Non-Hodgkin lymphomas (NHLs) are malignancies that arise from white blood cells in the lymphatic system. More specifically, they develop from B-lymphocytic and T-lymphocytic cells, which are more commonly known as white blood cells. Unlike Hodgkin lymphomas, non-Hodgkin lymphomas do not have Reed-Sternberg cells present.
The lymphatic system is a network of tissues and organs that help our bodies fight infection and disease. It is composed of lymph vessels (carries lymph fluid around the body), lymph fluid (carries nutrients around the body and removes unwanted bacteria/viruses) and lymph nodes/glands (filters lymph fluid and empties it into the bloodstream). Some of the most well-known lymph tissues include the bone marrow, the spleen, and the tonsils.
This page will focus on aggressive NHLs that develop from B-lymphocytes. B-cell lymphomas are the most common subtype of all lymphomas (including Hodgkin lymphomas), and aggressive lymphomas tend to be more common than indolent (or slow-growing) lymphomas.
In general, NHLs are more commonly found in men, and are generally diagnosed after the age of 60. However, anyone can develop this disease.
Types of Non-Hodgkin Lymphomas (Aggressive B-cell)
There are several types of aggressive B-cell NHLs, which are often categorised based on cellular appearance under the microscope, tumour behaviour, and/or location of disease.
Diffuse Large B-cell Lymphoma (DLBCL)
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of all NHLs, and has many different subtypes.
Primary Mediastinal B-cell Lymphoma (PMBCL)
Primary mediastinal B-cell lymphoma (PMBCL) is a rare subtype of DLBCL that develops from the thymus gland in the mediastinum (space between the lungs that hold many important structures, including the heart, trachea, and oesophagus). Unlike most NHLs, it mainly occurs in adults between the ages of 25-40, and is more common in women. While PMBCL can metastasise, it often has a good prognosis.
T-Cell/Histiocyte rich B-cell Lymphoma (T/HRBCL)
T-cell/histiocyte rich B-cell lymphoma (T/HRBCL) is a rare subtype of DLBCL that is characterised by the presence of excess T-lymphocytes, excess histiocytes (a type of immune cell), and cancerous B-lymphocytes. This type of cancer is often difficult to diagnose, as it can resemble Hodgkin’s lymphoma and peripheral T-cell lymphoma. As it is often diagnosed at a late stage, T/HRBCL may not have as good of a prognosis as other types of NHL.
Primary Central Nervous System Lymphoma (PCNSL)
Primary central nervous system lymphoma (PCNSL) is a rare subtype of DLBCL that often originates in the central nervous system (CNS). The CNS is responsible for all sensory and motor functions in the body, and is composed of the brain and the spinal cord. While it is most commonly found in the brain, it can also develop in the spinal cord, eye(s), and leptomeninges (the inner membranes surrounding the brain and spinal cord). Unfortunately, due to the delicate locations of the disease, the prognosis for PCNSL may be poor.
Cutaneous B-cell Lymphoma
Cutaneous B-cell lymphoma (CBCL) is a rare subtype of NHL that usually begins in the skin. There are two types of indolent CBCL, and one aggressive type called primary cutaneous diffuse B-cell lymphoma, leg type (PCDLBL-LT).
PCDLBL-LT is very rare, and is generally found in the lymphatic nodules in the legs. It is commonly found in patients over 70 years old and unlike most NHLs, is significantly more common in women than men. PCDLBL-LT can have a good prognosis when caught early.
For more information on the indolent forms of CBCL, please refer to the Rare Cancers Australia Non-Hodgkin Lymphoma (Indolent B-Cell) page.
Plasmablastic Lymphoma
Plasmablastic lymphoma (PBL) is a rare and aggressive subtype of NHL that is associated with having a weakened immune system, most commonly from an infection with the human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), and/or post organ transplant. Unlike most other forms of NHL, plasmablastic lymphoma tends to be diagnosed in patients between the ages of 40-50, but is still slightly more common in males. It is most commonly found in the oral cavity and the gastrointestinal tract, however it has also been found in the head and neck region, skin, and bone. This disease is often diagnosed at a late stage, is often aggressive, and may not have as good of a prognosis as other NHL subtypes.
Rare Types of DLBCL
These types of DLBCL are considered very rare:
- Intravascular large B-cell lymphoma.
- EBV-positive DLBCL not otherwise specified.
- Double hit lymphoma (DHL).
- Triple hit lymphoma (THL).
- ALK-positive large B-cell lymphoma.
Mantle Cell Lymphoma
Mantle cell lymphoma (MCL) is a rare subtype of NHL that develops from the ‘mantle zone’ (outer edge) of the lymph nodes. While this type of cancer is usually aggressive, it can behave like an indolent (slow growing) cancer in rare instances. MCL often has a high recurrence rate, but can have a good prognosis when caught early.
Grey Zone Lymphoma
Grey zone lymphoma (GZL) is a very rare subtype of NHL that often develops in the mediastinum (space between the lungs that hold many important structures, including the heart, trachea, and oesophagus). It has characteristics of both classical Hodgkin lymphoma, and a subtype of DLBCL called primary mediastinal B-cell lymphoma (PMBCL). Although it is often difficult to diagnose, GZL can have a good prognosis when caught early.
Burkitt Lymphoma
Burkitt lymphoma (BL) is a rare subtype of NHL that affects both children (between the ages of 5-10) and, rarely, adults (between the ages of 30-50). It has often been associated with viral infections, such as the Epstein-Barr virus (EBV) and the Human-immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). There are three main subtypes of BL.
Endemic (African) Burkitt Lymphoma
Endemic BL is most commonly found in children of African descent, who are between four to seven years old. It is strongly associated with EPV and chronic malaria infections, and is rarely found outside of Africa. In both adult and paediatric cases, it is usually found in the jaw and facial bones, and can have a good prognosis.
Sporadic (non-African) Burkitt Lymphoma
Sporadic BL is found throughout the world, and is most commonly found in the abdomen. It is commonly found in children, but can also be found in adults. Sporadic BL can be associated with an EPV infection, and can have a good prognosis.
Immunodeficiency-associated Burkitt Lymphoma
Immunodeficiency-associated BL is also found throughout the world, and most commonly affects people with the Human-immunodeficiency virus and/or acquired immunodeficiency syndrome (HIV/AIDS). It can also occur in people with inherited immunodeficiency syndromes, or patients who take immunosuppressive medications after an organ transplant. Immunodeficiency-associated BL can have a good prognosis when caught early.
AIDS-Related Lymphoma
AIDS-related lymphoma is when a patient with AIDS is diagnosed with a lymphoma (in most cases, a NHL). The two primary types of AIDS-related lymphomas include:
- Diffuse large B-cell lymphoma.
- Burkitt lymphoma.
Precursor B-cell Lymphoblastic Lymphoma
Lymphoblastic lymphoma (LL) is a rare subtype of NHL that is commonly diagnosed around 20 years of age. It most commonly develops from T-lymphocytes, but can rarely develop from B-lymphocytes.
Precursor B-cell lymphoblastic lymphoma develops from immature B-cell lymphocytes, generally in the lymph nodes. It behaves similarly to B-acute lymphoblastic leukaemia, but is much less common. While this type of cancer has a high recurrence rate, precursor B-cell lymphoblastic lymphoma can have a good prognosis.
Treatment
If an aggressive B-cell NHL is detected, it will be staged and graded based on size, metastasis (whether the cancer has spread to other parts of the body) and how the cancer cells look under the microscope. Staging and grading helps your doctors determine the best treatment for you.
All NHLs are staged using the Lugano classification system, which may also be referred to as a modification of the Ann Arbor staging system. In this system, NHLs are assigned numerical values, from stage I-IV:
- Stage I: cancer cells are confined to a single lymph node area, either above or below the diaphragm (large muscle separating the abdomen from the chest). This stage is also known as early-stage cancer.
- Stage II: cancer cells have spread to two or more lymph node areas on the same side of the diaphragm. This is also known as localised cancer.
- Stage III: the cancer has become larger and affected lymph node areas on both sides of the diaphragm. This is also known as localised cancer.
- Stage IV: Lymphoma is in multiple lymph node areas and may be present in other parts of the body, such as bone marrow, liver, and/or lungs. This is also known as advanced or metastatic cancer.
In addition to the numerical system, your doctor may also stage your cancer with a letter, which gives more information about your symptoms and how your body is being affected by the disease. These letters include:
- A – You feel well and have no B-symptoms of lymphoma.
- B – You have some or all of the B-symptoms of lymphoma.
- E – You have NHL in an organ that is not a part of the lymphatic system (such as lungs, skin, bladder etc.).
- X – You have a tumour that is greater than 10cm in size. This is also called ‘bulky disease’.
- S – You have a lymphoma in your spleen.
As all cancers discussed on this page are classified as ‘aggressive’, these cancers are usually all high grade.
Once your tumour has been staged and graded, your doctor may recommend genetic testing, which analyses your tumour DNA and can help determine which treatment has the greatest chance of success. They will then discuss the most appropriate treatment option for you.
Treatment is dependent on several factors, including location, age, stage of disease and overall health.
Treatment options for aggressive B-cell NHLs may include:
- Chemotherapy.
- Immunotherapy, potentially including:
- CAR T-cell therapy.
- Rituximab.
- Radiation therapy.
- Targeted therapy, potentially including monoclonal antibodies.
- Steroid therapy, potentially including corticosteroids.
- Stem cell transplant, potentially including:
- Autologous transplant (stem cells removed from your own blood and later reinfused into your body).
- Allogenic transplant (stem cells are collected from another person).
- Photodynamic therapy.
- Surgery to remove skin lesion (only in patients with a lymphoma of the skin).
- Clinical trials.
- Palliative care.
For more information on the treatment options, please refer to the Rare Cancers Australia treatment options page.
Risk factors
While the cause of all NHLs remains unknown, the following factors may increase the likelihood of developing the disease:
- Previous infections with viruses, including:
- Epstein-Barr virus (EBV).
- Human immunodeficiency virus (HIV).
- Acquired immunodeficiency syndrome (AIDS).
- Human T-lymphotropic virus type 1 (HTLV-1).
- Hepatitis C (Hep C).
- Human herpesvirus-8 (HHV-8)
- Chemical exposure to pesticides, fertilisers, and/or solvents.
- Having an autoimmune disease, such as:
- Rheumatoid arthritis.
- Scleroderma.
- Sjögren’s syndrome.
- Infections with certain bacteria, such as helicobacter pylori (H. pylori – known to cause stomach ulcers).
- Having a family history of lymphoma.
- Obesity (past or present).
- Taking immunosuppressant medication, such as after an organ transplant.
Not everyone with these risk factors will develop the disease, and some people who have the disease may have none of these risk factors. See your general practitioner (GP) if you are concerned.
Early symptoms
Most patients with an aggressive B-cell NHL will appear asymptomatic in the early stages of disease. As the cancer progresses, some of the following symptoms may appear.
General Symptoms
General symptoms of an aggressive B-cell NHL may include:
- B-symptoms, which include:
- Drenching night sweats.
- Unexplained weight loss.
- Persistent fevers over 37.5°C.
- Fatigue.
- Itchy skin.
- Shortness of breath.
- Low blood counts, potentially including anaemia (deficiency of red blood cells in the body), thrombocytopenia (deficiency of platelets in the body), and/or neutropenia (deficiency of neutrophils (a type of white blood cell) in the body), which may cause the following symptoms:
- Shortness of breath.
- Fatigue.
- Dizziness.
- Confusion.
- Difficulty concentrating.
- Paleness.
- Abnormal protein levels, which may cause the following symptoms:
- Poor circulation (causing blue fingers and/or toes, numbness and/or tingling in fingers and toes etc.).
- Confusion.
- Headaches.
- Nosebleeds.
- Blurred vision.
Symptoms of diffuse large B-cell lymphoma
In addition to the general symptoms listed above, patients with DLBCL may experience the following symptoms:
- Nausea and/or vomiting.
- Diarrhea.
- Constipation.
- Blood in urine and/or stool.
- Feeling full after little food.
- Chest pain.
- Dry cough.
- Recurrent infections.
- Easy bruising and/or bleeding.
- Red/purple rash.
- Skin lumps and bumps.
Primary mediastinal B-cell lymphoma
In addition to general DLBCL symptoms, patients with PMBCL may also experience:
- Pains/aches in the chest.
- Voice hoarseness.
- Swelling of the neck and/or face.
- Dizziness.
- Headaches, which are worse when bending forward.
- More visible chest veins.
T-cell/histiocyte rich B-cell lymphoma
In addition to general DLBCL symptoms, patients with T/HRBCL may also experience:
- Swelling of the liver and/or spleen.
- General feeling of unwellness.
- Abdominal swelling/discomfort.
Primary Central Nervous System Lymphoma
In addition to general DLBCL symptoms, patients with PCNSL may also experience:
- Confusion.
- Memory changes.
- Personality changes.
- Seizures.
- Weakness, numbness, burning and/or pins and needles in the arms and/or legs.
Cutaneous B-cell Lymphoma
In addition to general DLBCL symptoms, patients with CBCL may also experience:
- Small, raised, solid lumps on the skin called papules (look like pimples).
- Thickened, flat, larger lumps.
- Nodules that are red or pink in colour.
- Ulcerations, which may occur with an infection.
Plasmablastic Lymphoma
In addition to general DLBCL symptoms, patients with PBL may also experience:
- A lump or sore in the mouth that may or may not bleed.
- Gastrointestinal symptoms, such as:
- Abdominal pain.
- Diarrhoea.
- Blood in your stool.
- Nose bleeds.
- Frequent runny noses.
- Sinus inflammation.
- Lump in the skin.
- Swollen lymph nodes.
Symptoms of Mantle Cell Lymphoma
In addition to the general symptoms listed above, patients with MCL may experience the following symptoms:
- Swelling of the lymph nodes (especially in the neck, armpit, and groin).
- Diarrhea.
- Stools with blood of them.
- Iron deficiency.
- Abdominal bloating.
- Loss of appetite.
Symptoms of Grey Zone Lymphoma
In addition to the general symptoms listed above, patients with GZL may experience the following symptoms:
- Dry cough.
- Swelling of the lymph nodes (especially in the neck, armpit, and groin).
- Loss of appetite.
Symptoms of Burkitt Lymphoma
Adult
In addition to the general symptoms listed above, adult patients with BL may experience the following symptoms:
- Abdominal swelling.
- One or more lumps (clustering of lymphoma cells).
- Bleeding from the bowel.
- Pain (from bowel obstruction).
- Loss of appetite.
- Nausea.
- Diarrhea.
Childhood
In addition to the general symptoms listed above, children with BL may experience the following symptoms:
- Recurrent infections.
- Swelling of lymph nodes (especially in the neck, armpit, or groin).
- Dry cough.
- Difficulty recurring from infection.
Precursor B-cell Lymphoblastic Lymphoma
In addition to the general symptoms listed above, patients with PBCLL may experience the following symptoms:
- Swelling of lymph nodes (especially in the neck, armpit, or groin).
- Easy bruising.
- Paleness of the skin (pallor).
- Dry cough.
- Difficulties recovering from an infection.
Not everyone with the symptoms above will have cancer, but see your GP if you are concerned.
Diagnosis/diagnosing
If your doctor suspects you have an NHL, they may order the following tests to confirm the diagnosis and refer you to a specialist for treatment.
Physical examination
Your doctor will collect your overall medical history, as well as your current symptoms. Following this, they may examine your body to check for any abnormalities.
Blood tests
Your doctor will recommend a blood test for check for signs of Hodgkin lymphoma and determine overall health. The most common test is a full blood count, which will analyse the levels of red blood cells, white blood cells and platelets in the blood. Low counts in any of these categories could be indicative of disease.
Imaging
The doctor will take images of your body using magnetic resonance imaging (MRI), a computed tomography scan (CT scan), ultrasound, and/or positron emission tomography (PET scan), to check for signs of tumours and/or metastasis.
Lumbar puncture
A lumbar puncture, or spinal tap, involves inserting a needle between two vertebrae in the lower spine and extracting a sample of cerebrospinal fluid (CSF) for analysis. A local anaesthetic or sedative is given prior to the procedure. Your doctor will discuss any risks and possible complications with you prior to the procedure.
Endoscopy
An endoscopy is a surgical procedure that involves inserting a long, flexible tube with a light and small camera through the oesophagus and into the stomach to examine the gastrointestinal tract. This procedure is used if it is suspected you have a B-cell lymphoma in this area. You will be given a sedative or anaesthetic throughout the procedure. You will be asked to fast for several hours prior to the procedure. An endoscopy is often done as a day surgery. Your doctor will discuss the risks and any possible complications prior to the procedure.
Throughout the procedure, your doctor may also perform an endoscopic ultrasound to guide the needle during a biopsy, or to check for signs of cancer metastasis.
Biopsy
Once the location of the cancer has been identified, the doctor will perform a biopsy to remove a section of tissue using a needle. In most cases, this may be done by either an excision biopsy (where the lymph node is completely or partially removed), a fine needle biopsy (a fine needle is inserted into the lymph node to remove a sample), or a core needle biopsy (where a bigger needle is inserted into the lymph node to remove a sample). Both procedures are often performed as a day surgery. In rare cases, a bone marrow biopsy may be performed to see if it contains any cancerous cells. This process involves inserting the needle into the hipbone (or the breastbone in some cases) to remove samples of solid and liquid bone marrow. These samples will then be analysed for cancer cells.
Prognosis (Certain factors affect the prognosis and treatment options)
While it is not possible to predict the exact course of the disease, your doctor may be able to give you a general idea based on the rate and depth of tumour growth, susceptibility to treatment, age, overall fitness, and medical history. Generally, early-stage NHLs have a better prognosis and survival rates. However, if the cancer is advanced and has spread, the prognosis may not be as good and there may be a higher risk of cancer recurrence. It is very important to discuss your individual circumstances with your doctor to better understand your prognosis.
References
Some references are to overseas websites. There may be references to drugs and clinical trials that are not available here in Australia.