Also known as:
- DLBCL
Additional notes on names/types
- DLBCL is a type of Non-Hodgkin’s lymphoma, a blood cancer
- The world health organisation has identified several different types of DLBCL which are listed at the end of this article.
- More than 80% of DLBCLs are described as “not otherwise specified” or NOS. This is because they do not have features that would put them in one of the other categories . DLBCL-NOS has two types:
- Germinal Center B-Cell-like (GCB) DLBCL
- Activated B-Cell-like (ABC) DLBCL, named after the place in the body where they develop.
Contents
How rare is diffuse large B-cell lymphoma (DLBCL)?
In the UK and Europe the usual definition of a rare cancer is one that occurs in less than 6 people out of every 100,00 each year. Because there are around 200 rare cancers, this means that they make up about 24% (nearly a quarter) of all cancers.
According to Blood Cancer UK over 14,000 people develop some type of lymphoma each year, making it the most common blood cancer and in the “top ten” most common cancers. There are many different lymphomas, divided into two large groups, Hodgkin’s (20% of total) and non-Hodgkin’s (80% of total).
DLBCL makes up about 40% of all cases of non–Hodgkin’s lymphoma with, an incidence rate of 4.68 cases per 100,000 people,
Once you start to count the cases of individual subtypes they are very rare, the sort of condition that most GPs will only encounter a handful of times in their careers.
The incidence of DLBCL increases with age. It is highest in people aged 80-85. It is possibly more common in men and people with a white background. Certain subtypes, such as primary mediastinal BCL are found in much younger people, typically under 30. Some types are linked with certain viruses such as Epstein Barr.
What is DLBCL?
DLBCL is an aggressive blood cancer that affects a type of white blood cell, part of your immune system, called a B-lymphocyte or B-cell. It leads to a large build up of faulty, immature B-cells in lymph nodes that can spread to other parts of the body such as the liver, spleen, bones and occasionally the spine and brain.
It can be a progression from a much less aggressive cancer called follicular lymphoma (FL). About 3 people in every 100 with FL will develop DLBCL each year.
Where does it come from? – A family of blood cells.
When we are in the early stages of growth as an embryo, we are just a ball of cells of no particular type. These are called stem cells that can change to become all of the different cells that make up a human being. Once we are born only a very few cells keep the ability to do this. The most important of these are found in our bone marrow where a single type of stem cell is responsible for producing all the cells that are found in our blood- the oxygen carrying red blood cells, the many types of white blood cells that fight infections and the platelets that help our blood to clot.
The picture below shows the family tree of these blood cells. All of them come from the haematopoietic stem cells (haematopoietic means blood forming). The stem cells will multiply and become more specialised as they develop down the branches of the tree.
Source – wikipedia creative commons
There are two big families within the blood cells. The myeloid cells on the left of the picture and the lymphoid cells on the right.
Blood cancer can develop from any of these cells at different stages of their development and this is reflected in the name given to the cancer. The most well known are the leukaemias which affect cells from both groups that are developing in the bone marrow, and lymphomas that affect lymphocytes, the T-cells, B-cells and NK cells in the lymph nodes.
B-cells are normally known for their role in producing antibodies – proteins that recognise and stick to invaders, marking them for destruction, and becoming the “memory” cells that are responsible for our immunity to infections we’ve had or been vaccinated against. It is these B-cells that can develop DLBCL.
How DLBCL develops:
In the nucleus of our cells is the molecule of inheritance, DNA. It contains the instructions for everything a cell does in the order of chemical bases in its structure. A gene is a short section of that DNA which contains the instructions for making one protein molecule. Proteins make up much of the structure and carry out most of the functions of all our cells. Any change to the DNA is called a mutation and these can lead to changes that affect the function or amount of a protein that is produced. Sometimes these mutations will result in cells dividing uncontrollably and surviving when they shouldn’t – cancer.
Normally our bone marrow produces a variety of white blood cells, including B-cells that are released into the body to help find and remove infections. When they meet an invading organism the B-cells go to the lymph nodes, to mature and multiply before being released to deal with the infection. Lymph nodes are part of a second system of tubes in our bodies whose main job is dealing with infections. For more information see this explanation from CRUK.
In part of the lymph node, called germinal centres, B-cells develop many genetic changes to adapt them to deal with a particular pathogen (disease causing organism). In order to do this some of the mechanisms that normally protect cells from DNA damage or changes are shut down. This also sets the stage for the potential development of cancer. This is such an important factor in the development of lymphoma that it partly explains why only around 4% of lymphomas are believed to be due to preventable causes. Compare this with the estimate that 30-50% of all cancers develop from preventable causes such as smoking.
Scientists have found that certain important genes can accidentally become mutated when B-cells are developing. Which genes, and at what stage of the B–cell development process they become mutated can influence the course of the disease and its treatment.
Some of the most important of these genes in DLBCL are called BCL2, BCL6 and MYC, although because of the nature of these B-cells, there are very many others. BCL2 stops cells from completing a self-destruct process called apoptosis that normally removes damaged cells. BCL6 is needed in order to finish the development of working B-cells and MYC controls the behaviour of many other genes.
Sometimes a diagnosis of DLBCL is described as being a “double” or ”triple” hit when two, or all three of these genes are affected.
Two main forms of the disease:
Scientists have found that there are two slightly different forms of the most common form of DLBCL. They start in B-cells that are at different stages of their journey to becoming normal active white blood cells.
Germinal centre B-cells (GCB): These are B-cells that are actively undergoing a controlled set of genetic mutations that fine tune the cells to be more effective at recognising and destroying infections. When the lymphoma has developed from these cells it is often easier to treat effectively than the second type of DLBCL.
Activated B-cells: These cells have almost completed their processing ready to be released into the bloodstream. They are less likely to have a BCL6 mutation or a protein called CD10 which is one way of telling it apart from GCB.
Symptoms:
Most people will notice a rapidly growing lump in an area where lymph nodes are close to the surface – often the neck, armpit or groin.
The picture below shows where the most commonly affected lymph nodes are.
Source – CRUK / Wikimedia commons
There might also be more general symptoms (sometimes called B symptoms) such as fever, itching, night sweats and unexplained weight loss which are linked to the effect of the cancer on the body. If the lymph nodes deeper in the body are affected there may be other symptoms such as breathlessness, diarrhoea or constipation.
Diagnosis:
There are a number of scans and tests that will be used to confirm a diagnosis of DLBCL and identify features that might affect the treatment that is offered.
Imaging:
Various scans can allow doctors to see where any tumours are in the body- if they are just in the lymph nodes, which ones or if they have spread to other organs. Whilst X-rays and CT scans are useful, PET scans are commonly used as the radioactive dye used is picked up very well by lymphoma cells.
Biopsy:
This is where either a whole or part of a lymph node is removed in a small operation. Alternatively a small piece of the lymph node is removed using a fine needle. The cells are studied under the microscope and their size, shape and arrangement will give an idea of what disease is present. DLBCL will have B -cells that are much larger than normal (the first L in DLBCL) and they will be quite spread out (D- diffuse). They will also have an unusual looking nucleus – the part of the cell where genetic information is kept. Extra tests are needed to confirm it is DLBCL and identify the exact type, which will affect what treatment is given.
If you were to zoom extraordinarily close to cells you would see that all over the surface and all through the inside were millions of tiny structures. These would be individual proteins, molecules that make up most of the structure of a cell as well as helping it to carry out all the functions that it needs to live and interact with other cells and its environment.
Different types of cells make different proteins to help them do their usual jobs and when cells become cancerous these change in ways that can be used to confirm exactly what type of cancer it is. These differences can also be used as targets by people developing new medicines for DLBCL.
Whilst individual proteins are too small to see, special staining methods and other scientific techniques can be used to check which proteins are present. In particular to distinguish between germinal centre B-cell (GCB) and activated B-cell (ABC) forms of lymphoma as this affects some of the clinical decisions that are made. In particular, one protein called CD20 is used to confirm that they are B-cells, and this protein is also important for one of the main treatments.
Genetics:
Genetic testing might be used to confirm whether the main genetic mutations are present (BCL2, BCL6, MYC) or other mutations that would give diagnosis of one of the rarer subtypes.
What are the current treatment options for DLBCL?
What treatment is given will depend on several factors including a person’s overall age, health and wishes as well as the stage of the disease. The stage is determined by the number and location of lymph nodes involved.
Stages 1 and 2 (1 or 2 lymph nodes on one side of the diaphragm/waist) are treated slightly differently to stages 3 and 4 (more advanced disease that is spread out further or involves other organs).
We are still learning about how best to treat the different subtypes of DLBCL as some relapse (return) more often than others. Double and triple hit DLBCL is known for this.
The gold standard treatment that is used for most patients with DLBCL is called R-CHOP. This treatment uses five different drugs in combination and is sometimes called chemo-immunotherapy because the drugs are a mix of chemotherapy and one that activates the immune system against the cancer.
R= Rituximab. This is a drug that was originally made by a B-cell grown in the lab! It is an antibody that sticks to the CD20 molecule on the surface of B-cells. In doing so it marks the B-cells for destruction, just like any other infection. Rituximab is also used for several conditions where B–cells are overactive, such as rheumatoid arthritis.
C= cyclophosphamide. This is a drug that reacts with the DNA of dividing cells causing them to die instead.
H= Hydroxydaunorubicin (doxorubicin). This drug sits in the DNA ladder and blocks the machinery that copies the DNA before a cell can divide.
O= Oncovin (vincristine). This plant derived drug stops cells dividing by sticking to the mechanism that moves the DNA into the right place during division.
P= Prednisolone. This drug is a steroid that is toxic to cells in the immune system, but also increases appetite, increases the effect of chemotherapy and reduces the side-effects of treatment.
R-CHOP is usually given over 3-4 cycles of 3 weeks, a shorter course, for stages 1 and 2 or as 6 cycles for stages 3 and 4, but there will be variations depending on an individual’s circumstances.
It may be combined with radiotherapy to support the treatment if it is working slowly or there are large masses of tissue containing the cancerous B-cells.
This treatment can be very effective for patients whose disease is caught at an early stage – well over half of patients are cured with the R-CHOP regimen.
If the DLBCL returns or relapses after this treatment there are alternative combinations of drugs and rituximab based immunotherapies that can be used. Acronyms such as R-DHAP, R-ICE, R-ESHAP, R-GEM-P are used for some of these treatments.
Research into DLBCL and all blood cancers is very active and there are many new treatments available or that are being developed for it. Below are a few examples.
Xpovio allows the cells to build up the amount of natural tumour suppressing substances.
Monjuvii is another antibody drug that sticks to a different molecule on the surface of the cancer cells (called CD19), which is given with a drug called lenalidomide – a relative of thalidomide that stops new blood vessels forming to supply cancers, and encourages cancer cells to die through a process called apoptosis.
Stem cell transplants are also used with high dose chemotherapy.
CAR-T therapy uses a patient’s own T-cells (another immune cell) which are adapted so they stick to the cancer cells and start the process of destroying them.
A targeted therapy, Polivy uses an antibody that only sticks to cancer cells, but the antibody is attached to an extremely toxic chemical, MMAE that is only released once the drug has entered the cancer cell.
BCL2 produced by the cancer cells helps them survive. BCL2 inhibitors (drugs that stop a protein working) such as venetoclax, that stop this happening, are being studied to use in support of other treatments.
What current clinical trials are there for DLBCL?
Information current as of: 19th July 2023
There are 14 clinical trials currently recruiting in the uk according to clinicaltrials.gov.
This includes :
ECHELON-3 study – The combination of Brentuximab- vedotin – which is an antibody that sticks to a cancer cell protein called CD30, attached to a cell killing drug, plus lenalidomide (which stops new blood vessels and encourages tumour cells to die through a process called apoptosis) and rituximab, the key part of the R-CHOP treatment.
Learn more about this study by joining RareCan
NX-1607 – a drug that help the T-ells of the immune system attack the cancer
LOTIS-7 – another antibody drug attached to a cell killing compound
ELM-1 – an antibody that sticks to both the cancer cells and T–cells from the immune system, bringing them together, making it easier for the immune system to destroy them.
Where can I find DLBCL support groups?
Name
Website
Notes
Blood Cancer UK
UK charity supporting patients and researchers for all blood cancers. Information is clearly presented and there are excellent opportunities to get support or be involved in fundraising.
Lymphoma Action
https://lymphoma-action.org.uk/
Another excellent source of information with many stories from patients, families and volunteers.
Leukaemia and Lymphoma Society
https://www.lls.org/
Major US non-profit organisation dedicated to researching and supporting blood cancers. They have an extensive library of free information about blood cancers as well as other information about new medicines, testing and living with cancer.
Awareness, events, and symbols
The awareness ribbon for all of the lymphomas and leukaemias is orange.
World Lymphoma day is held on 15th September every year.
It is part of blood cancer awareness month.
World blood cancer day is held on May 28th every year.
Apppendix: List of DLBCL subtypes.
Source RDA
- DLBCL, not otherwise specified (DLBCL, NOS)
- DLBCL subtypes found in specific anatomic sites
- Primary CNS DLBCL
- Primary cutaneous DLBCL, leg type
- Intravascular large B-cell lymphoma
- T cell/histiocyte rich large B-cell lymphoma (T/HRLBCL)
- Epstein-Barr virus (EBV)-positive DLBCL
- DLBCL associated with chronic inflammation
- Primary mediastinal (thymic) large B-cell lymphoma (PMBL)
- DLBCLs with plasma cell immunophenotype
- ALK-positive large B-cell lymphoma
- Plasmablastic lymphoma (PBL)
- Primary effusion lymphoma (PEL)
- DLBCL arising in HHV-8 associated multicentric Castleman Disease (MCD)
- B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma (B-UNC/BL/DLBCL)
- Double-hit lymphomas
- Triple-hit lymphomas
- B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma (B-UNC/cHL/DLBCL)
