eMedicine Specialties > Hematology > Stem Cells and Disorders

Lymphoma, Diffuse Large Cell

Author: Andre M Kallab, MD, Clinical Associate Professor of Oncology, Medical College of Georgia; Consulting Staff, Department of Oncology, Northeast Georgia Diagnostic Clinic
Contributor Information and Disclosures

Updated: Nov 4, 2009

Introduction

Background

The non-Hodgkin lymphomas (NHLs) constitute a heterogeneous group of lymphoid system neoplasms with varying presentation, natural history, and response to therapy.

Since the late 20th century, considerable progress has been made in NHL classification. In 1982, the National Cancer Institute introduced the International Working Formulation, a translation system for other older classifications, including the Rappaport and the immunologically oriented Lukes-Collins and Kiel systems. The working formulation provided a conceptual framework that groups lymphomas as low-grade (indolent), intermediate-grade, or high-grade with respect to their natural histories.

In 1994, the International Lymphoma Study Group proposed the Revised European-American Lymphoma (REAL) classification schema. It classifies NHLs as being derived from B or T/NK-cells, and it includes new disease entities that were not part of the working formulation.

The diffuse large cell lymphoma (DLCL) of the REAL classification combines the large cell and the immunoblastic categories of the working formulation. These lymphomas currently are considered a single group because they behave similarly and, therefore, have similar prognoses. DLCL is the most common lymphoma, representing 31% of NHLs, and is rapidly fatal if untreated. (See images below.) For information on staging, see Staging.

Pathophysiology

Under the International Working Formulation in the classification of intermediate-grade DLCLs, approximately 79% of DLCLs were of B-cell origin, 16% of T-cell origin, and 5% were unclassifiable. Exceptional cases expressed both B-cell and T-cell markers.

Incorporation of the REAL classification system for lymphomas has been strongly encouraged. In addition to morphologic descriptions, this schema includes immunologic, cytogenetic, and molecular information in order to define distinct lymphoma entities. Currently, the diffuse large B-cell lymphomas are considered in the REAL classification as the classic DLCL of B-cell origin defined by the working formulation. Lymphomas of T-cell or NK-cell origin exhibit biological and clinical features distinct from diffuse large B-cell lymphomas.

B-cell restricted markers (CD19, CD20, CD22) are expressed consistently. Activation antigens are variably expressed by B-cell DLCLs, with HLA-DR being the most frequent and CD23 being expressed uncommonly (0-25%). The presence of CD10 or CD5 suggests that at least one third of DLCLs may have transformed from follicular lymphomas or a small lymphocytic lymphoma.

The majority of B-cell DLCLs demonstrate rearrangements of the immunoglobulin genes by DNA hybridization techniques, proving their B-cell lineage.

Mutations or allelic losses of the p53 tumor suppressor gene or 17p13.1 are common in DLCLs, particularly in the immunoblastic type. Changes of p53 appear especially involved in the evolution of follicular lymphoma to DLCL. A number of cytogenetic abnormalities have been reported in DLCLs, including t(14;18), t(8;14), trisomy 12, and deletion of 6q.

Frequency

United States

The incidence of NHL has been increasing more rapidly than many other malignancies. Overall, the incidence has increased more than 73% between 1973 and 1991. The current US age-adjusted rate is 15.1 cases per 100,000 person-years for both sexes. The estimated rate for DLCLs is approximately 4.68 cases per 100,000 person-years.

International

In general, age-adjusted incidence is higher in developed countries. For men, it varied from 3.7-14 cases per 100,000 persons per year from 1983-1987. Over the past 2 decades, rates for both men and women have increased by 50% or more in 20 different countries. The rates by subtype, such as Burkitt lymphoma (Epstein-Barr virus–associated) and human T-cell leukemia virus type 1–related lymphoma/leukemia, also vary widely in different geographic areas and are much more frequent in endemic areas.

Mortality/Morbidity

• Mortality rates have increased significantly in each race/sex group. Rates of change are highest in areas where HIV is epidemic and in patients with posttransplant lymphoproliferative diseases.
• Data suggest that 5-year survival rates are higher for Caucasians compared to people of African descent, which may or may not reflect socioeconomic factors.
• Women have a better survival outcome, as do patients younger than 65 years.¹

Race

• Incidence varies by race.
• Caucasians have higher rates than people of African or Asian descent.²
• The Surveillance, Epidemiology, and End Results registry demonstrates rates in white men that are 49% higher than in African Americans, 54% higher than in Japanese Americans, and 27% higher than in Chinese Americans. These differences also apply to women.

Sex

• The male-to-female disease incidence ratio is 1.3:1.

Age

• Although DLCLs can occur at any age, in general, they occur in middle-aged and older adults.

Clinical

History

• The clinical manifestations of DLCLs are diverse and depend on the site of disease involvement.
• These tumors have a rapid growth rate.
• They present as masses, causing symptoms when they infiltrate tissues or obstruct organs.
• Pain in an enlarged lymph node or organ may be noted if the lymphomatous mass enlarges rapidly.
• As with other types of NHL, DLCLs can present with B symptoms, including fever, drenching night sweats, and weight loss. Generalized pruritus also may be present.

Physical

• Most frequently, DLCLs appear in lymphoreticuloendothelial tissues, which include the lymph nodes, spleen, liver, and bone marrow. However, any extranodal site may be primarily or secondarily involved, including the central nervous system (CNS), lungs, gastrointestinal tract, genitourinary tract, and the bones.
• Involvement of sanctuary sites, including the CNS and testicles, is more frequently associated with Burkitt and non-Burkitt lymphoma, HIV-associated lymphoma, human T-cell leukemia virus type 1–associated lymphoma, primary CNS lymphoma, and primary testicular DLCL.
• Involvement of the cerebrospinal fluid (CSF) with DLCL is observed more frequently with advanced-stage disease and bone marrow involvement.

Causes

• NHLs have been associated with the following conditions:
  • Hereditary immunodeficiency disorders such as ataxia-telangiectasia syndrome, Bruton-type agammaglobulinemia, severe combined immunodeficiency, Wiskott-Aldrich syndrome, Duncan syndrome, and Chediak-Higashi syndrome
  • Infections such as HIV, Epstein-Barr virus (EBV), Helicobacter pylori infection, hepatitis C, human T-cell leukemia virus (HTLV), and human herpes virus–type infections
  • Autoimmune disorders such as rheumatoid arthritis, Sjögren syndrome, and systemic lupus erythematosus
  • Use of drugs such as immunosuppressants and chemotherapeutic agents
  • Exposure to environmental toxins such as herbicides, vinyl chloride, and organic solvents³

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