eMedicine Specialties > Hematology > Stem Cells and Disorders

Lymphoma, Non-Hodgkin

Author: Sanjay Vinjamaram, MD, MPH, Fellow in Hematology/Oncology, Roswell Park Cancer Institute
Coauthor(s): Francisco J Hernandez-Ilizaliturri, MD, Assistant Professor, Departments of Medicine and Immunology, Roswell Park Cancer Institute, State University of New York at Buffalo; Dolores A Estrada, MD, Consulting Staff, Hematology-Oncology, Cancer Care Specialists of Central Illinois; Lakshmi Rajdev, MD, Site Director, Jacobi Medical Center; Assistant Professor, Department of Radiation Oncology, Albert Einstein College of Medicine; Joseph A Sparano, MD, Professor of Medicine, Albert Einstein College of Medicine/Cancer Center; Program Director, Director of Breast Medical Oncology, Department of Internal Medicine, Division of Oncology, Montefiore Medical Center
Contributor Information and Disclosures

Updated: Sep 2, 2009

Introduction

Background

The term lymphoma describes a heterogenous group of malignancies with different biology and prognosis. In general lymphomas are divided into 2 large groups of neoplasms, namely non-Hodgkin lymphoma (NHL) and Hodgkin disease. About 85% of all malignant lymphomas are NHLs. The median age at diagnosis is the sixth decade of life, with some exceptions. (Burkitt lymphoma and lymphoblastic lymphoma occur in younger patients.) NHL includes many clinicopathologic subtypes, each with distinct epidemiologies; etiologies; morphologic, immunophenotypic, genetic, and clinical features; and responses to therapy.

Currently, several NHL classification schemas exist, reflecting the growing understanding of the complex diversity of the NHL subtypes. The Working Formulation, originally proposed in 1982, classified and grouped lymphomas by morphology and clinical behavior (ie, low, intermediate, or high grade). In the 1990s, the Revised European-American Lymphoma (REAL) classification attempted to apply immunophenotypic and genetic features in identifying distinct clinicopathologic NHL entities. The World Health Organization (WHO) classification further elaborates upon the REAL approach. This classification divides NHL into those of B-cell origin and those of T-cell and NK-cell origin.

For clinical oncologists, the most practical way of sorting the currently recognized types of NHL is according to their predicted clinical behavior; each classification schema contributes to a greater understanding of the disease, which dictates prognosis and treatment.

Pathophysiology

NHLs are tumors originating from lymphoid tissues, mainly of lymph nodes. Various neoplastic tumor cell lines correspond to each of the cellular components of antigen-stimulated lymphoid follicles.

NHL represents a progressive clonal expansion of B cells or T cells and/or natural killer (NK) cells arising from the accumulation of genetic lesions that affect proto-oncogenes or tumor suppressor genes, resulting in cell immortalization. These oncogenes can be activated by chromosomal translocations (ie, the genetic hallmark of lymphoid malignancies), or tumor suppressor loci can be inactivated by chromosomal deletion or mutation. In addition, the genome of certain lymphoma subtypes can be altered with the introduction of exogenous genes by various oncogenic viruses. Several cytogenetic lesions are associated with specific NHLs, reflecting the presence of specific markers of diagnostic significance in subclassifying various NHL subtypes.

Most NHLs are of B-cell origin (almost 85%); only 15% are derived from T/NK cells, and the small remainder stem from macrophages. These tumors are characterized by the level of differentiation, the size of the cell of origin, the origin cell's rate of proliferation, and the histologic pattern of growth. For many of the B-cell NHL subtypes, the pattern of growth and cell size may be important determinants of tumor aggressiveness. Tumors that grow in a nodular pattern, which vaguely recapitulate normal B-cell lymphoid follicular structures, are generally less aggressive than lymphomas that proliferate in a diffuse pattern. Lymphomas of small lymphocytes generally have a more indolent course than those of large lymphocytes, which may have intermediate-grade or high-grade aggressiveness. However, some subtypes of high-grade lymphomas are characterized by small cell morphology.

Frequency

United States

The American Cancer Society estimated that approximately 63,190 new cases of NHL would be diagnosed in 2007. Since the early 1970s, the incidence rates of NHL have nearly doubled. Although some of this increase may be attributable to earlier detection (resulting from improved diagnostic techniques and access to medical care), or possibly to HIV-associated lymphomas, for the most part the rise is unexplained.

International

NHL is the most prevalent hematopoietic neoplasm, representing approximately 4% of all cancer diagnoses and ranking seventh in frequency among all cancers. NHL is more than 5 times as common as Hodgkin disease.

Mortality/Morbidity

• Of the estimated 63,190 new cases of NHL in the United States in 2007, approximately 18,660 people are expected to die from the disease. The 5-year relative survival rate of patients with NHL is approximately 63%. Of interest, the survival rate for patients with Non-Hodgkin lymphomas has steadily improved over the last 2 decades. The improvement in medical and nursing care, development of novel therapeutic strategies (ie, monoclonal antibodies), validation of biomarkers of response, and the implementation of tailored treatment are some of the factors that have modified the life expectancy of patients with NHL.
• The potential for cure varies among the different histological subtypes and directly relates to the stage at presentation and patient response to initial therapy.
• In general, low-grade lymphomas are indolent tumors associated with a predicted median survival time of 5-10 years. Intermediate-grade and high-grade lymphomas are more aggressive but are more responsive to chemotherapy. They are associated with a predicted median survival time of 2-5 years and less than 2 years (unless cure is achieved), respectively.

Race

Incidence varies with race; white people have a higher risk than black and Asian American people.

Sex

In general, incidence is slightly higher in men than in women, with a male-to-female ratio of approximately 1.4:1, but the ratio may vary depending on the subtype of NHL; for example primary mediastinal diffuse large B-cell lymphoma occurs more frequently in females than in males.

Age

• The median age at presentation for all subtypes of NHL is older than 50 years, except for patients with high-grade lymphoblastic and small noncleaved lymphomas, which are the most common types of NHL observed in children and young adults.
• At diagnosis, low-grade lymphomas account for 37% of NHLs in patients aged 35-64 years but account for only 16% of cases in patients younger than 35 years. Low-grade lymphomas are extremely rare in children.

Clinical

History

In general, the clinical manifestations of patients with NHL depend on various factors such as the location of the lymphomatous process, the rate of tumor growth, and the function of the organ being compromised or displaced by the malignant process. 

The Working Formulation classification groups the subtypes of non-Hodgkin lymphoma (NHL) by clinical behavior, that is, low-grade, intermediate-grade, and high-grade. Because the Working Formulation is limited to classification based upon morphology, it cannot encompass the complex spectrum of NHL disease, excluding important subtypes such as mantle cell lymphoma or T/NK lymphomas. However, it continues to serve as a basis for understanding the clinical behavior of groups of NHLs.

• Low-grade lymphomas
• Peripheral adenopathy that is painless and slowly progressive is the most common clinical presentation in these patients.
• Spontaneous regression of enlarged lymph nodes can occur in low-grade lymphoma, potentially causing confusion with an infectious condition.
• Primary extranodal involvement and B symptoms (ie, temperature >38°C, night sweats, weight loss >10% from baseline within 6 mo) are not common at presentation, but they are common in patients with advanced, malignant transformation (ie, evolution from a low-grade to an intermediate- or high-grade lymphoma) or end-stage disease.
• Bone marrow is frequently involved and may be associated with cytopenia or cytopenias.¹
• Fatigue and weakness are more common in patients with advanced-stage disease.
• Intermediate- and high-grade lymphomas
• These types of lymphomas cause a more varied clinical presentation.
• Most patients present with adenopathy.
• More than one third of patients present with extranodal involvement; the most common sites are the GI tract (including the Waldeyer ring), skin, bone marrow, sinuses, genitourinary (GU) tract, thyroid, and CNS.
• B-symptoms are more common, occurring in approximately 30-40% of patients.
• Lymphoblastic lymphoma, a high-grade lymphoma, often manifests with an anterior-superior mediastinal mass, superior vena cava (SVC) syndrome, and leptomeningeal disease with cranial nerve palsies.
• Patients with Burkitt lymphoma (occurring in the United States) often present with a large abdominal mass and symptoms of bowel obstruction.
• Obstructive hydronephrosis secondary to bulky retroperitoneal lymphadenopathy obstructing the ureters can also be observed in these patients.
• Primary CNS lymphomas are high-grade neoplasms of B-cell origin. Most lymphomas originating in the CNS are large cell lymphomas or immunoblastomas, and they account for 1% of all intracranial neoplasms. These lymphomas are more commonly observed in patients who are immunodeficient because of conditions such as Wiskott-Aldrich syndrome, transplantation, or AIDS.²

Physical

• Low-grade lymphomas
  • Peripheral adenopathy
  • Splenomegaly: Splenomegaly is observed in approximately 40% of patients; the spleen is rarely the only involved site at presentation.
  • Hepatomegaly
• Intermediate- and high-grade lymphomas
  • Rapidly growing and bulky lymphadenopathy
  • Splenomegaly
  • Hepatomegaly
  • Large abdominal mass: This usually occurs in Burkitt lymphoma.
  • Testicular mass
  • Skin lesions: Lesions are associated with cutaneous T-cell lymphoma (mycosis fungoides), anaplastic large-cell lymphoma, and angioimmunoblastic lymphoma.³
  • Chest radiograph: The chest radiograph may demonstrate a bulky mediastinal mass, which is associated with primary mediastinal large B-cell lymphoma or lymphoblastic lymphoma.

Causes

• Chromosomal translocations and molecular rearrangements play an important role in the pathogenesis of many lymphomas and correlate with histology and immunophenotype.
• t(14;18)(q32;q21): This translocation is the most common chromosomal abnormality associated with NHL. This translocation occurs in 85% of follicular lymphomas and 28% of higher-grade NHLs. This translocation results in the juxtaposition of the bcl -2 apoptotic inhibitor oncogene at chromosome band 18q21 to the heavy chain region of the immunoglobulin (Ig) locus within chromosome band 14q32.
• t(11;14)(q13;q32): This translocation has a diagnostic nonrandom association with mantle cell lymphoma. This translocation results in the overexpression of bcl -1 (cyclin D1/PRAD 1), a cell-cycle regulator on chromosome band 11q13.
• 8q24 translocations: The 8q24 translocations lead to c-myc dysregulation. This is frequently observed in high-grade small noncleaved lymphomas (Burkitt and non-Burkitt types), including those associated with HIV infection.
• t(2;5)(p23;q35): This translocation between the nucleophosmin (NPM) gene and the anaplastic lymphoma kinase (ALK1) gene results in the expression of an aberrant fusion protein found in a majority of anaplastic large cell lymphomas.
• t(11;18)(q21;q21) and t(1;14)(p22;132): Two chromosomal translocations are associated with mucosa-associated lymphoid tissue (MALT) lymphomas. The more common (ie, t[11;18][q21;q21]) translocates the apoptosis inhibitor AP12 gene with the MALT1 gene, resulting in the expression of an aberrant fusion protein. The other translocation,  t(1;14)(p22;132), involves the translocation of the bcl -10 gene to the immunoglobulin gene enhancer region.
• Some viruses are implicated in the pathogenesis of NHL, probably because of their ability to induce chronic antigenic stimulation and cytokine dysregulation, which leads to uncontrolled B- or T-cell stimulation, proliferation, and lymphomagenesis. These viruses include the following:
• Epstein-Barr virus (EBV) is a DNA virus that is associated with Burkitt lymphoma (especially the endemic form in Africa), Hodgkin disease, lymphomas in immunocompromised patients (eg, from HIV infection,² organ transplantation), and sinonasal lymphoma.
• Human T-cell leukemia virus type 1 (HTLV-1) causes a latent infection via reverse transcription in activated T-helper cells. This virus is endemic in certain areas of Japan and the Caribbean islands, and approximately 5% of carriers develop adult T-cell leukemia or lymphoma.
• Hepatitis C virus (HCV) is associated with the development of clonal B-cell expansions and certain subtypes of NHL (ie, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia), especially in the setting of essential (type II) mixed cryoglobulinemia.
• Kaposi sarcoma–associated herpesvirus (KSHV) is associated with body cavity–based lymphomas in patients with HIV infection and in patients with multicentric Castleman disease.
• Environmental factors linked to the development of NHL include chemicals (eg, pesticides, herbicides, solvents, organic chemicals, wood preservatives, dusts, hair dye), chemotherapy, and radiation exposure.
• Congenital immunodeficiency states (eg, severe combined immunodeficiency disease [SCID], Wiskott-Aldrich syndrome), acquired immunodeficiency states (eg, AIDS), and induced immunodeficiency states (eg, immunosuppression) are associated with increased incidence of NHL and are characterized by a relatively high incidence of extranodal involvement, particularly of the GI tract, and with aggressive histology. Primary CNS lymphomas can be observed in about 6% of patients with AIDS.
• The chronic inflammation observed in patients with autoimmune disorders, such as Sjögren syndrome and Hashimoto thyroiditis, promotes the development of MALT and predisposes patients to subsequent lymphoid malignancies. Hashimoto thyroiditis, which occurs in 16-23% of middle-aged and elderly females, is a preexisting condition in 23-56% of primary thyroid lymphomas.
• Helicobacter pylori infection is associated with the development of primary GI lymphomas, particularly gastric MALT lymphomas.

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