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DIFFUSE LARGE B CELL LYMPHOMA OVERVIEW — Lymphoma is a cancer of lymphocytes, a type of white blood cell. Lymphocytes circulate in the body through a network referred to as the lymphatic system, which includes the bone marrow, spleen, thymus, and lymph nodes. The organs and vessels of the lymphatic system work together to produce and store cells that fight infection (figure 1).
There are two main types of lymphoma:
●Hodgkin lymphoma (HL)
●Non-Hodgkin lymphoma (NHL)
NHL is the most common type of lymphoma. Although there are more than 60 types of NHL, diffuse large B cell lymphoma (DLBCL) is the most common type, making up about 30 percent of all lymphomas. In the United States, DLBCL affects about 7 out of 100,000 people each year.
DLBCL is a fast-growing, aggressive form of NHL. DLBCL is fatal if left untreated, but with timely and appropriate treatment, approximately two-thirds of all people can be cured. The following discussion will review the risk factors, classification, symptoms, treatment, and prognosis of this type of non-Hodgkin lymphoma.
CANCER CARE DURING THE COVID-19 PANDEMIC — COVID-19 stands for "coronavirus disease 2019." It is an infection caused by a virus called SARS-CoV-2. The virus first appeared in late 2019 and has since spread throughout the world. Getting vaccinated lowers the risk of severe illness; experts recommend COVID-19 vaccination for anyone with cancer or a history of cancer.
In some cases, if you live in an area with a lot of cases of COVID-19, your doctor might suggest rescheduling or delaying medical appointments. But this decision must be balanced against the importance of getting care to screen for, monitor, and treat cancer. Your doctor can talk to you about whether to make any changes to your appointment schedule. They can also advise you on what to do if you test positive or were exposed to the virus.
DIFFUSE LARGE B CELL LYMPHOMA RISK FACTORS — Age, gender, and ethnicity affect a person's likelihood of developing DLBCL. Although DLBCL has been found in people of all age groups, it is found most commonly in middle-aged or older adults. The average age at the time of diagnosis is 64 years. Men are slightly more likely to develop DLBCL than women. In the United States, white people are more likely to develop this type of lymphoma than people of Asian or African descent.
DLBCL is not an inherited disease. Siblings and children of people with DLBCL do not have a substantially increased risk of developing DLBCL. Most people have no family history, but approximately 9 percent of people have a first degree relative (eg, parent or sibling) with lymphoma or chronic lymphocytic leukemia.
WHAT IS DIFFUSE LARGE B CELL LYMPHOMA? — 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 (figure 1). Lymphatic fluid contains white blood cells called lymphocytes.
There are two primary types of lymphocytes: B cells and T cells. Diffuse large B cell lymphoma (DLBCL) is a cancer of B lymphocytes. 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. B cells instead continue to develop and mature in the bone marrow and lymph nodes. In DLBCL, the abnormal B cell lymphocytes are larger than normal, and they have stopped responding to signals that usually limit the growth and reproduction of cells.
This subtype of lymphoma is called diffuse large B cell because of the way the malignant large B cells are distributed within the lymph nodes when examined with a microscope.
There are different varieties of DLBCL that can be identified by performing advanced tests on the lymph node specimen. Particular varieties of DLBCL may be more likely to respond to certain treatments.
DLBCL can either develop as a transformation from a less aggressive form of lymphoma or as a first occurrence of lymphoma (called de novo).
DIFFUSE LARGE B CELL LYMPHOMA SYMPTOMS — The first sign of DLBCL is often a quickly growing, non-painful mass that is typically an enlarged lymph node in the neck, groin, or abdomen. People may also experience fever, weight loss, drenching night sweats, or other symptoms.
Extranodal disease — In about 40 percent of cases, the cancer does not begin in the lymph nodes, but instead develops elsewhere. This is called extranodal disease. The most common site of extranodal involvement is the stomach or gastrointestinal tract, but the disease can arise in virtually any normal organ.
Advanced versus localized disease — Most people (about 60 percent) are not diagnosed with DLBCL until the disease is advanced (stage III or IV). In the remaining 40 percent of people, the disease is confined to one side of the diaphragm (above or below the diaphragm). This is called localized disease.
DIFFUSE LARGE B CELL LYMPHOMA DIAGNOSIS — The diagnosis of DLBCL is confirmed by removing part or all of an enlarged lymph node with a biopsy. This procedure may be performed with local anesthesia if the involved tissue is relatively close to the skin's surface. If the node is deeper, general anesthesia is required. The cells from the tissue are then examined in detail using a microscope and other techniques.
Staging — Once the diagnosis is confirmed, additional tests are performed to obtain more information about the extent to which the disease has spread in the body. This process is called staging. The results of these tests will help determine the most effective course of treatment.
History and physical exam — A careful interview and physical examination will begin to determine the extent of the disease. The physical exam may reveal swollen lymph nodes in various locations (figure 1).
Staging tests — A number of tests are available to help determine which areas of the body have been affected by follicular lymphoma. Tests that may be done include:
●Bone marrow biopsy
●CT scan (not performed if a combined PET/CT is used)
Staging terms — The following are terms used in the staging criteria:
●Lymph node regions: An area of lymph nodes and the surrounding tissue. Examples include the cervical nodes in the neck (figure 2), the axillary nodes in the armpit, the inguinal nodes in the groin, or the mediastinal nodes in the chest (figure 1).
●Lymph structures: Organs or structures that are part of the lymphatic system, such as the lymph nodes, spleen, and thymus gland.
●Diaphragm: A large muscle that separates the chest cavity from the abdominal cavity.
Stage grouping — Staging involves dividing people into groups (stages) based upon how much of the lymphatic system is involved at the time of diagnosis. Staging helps determine a person's prognosis and treatment options (table 1).
Here is how the stages of lymphoma are defined:
●Stage I – Only one lymph node region is involved, only one lymph structure is involved, or only one extranodal site (IE) is involved.
●Stage II – Two or more lymph node regions or lymph node structures on the same side of the diaphragm are involved.
●Stage III – Lymph node regions or structures on both sides of the diaphragm are involved.
●Stage IV – There is widespread involvement of a number of organs or tissues other than lymph node regions or structures, such as the liver, lung, or bone marrow.
When a stage is assigned, it also includes a letter, A or B, to denote whether fever, weight loss, or night sweats are present. "A" means these symptoms are not present; "B" means they are. For example, a person with stage 1B disease has evidence of cancer in one lymph node region and has "B" symptoms (fever, weight loss, or night sweats). (See 'Diffuse large B cell lymphoma symptoms' above.)
DIFFUSE LARGE B CELL LYMPHOMA TREATMENT — The treatment of DLBCL depends upon whether the disease is advanced or localized.
Advanced disease — The standard treatment of advanced DLBCL is combination chemotherapy plus immunotherapy.
Chemotherapy drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are less affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract.
Immunotherapy uses antibodies that target a specific group of cells (usually cancer cells). Rituximab is an antibody that targets B lymphocytes.
The most common chemotherapy regimens for advanced DLBCL are:
●R-CHOP includes rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. The first four drugs are given into a vein (IV) over the course of one day, while prednisone is taken by mouth for five days. In the United States, this regimen is generally given every three weeks for six cycles.
A cycle of chemotherapy refers to the time it takes to give the treatment and then allow the body to recover from the effects. Thus, six cycles of treatment would last 18 weeks (nearly five months). During this time, the person is closely monitored for signs of drug toxicity and side effects.
Side effects of chemotherapy — Most people who are treated with R-CHOP develop side effects, with the most common including:
●Fever and low blood counts – A potentially life-threatening side effect of chemotherapy is fever and lowered levels of a type of white blood cell, called neutrophils (the condition is called febrile neutropenia).
Anyone who is getting chemotherapy and who develops a temperature higher than 100.4°F (38°C) should immediately call his or her healthcare provider. This condition is a medical emergency and requires prompt treatment, usually with admission to a hospital and antibiotics by vein (IV).
Treatment may also be associated with low red blood cell count (anemia; causing weakness, fatigue, and other symptoms) and low platelet counts (causing easy bruising/bleeding).
●Nausea and vomiting – Between 30 and 90 percent of people develop nausea and vomiting after R-CHOP. Several medications may be given before and after chemotherapy to reduce its severity. This often includes dexamethasone and aprepitant (sample brand name: Emend), and a 5-HT3 receptor antagonist such as ondansetron (brand name: Zofran), and granisetron (sample brand names: Kytril, Sancuso, Sustol).
●Hypersensitivity reaction – Hypersensitivity reactions may occur the first time a chemotherapy or immunotherapy drug is given, causing flushing; itching; chest, back, or abdominal pain; fever; nausea; dizziness; and other symptoms. It is not clear why this type of reaction occurs. Several medications are usually given before chemotherapy to reduce the severity of these symptoms, including acetaminophen (sample brand name: Tylenol), diphenhydramine (sample brand name: Benadryl), hydrocortisone (a steroid), and a stomach-acid-reducing medication, such as famotidine (brand name: Pepcid).
●Tumor lysis syndrome – Tumor lysis syndrome is a serious, potentially life-threatening condition that can occur after beginning treatment with chemotherapy. It happens because the tumor cells die quickly and release toxic break-down products into the bloodstream. Symptoms can include nausea, vomiting, diarrhea, lack of appetite, lethargy, blood in the urine, heart problems, seizures, muscle cramps, and others. Preventive treatments are usually given before chemotherapy to reduce the risk of developing tumor lysis syndrome, including IV fluids and medications. In addition, blood tests are often done during and after treatment to monitor for the condition.
●Other potential complications – Other potential complications of chemotherapy include damage to the heart (called cardiotoxicity) or the nerves (called neurotoxicity), loss of the ability to have children (infertility), and increased risk of some types of cancer. These risks, as well as ways to manage or monitor for them, should be discussed with a healthcare provider before beginning treatment.
Localized disease — People with localized disease may be treated with fewer cycles (usually three cycles) of R-CHOP chemotherapy in combination with radiation therapy to the involved area.
Radiation therapy — Radiation therapy (RT) refers to the exposure of a tumor to high-energy X-rays in order to slow or stop its growth. Exposure to X-rays damages cells. Unlike normal cells, cancer cells cannot repair the damage caused by exposure to X-rays over several days. This prevents the cancer cells from growing further and causes them to eventually die.
RT for lymphoma is usually given as external-beam RT, meaning that the radiation beam is generated by a machine that is outside the body. Exposure to the beam typically takes only a few seconds (similar to having an X-ray). In general, RT is given daily, five days per week, for approximately three to four weeks.
SURVIVING DIFFUSE LARGE B CELL LYMPHOMA — The chance of surviving DLBCL depends upon many factors. The following factors are known to reduce the chances of survival:
●Age older than 60
●Lactate dehydrogenase level higher than normal – Lactate dehydrogenase is a protein found in blood whose levels increase when tissues have been damaged. It can also be produced by the cancer cells.
●Poor general health status (ECOG performance status score of 2 or greater) (table 2)
●Stage III or IV disease (table 1)
●More than one involved extranodal disease site
A scoring system, known as the International Prognostic Index (IPI), gives one point for each of the above characteristics, for a total score ranging from zero to five, representing three risk groups :
●Low risk – IPI score of 0 or 1 (91 percent of people in this risk group are still alive at three years)
●Low to intermediate risk – IPI score of 2 (81 percent of people in this risk group are still alive at three years)
●High to intermediate risk – IPI score of 3 (65 percent of people in this risk group are still alive at three years)
●High risk – IPI score of 4 or more (59 percent of people in this risk group are still alive at three years)
FOLLOW-UP AFTER TREATMENT OF DIFFUSE LARGE B CELL LYMPHOMA
Response evaluation — After finishing the planned course of treatment, the person will have a medical history, physical examination, and laboratory testing to gauge his or her response to treatment.
A radiologic imaging test (PET/CT) is recommended, either six to eight weeks after finishing chemotherapy or 12 weeks after finishing radiation therapy.
A complete response has been achieved if all of the following criteria are met:
●There is no evidence of disease or disease-related symptoms on history and physical examination.
●The spleen and liver cannot be felt during the physical examination.
●Any abnormalities seen on the CT scan do not "light up" on the PET scan.
●If a pretreatment bone marrow biopsy was positive, a repeat bone marrow biopsy must be negative.
People who do not have a complete response are treated for refractory disease.
Surveillance for relapse — People who achieve a complete response must be evaluated on a regular basis after treatment. The visits usually include a medical history and physical examination, blood tests, and may include a radiologic imaging test, such as a CT scan. The purpose of these visits is to monitor for treatment complications and possible relapse. If there are new signs of a relapse, a biopsy must be done to confirm the diagnosis.
The frequency of these visits depends upon the comfort of both the person and physician. When deciding how often these visits should occur, the person and physician must consider the following:
●The majority of relapses occur during the first two years after finishing treatment.
●Relapses usually cause the person to have symptoms and are rarely found solely on the basis of routine radiologic imaging tests.
●If a relapse is picked up a few weeks earlier because of more intense monitoring, it is unlikely to improve outcome.
●The number of CT scans should be limited, particularly in younger individuals, to limit radiation exposure and the risk for second cancers.
There is no role for routine PET or PET/CT imaging in the long-term follow-up of people who do not have any symptoms. There are limited data to support performing CT scans periodically to monitor for relapse. Whether or not to use CT scans in a person without symptoms should be determined on an individual basis.
RECURRENT OR REFRACTORY DIFFUSE LARGE B CELL LYMPHOMA TREATMENT — Recurrent disease is the term used to describe disease that returns after an initial remission. Refractory disease is the term used to describe disease that does not fully respond to treatment in the first place. (See 'Response evaluation' above.)
Depending upon the person's age, underlying medical problems, and preferences, treatment may use:
●Immunotherapy, which are antibody-based treatments such as "CAR-T cell" therapy or others that directly target the cancer cells.
●Intensive chemotherapy followed by a specific kind of bone marrow transplantation, autologous transplantation, in which a person's own cells are used to "rescue" his or her bone marrow from the intensive chemotherapy. (See "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)".)
●Some people with refractory DLBCL choose less intensive treatments or management with supportive care and no active therapy.
CLINICAL TRIALS — A clinical trial is an approved research study that is designed to determine the best treatment for a particular disease. Clinical trials are especially important in DLBCL, since there no treatment program capable of curing all people with this disease.
Enrollment in a clinical trial, if available, is always recommended. Ask your doctor for more information, or read about clinical trials at:
Videos addressing common questions about clinical trials are available from the American Society of Clinical Oncology (https://www.cancer.net/research-and-advocacy/clinical-trials/welcome-pre-act).
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem.
This article will be updated as needed on our web site (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for healthcare professionals, are also available. Some of the most relevant are listed below.
Patient level information — UpToDate offers two types of patient education materials.
The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.
Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.
Classification of hematopoietic neoplasms
Clinical presentation and initial evaluation of non-Hodgkin lymphoma
Pretreatment evaluation and staging of non-Hodgkin lymphomas
Autologous hematopoietic cell transplantation in follicular lymphoma
Initial treatment of stage I follicular lymphoma
Mantle cell lymphoma: Initial management
Natural killer (NK) cell large granular lymphocyte leukemia
Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma
Treatment of large granular lymphocyte leukemia
Treatment and prognosis of Waldenström macroglobulinemia
Treatment of advanced stage (IIB to IV) mycosis fungoides
Treatment of early stage (IA to IIA) mycosis fungoides
Treatment of hairy cell leukemia
Treatment of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma)
Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit
Treatment of relapsed or refractory mantle cell lymphoma
The following organizations also provide reliable health information.
●American Cancer Society
●National Cancer Institute
●National Library of Medicine
●The Leukemia & Lymphoma Society
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