Diffuse large B-cell lymphoma

INTRODUCTION — Diffuse large B-cell lymphoma (DLBCL) is a fast-growing, aggressive form of non-Hodgkin's lymphoma (NHL), a cancer of the body's lymphatic system. The lymphatic system includes the tissues and organs (including the bone marrow, spleen, thymus and lymph nodes) that produce and store cells that fight infection. Although there are more than 20 types of NHL, DLBCL is the most common type, making up about 30 percent of all lymphomas [1]. In the United States, DLBCL affects about 5 people out of 100,000 each year [2].

Diffuse large B-cell lymphoma can be fatal if left untreated, but with timely and appropriate treatment, up to half of all patients are curable. The following discussion will review the risk factors, classification, clinical symptoms, and prognosis of this type of non-Hodgkin's lymphoma.

RISK FACTORS — Age, gender, and race/ethnicity affect a person's likelihood of developing diffuse large B-cell lymphoma. Although DLBCL has been found in people of all age groups, it is found most commonly in people who are middle-aged or elderly. The average age at the time of diagnosis is 64 years. Men are slightly more likely to develop DLBCL than women. People who are white are more likely to develop this type of lymphoma than people of African or Asian race/ethnicity.

CLASSIFICATION — Diffuse large B-cell lymphoma is a cancer of B lymphocytes. The lymph organs include the bone marrow, thymus, spleen, and lymph nodes. These help to fight infection throughout the body. The organs of the lymphatic systems are connected by a network of lymphatic and blood vessels, through which lymphatic fluid flows. Lymphatic fluid contains white blood cells called lymphocytes (show figure 1).

There are two primary types of lymphocytes: B-cells and T-cells. Almost all lymphocytes begin growing in the bone marrow or lymph nodes. T-cells leave the bone marrow before they are completely matured, and finish maturing in the thymus gland. However, B-cells continue to develop and mature in the bone marrow and lymph nodes.

In DLBCL, the abnormal B-cell lymphocytes are larger than normal. The presence of these large cells characterizes DLBCL; typically, the large cells present in DLBCL have nuclei at least twice the size of small lymphocytes. Researchers have identified several variants of DLBCL, including a centroblastic variant, immunoblastic variant, anaplastic variant, T-cell histiocyte rich large B-cell lymphoma, and T-cell infiltration. It is not clear whether understanding the differences between these variants can improve patients' symptoms or overall prognosis.

Genetic events and chromosomal abnormalities are suspected to be related to the development of DLBCL. In 30 percent of cases of diffuse large B-cell lymphoma, an abnormal transfer (translocation) of part of a chromosome occurs (the t(3;14) gene translocation). This translocation causes a rearrangement in a gene called BCL-6. As a result, the abnormal gene signals the body to produce a protein that alters the growth and development of these cells [3].

PRIMARY MEDIASTINAL LARGE B-CELL LYMPHOMA — Patients with this subtype of DLBCL have tumors within the chest cavity that usually involve the thymus, the gland of the immune system that is located in the front upper middle of the chest and extends from the base of the throat to the front of the heart.

Primary mediastinal large B-cell lymphoma comprises 7 percent of all diffuse large B-cell lymphomas and accounts for 2.4 percent of all non-Hodgkin's lymphomas. Women are slightly more likely to develop this disorder, and the median age of diagnosis occurs in the fourth decade of life.

People who have this form of DLBCL usually present to their physicians with a malignant tumor in the chest cavity that causes difficulty breathing and a condition known as superior vena cava syndrome. If this subtype of diffuse large B-cell lymphoma recurs, it can cause problems with other organs, including the liver, gastrointestinal tract, kidneys, ovaries, and central nervous system.

This type of tumor is aggressive, but it is treatable with programs that combine chemotherapy and radiation.

SYMPTOMS — The first noticeable symptom that patients with diffuse large B-cell lymphoma experience is a quickly growing mass, which may be found either in the neck, groin, or abdomen.

In about one in five patients, tumors caused by DLBCL are confined to one part of the body. However, in about 40 percent of people diagnosed with this type of NHL, the cancer spreads from the lymph system into adjacent organs, a condition known as extranodal infiltration. In some patients, DLBCL spreads to the bone marrow.

As DLBCL spreads from the original site of the tumor throughout the body, it may involve other organs, such as the liver, kidney, and lungs, and cause the following complications: Superior vena cava syndrome (SVCS), in which the blood vessels of the upper half of the body become compressed and partially blocked by the growing tumor, making it difficult for the body's circulatory system to transport blood from the head, neck, chest, and arms back to the heart. A person with SVCS may experience respiratory problems, coughing, and swelling in the upper half of the body. Tracheobronchial compression, in which the airways in the lung become compressed by the tumor, making it difficult to breathe Nerve damage Destruction of bone in the spinal column leading to compression of the spinal cord, with resulting back pain, leg weakness, or paralysis

Patients may also experience fever, weight loss, and drenching night sweats. These symptoms are called "B" symptoms and may alert the physician to the possible diagnosis of lymphoma.

In addition to occurring on its own (de novo DLBCL), DLBCL may occur as other indolent or low-grade forms of B-cell lymphoma change and progress during the disease process (transformed diffuse large B-cell lymphoma). DLBCL may develop from the following types of low-grade lymphomas: B-cell chronic lymphocytic leukemia (Richter's transformation) Lymphoplasmacytic lymphoma Follicular lymphoma Mucosa-associated lymphoid tissue (MALT) lymphoma Splenic marginal zone lymphoma

DIAGNOSIS — Physicians confirm a diagnosis of DLBCL by removing an enlarged lymph node or a portion of an involved organ in a procedure known as a biopsy. This procedure may be performed under a local anesthetic if the involved tissue is relatively close to the surface. In other cases, a sample of tissue must be obtained under a general anesthetic. The cells from the removed tissue are then examined in detail, using a number of different techniques to determine the nature of the abnormal cell.

Physicians also order blood tests, x-rays, imaging scans, and bone marrow samples to obtain more information about the type of lymphoma and the extent to which it has spread in the body, a process termed "staging" (show table 1). The results of these tests will help physicians decide on the most effective course of treatment. As an example of the importance of staging, treatment of diffuse large B-cell lymphoma is generally more likely to provide a cure when the lymphoma is localized than when it has spread to other parts of the body.

Gene studies, such as the use of gene expression profiling, may allow clinicians to determine which patients have a reduced chance of remission after standard treatments and could suggest which patients would be candidates for more aggressive treatment [4]. These studies are investigational and are not yet part of standard practice.

TREATMENT — The standard of treatment of DLBCL is combination chemotherapy, occasionally with the addition of radiation to areas of large, bulky disease. The most common chemotherapeutic program for patients with advanced disease consists of 5 medicines (called CHOP-rituximab or CHOP-R) given every three weeks for 6 to 8 cycles. Patients with only localized disease may be treated with fewer cycles of chemotherapy in combination with radiation therapy to the involved area.

PROGNOSIS — The five-year survival rate of patients with DLBCL is between 26 and 73 percent, meaning that between one quarter and three quarters of patients with DLBCL will be disease-free for five years after diagnosis. Relapses tend to occur within the first two to three years after the diagnosis of DLBCL; the disease rarely recurs if the patient has been disease-free for four or more years.

The following factors were found to correlate with significantly shorter overall or relapse-free survival and have been incorporated into an International Prognostic index: Age >60 Serum lactate dehydrogenase (LDH, a protein in the blood) concentration greater than normal Poor performance status (ECOG performance status 2) (show table 2) Advanced Ann Arbor clinical stage (III or IV) (show table 1) Number of involved extranodal disease sites >1

In this system, one point is given for each of the above characteristics present in the patient, for a total score ranging from zero to five, representing increasing degrees of risk: Low risk — IPI score of zero or one Low intermediate risk — IPI score of two High intermediate risk — IPI score of three High risk — IPI score of four or five

When applied to patients with aggressive NHL, such as diffuse large B-cell lymphoma, five-year overall survivals for patients with scores of 0 to 1, 2, 3, and 4 to 5 were 73, 51, 43, and 26 percent, respectively (show table 3).

CLINICAL TRIALS — A clinical trial is an approved research study which seeks to determine the best treatment for a particular disease. This is especially important in diffuse large B-cell lymphoma, since there is no currently approved treatment program capable of curing all patients with this disorder.

Therefore, for all patients with diffuse large B-cell lymphoma, enrollment in a clinical trial, if available, is always recommended. Ask your doctor for more information, or read about clinical trials at: www.cancer.gov/clinical_trials/ and at http://clinicaltrials.gov/

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. American Cancer Society

(www.cancer.org)
National Cancer Institute

(www.cancer.gov)
National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)
The Leukemia & Lymphoma Society

(www.leukemia-lymphoma.org)
People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)


[1-5]


Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Armitage, J, Weisenburger, D. New approach to classifying Non-Hodgkin's lymphomas: Clinical features of the major histologic subtypes. J Clin Oncol 1998; 16:2780.
2. Kallab, AM. Diffuse large cell lymphoma. January 31, 2002. Available online at www.emedicine.com/med/topic1360.htm (Accessed 3/7/05).
3. Huang, JZ, Sanger, WG, Greiner, TC, et al. The t(14;18) defines a unique subset of diffuse large B-cell lymphoma with a germinal center B-cell gene expression profile. Blood 2002; 99:2285.
4. Lossos, IS, Czerwinski, DK, Alizadeh, AA, et al. Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med 2004; 350:1828.
5. American Cancer Society. What is non-Hodgkin's lymphoma? www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_Is_Non_Hodgkins_Lymphoma_32.asp (Accessed 3/7/05).