Diffuse Large B cell Lymphoma (DLBCL)

Understanding Diffuse Large B cell Lymphoma (DLBCL)

DLBCL is an aggressive B-cell NHL and is the most common type of NHL accounting for 30% to 40% of all cases.

DLBCL gets its name from how the cancerous cells look under a microscope; the cells are large and spread out (diffuse) rather than grouped together.

DLBCL can develop in lymph nodes or outside of the lymphatic system in areas like the intestines, skin, bone, or brain. The cancer may be in one location or may have spread. About 50% of patients have organ involvement at the time of diagnosis, usually the digestive (gastrointestinal) tract and bone marrow.

  • The risk of developing DLBCL increases as you age. The average age of diagnosis for DLBCL is the mid-sixties, however, this cancer can also affect children and young adults. 
  • DLBCL can develop in people who have been diagnosed with an indolent lymphoma. Their original lymphoma transforms (changes) into DLBCL. If this happens, the lymphoma is treated as a DLBCL. 
  • People who have compromised immune systems due to autoimmune disorders, disease (like HIV/AIDS) or organ transplant have a higher rate of developing DLBCL than the general population, though the rate is still low. Most people with these conditions never develop lymphoma and most cases of DLBCL are not related to an underlying immune disorder.

Symptoms

The most common symptom of DLBCL is a painless swelling in the neck, armpit or groin caused by enlarged lymph nodes.Often lymph nodes in more than one area of the body are affected. DLBCL can develop deep in the body where you can't feel it. You may have other symptoms dependent on where the DLBCL is located. For instance, if it is in your chest you may have a cough or difficulty swallowing; if it is in your intestines, you may have stomach pain or diarrhea.About 50% of patients have organ involvement at the time of diagnosis with the most common organs involved being the digestive (gastrointestinal) tract and the bone marrow.

Patients may also have what are called B symptoms (symptoms that can occur when someone has a B cell lymphoma):

  • Fever without any sign of an infection;
  • Night sweats, enough to drench your pajamas or bedding;
  • Weight loss without trying (at least 10% of your body weight over 6 months).

Patients may also experience fatigue, loss of appetite, or itchy skin.

Diagnosis

DLBCL is commonly diagnosed with a biopsy. A biopsy involves removing a sample of tissue (cells), usually performed by a surgeon. The removed tissue is then sent to the pathology lab where it is looked at under a microscope.

You may have other tests like x-rays, bone marrow biopsies, or CT scans, to give your medical team more information about your lymphoma, including where the lymphoma is located in your body. You will also have tests to determine your overall health, including how well your organs work. This may be done through blood and urine tests. The results of these tests can impact which treatment you receive.

Subtypes

Not all DLBCLs are the same. There are different subtypes. The subtypes are generally named according to the cell where the cancer started. The subtype can affect the patient's prognosis and their treatment options. Many cases of DLBCL do not fall within any one of these subtypes and they are called DLBCL not otherwise specified (NOS).

DLBCL can be categorized by molecular subtype for most patients into:

  • Germinal centre B cell (GCB) DLBCLs get their name because they develop from lymphoid cells residing in the germinal centre of the lymph node. Patients with GBG-derived disease generally have better outcomes.
  • Activated B cell (ABC) DLBCLs develop from B cells that are in the process of differentiating from germinal centre B cells to plasma cells. ABC DLBCL is associated with a poorer outcome than GCB DLBC.


Subtypes include:

Primary mediastinal B cell lymphoma (PMBL)

PMBL arises from a thymic B cell. There is often fibrous (scar-like) lymph tissue present. It grows rapidly in the mediastinum (the central area of the upper chest, located behind the breastbone, containing the heart and blood vessels). It accounts for about 2-4% of all lymphomas and occurs mainly in young women.

The lymphoma may press on the trachea and cause trouble breathing or coughing and it can also block the large vein that returns blood to the heart from the arms and head (the superior vena cava), which can make the arms, neck and face swell. Other symptoms include difficulty swallowing (dysphagia), dizziness and headaches.

Treatment usually involves the use of R-CHOP followed by radiotherapy and PMBL usually responds well to treatment. Depending on your test results, your doctor may recommend a more intensive chemotherapy regimen. If PMBCL comes back (recurs) after treatment, it often comes back in organs or tissues outside the lymph nodes (called extranodal sites) including the kidneys or brain and spinal cord (called the central nervous system, or CNS).

Primary central nervous system (CNS) lymphoma

Primary CNS lymphoma only affects the brain and/or spinal column and rarely spreads outside the nervous system. It can also start in the eye (called ocular lymphoma). People with a weakened immune system such as in people who have HIV/AIDS, or have had an organ transplant are at increased risk of developing primary central nervous system lymphoma but this type is being seen with increased frequency in people with healthy immune systems. It is most common in people in the 50-60 age range, but it can occur at any age.

Symptoms include headaches, vision problems, dizziness, numbness, stroke-like events, other pains, and seizures or changes in mental status may occur.

Treatment includes radiation, chemotherapy or steroids. Intrathecal chemotherapy may be given, usually using the drug methotrexate. Steroid therapy (e.g. dexamethasone) may be given to reduce swelling and shrink the tumour. If the treatment doesn't work or the lymphoma relapses, you may be given a stem cell transplant, or newer drugs through a clinical trial.

EBV-positive DLBCL of the elderly

EBV-positive DLBCL of the elderly accounts for less than 5% of DLBCL cases, and is often seen in people age 50 and over, especially in those of Asian descent. While the disease name includes the term 'elderly' it does occur in people younger than 50 as well. EBV-positive refers to the fact patients are positive for Epstein-Barr virus (EBV), the virus that causes mononucleosis. Many people carry the Epstein-Barr virus but don't get sick and don't know they are infected. It is thought that the virus interferes with the immune system, causing lymphoma. We don't know why some people who are EBV-positive develop lymphoma and others don't.

The lymphoma is often extranodal (for example, the skin, lungs, tonsils or stomach) and may or may not involve the lymph nodes. Patients with EBV-positive DLBCL don't respond to treatment as well as those who have DLBCL and are EBV-negative.

T-cell/histiocyte-rich large B-cell lymphoma is more common in men aged over 50 years but can affect people of any age. Fewer than 10% of people with DLBCL will have this type. When looked at under a microscope, T-cells, histiocytes (another kind of immune cell) and large B-cells are all present.

Symptoms include swollen lymph nodes, B symptoms (fever, night sweats, unexplained weight loss) and swelling of the liver or spleen. People with this type of DLBCL will feel generally unwell and have abdominal swelling and discomfort.

Treatment is usually chemotherapy like R-CHOP. If it relapses, you may be given other high-dose chemotherapy regimens, a stem cell transplant, or newer drugs through a clinical trial.

Primary effusion lymphoma (PEL)

PEL is a rare subtype of diffuse large B-cell lymphoma (DLBCL) that may also be called body cavity–based lymphoma. It causes an abnormal buildup of fluid in the cavity (space) around the heart, the cavity around the lungs or the cavity in the abdomen. Lymphoma cells are found in the fluid in these body cavities. People with a weakened immune system (for instance people who have HIV/AIDS or have had an organ transplant) are at increased risk of developing this form of lymphoma. CHOP is a common treatment for PEL.

Intravascular large B-cell lymphoma (ILCL)

ILCL is a rare subtype where the lymphoma cells are only found inside small blood vessels (called capillaries), and usually not in the lymph nodes or bone marrow. It occurs more often in older adults with the average age at diagnosis being 65. ILCL can block small blood vessels in just about any part of the body and affect organs like the brain, spinal column, kidneys, lungs or skin.

Symptoms vary depending on which small blood vessels are affected, but 75% of people with this form of DLBCL experience stroke-like symptoms such as confusion, weakness, numbness or paralysis, difficulty speaking, loss of balance or unexplained falls, changes in vision, and severe headaches due to the impact of the lymphoma on the nervous system. Some people may also develop reddened patches or lumps in their skin or experience B symptoms (fevers, night sweats and unexplained weight loss).

ILCL is often treated with R-CHOP and/or more aggressive therapies. If the lymphoma only affects the skin, you may be treated with radiotherapy alone.

ALK-positive large B-cell lymphoma

ALK-positive large B-cell lymphomais a very rare type of DLBCL that affects people of all ages, occurring mainly in men. The lymphoma cells express a protein called 'anaplastic large-cell kinase (ALK)' on their surface. Most people have enlarged lymph nodes and it can often grow in the mediastinum (centre of the chest). Extranodal sites (outside of the lymph nodes) have also been reported. It is an aggressive disease with high relapse rates.

Double-hit lymphomas (DHL) or triple-hit lymphomas (THL)

DHL and THL affect approximately 5% to 10% of patients. DHL and THL describe patients whose lymphoma tumours have mutations in two or three significant genes (MYC, BCL2 and/or BCL6), where most lymphoma patients have a mutation in only one. Generally, these lymphomas are aggressive, developing rapidly and requiring early treatment. The average patient age is in the 70s. Patients often have advanced disease when diagnosed and many have extranodal involvement. Identifying these types of lymphoma from other B cell lymphomas can be difficult and testing is often complex.

Treatment is usually chemotherapy, but the regimens used vary depending on the patient's age, overall health and disease features. Treatment may also include intrathecal chemotherapy or radiation. Some patients may be given a stem cell transplant or offered newer drugs through a clinical trial. DHL is a research focus, in the hopes of improving outcomes.

Double-expressor lymphomas (DEL)

DEL co-express a high percentage of two significant genes that play a role in lymphoma development - MYC and BCL2. Unlike other subtypes, DEL doesn't have gene translocations. These are primarily ABC DLBCLs, which mean they have a poorer prognosis.

Treatment usually involves R-CHOP. DEL is a research focus, in the hopes of improving outcomes.

Treatment

Since DLBCL can grow quickly, it usually requires immediate treatment.

Overall, DLBCL is very sensitive to chemotherapy, so it is used as the main treatment. A combination of chemotherapy and the monoclonal antibody rituximab (Rituxan), with or without radiation therapy, can lead to disease remission for a large number of patients. The most commonly used treatment for DLBCL is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CHOP (the addition of rituximab). Most of these drugs are given intravenously (into a vein). The chemotherapy is usually given in a 3-week cycle. A cycle includes the treatment days and a period of rest and healing. The number of cycles you receive (called the 'course') depends on your disease and the recommendation of your medical team based on your test results. Most patients will be able to get their treatment on an out-patient basis, which means you will not have to stay in the hospital overnight.

If you have a subtype that is more difficult to treat, your doctor may recommend a more intensive chemotherapy regimen using different drugs like methotrexate, etoposide and cytarabine. Your chemotherapy regimen may also be changed if the doctor feels you are not well enough to tolerate the side effects of the drugs or if you have other health conditions that would make them unsuitable for you.

After your course of chemotherapy, you may have radiotherapy to the area affected by the lymphoma. In some cases, radiotherapy without chemotherapy is used, but this is rare.

For some types of DLBCL, intrathecal chemotherapy may be used to treat or try to prevent lymphoma cells from spreading to the brain and spinal cord. This means that the chemotherapy is injected directly into the cerebrospinal fluid (CSF). The drug often used in intrathecal chemotherapy is methotrexate.

For many patients, the initial treatment is effective and DLBCL does not return after treatment; however, for patients in whom the disease becomes refractory (does not respond to treatment) or relapses (returns after treatment), secondary therapies may be successful. This may include other chemotherapies, a stem cell transplant or newer drugs available through a clinical trial.