate this variability, investigators have applied molecular tools including gene expression profiling to DLBCL tumor samples, which examines tumor mRNA expression patterns. In one study, this approach identified three groups of patients whose gene-expression patterns suggested a distinct cell of origin of their tumor.⁷ These groups had significantly different prognoses, and the gene-expression technique provided prognostic information surpassing that gained using the clinically based International Prognostic Index (IPI, discussed later). However, the challenges for expression profiling are to isolate true driver mutations in lymphomagenesis and to prove them valuable in guiding clinical decisions (such as selection of initial therapy) via prospective trials.

Aggressive T cell lymphomas are rarer and less well understood than their B cell counterparts, and they generally have a poorer outcome. Only about one in three patients with advanced-stage nodal T cell lymphomas survives this diagnosis at 5 years. An exception is the group of ALK-positive (anaplastic lymphoma kinase–staining) T cell anaplastic large cell lymphomas, which occur in younger patients and have a more favorable prognosis. These lymphomas usually have a translocation between chromosomes 2 and 5, causing markedly increased ALK expression and altered intracellular signaling involved in disease pathogenesis.

Highly aggressive lymphomas, typified by adult Burkitt’s lymphoma and adult B and T cell lymphoblastic leukemia or lymphomas, can require immediate hospitalization and are some of the fastest-growing malignancies known. These diseases are in general highly sensitive to combination chemotherapy, and high cure rates (surpassing 60% in the highest-risk patients) are possible. In contrast to the heterogeneity of DLBCL, the highly aggressive Burkitt lymphoma is defined by the deregulation of a single transcription factor, the myc protein. Myc deregulation is observed in more than 90% of cases to be due to a translocation between chromosome 8 (containing the c-myc gene) and one of various partner chromosomes, most commonly chromosome 14. This results in widespread deregulation of genes involved in cell proliferation.

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