Overview of grey zone lymphoma (GZL)
Grey zone lymphoma (GZL) is a very rare and aggressive (fast-growing) B-cell non-Hodgkin lymphoma. GZL usually starts in the area called the mediastinum (centre of the chest), where most people with this lymphoma subtype develop a large mass in this area. It is thought that it starts from thymic B-cells (from the thymus gland) that transform into lymphoma. The mass can cause symptoms like breathing problems, as it can press on surrounding organs like the lungs. The lymphoma can start in other areas too.
It is called grey zone lymphoma (GZL) as it has clinical features of both classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL). GZL is usually a subtype of DLBCL called primary mediastinal B-cell lymphoma (PMBCL), making it very difficult to diagnose and decide on the best treatment options.
Grey zone lymphoma (GZL) might sometimes also be called ‘B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.’
Grey zone lymphoma is an aggressive disease that can be difficult to treat, however it is potentially curable with standard treatment that includes combination chemotherapy and immunotherapy (chemoimmunotherapy), sometimes with radiotherapy and stem cell transplant.
Who is affected by grey zone lymphoma (GZL)?
Grey zone lymphoma (GZL) can occur at any age but most commonly affects people aged between 20-40 years. Men are more likely to be affected than women. The causes of GZL are not known and like other cancers, it is not infectious and cannot be passed onto other people.
The cause of GZL is unknown. As with other subtypes such as Hodgkin lymphoma, diffuse large B-cell lymphoma or primary mediastinal B-cell lymphoma, a viral cause may be associated, such as the Epstein-Barr virus, a common virus that can also cause glandular fever.
Symptoms of grey zone lymphoma (GZL)
Grey zone lymphoma (GZL) usually starts in the mediastinum, which is the centre of the chest. The mass can press on surrounding organs like the lungs, that can result in:
- Shortness of breath
Some people may have other symptoms that may include:
- Painless swelling of lymph nodes in the neck, groin or armpit
- Fatigue (extreme tiredness)
- Loss of appetite
- Itchy skin (all over the body)
B-symptoms are what doctors call the following symptoms and can include:
- Night sweats (drenching sleep wear or bedding)
- Persistent high fevers (especially at night >38C)
- Unexplained weight loss
It is important to tell the doctor about all the symptoms as it can influence the decision around the type of treatment and how soon it needs to start.
Diagnosis and staging of grey zone lymphoma (GZL)
A biopsy is always required for a diagnosis of lymphoma. A biopsy is an operation to remove a lymph node or other abnormal tissue to look at it under the microscope by a pathologist. The biopsy can be done under local or general anaesthetic depending on what part of the body is being biopsied. The biopsy can be done one of three ways:
- Fine needle aspirate
- Core needle biopsy
- Excisional node biopsy
An excisional node biopsy is the best investigative option, as it collects the most adequate amount of tissue to be able to do the necessary testing for a diagnosis.
Waiting for results can be a difficult time and it may help to talk to family, friends or a specialist nurse.
Grey zone lymphoma (GZL) can be more challenging to diagnose, given the similar characteristics with Hodgkin lymphoma and primary mediastinal B-cell lymphoma.
It is recommended to consider a diagnosis of grey zone lymphoma (GZL) if:
- The biopsy results look like Hodgkin lymphoma under the microscope, but is strongly CD20 positive (a molecule or also known as an antigen found on the surface of some B-cells)
- The biopsy results look like primary mediastinal B-cell lymphoma (PMBCL) under the microscope andis strongly CD15 positive.
It is also highly recommended to re biopsy a patient that has not responded to standard treatment for Hodgkin lymphoma or primary mediastinal B-cell lymphoma to look for GZL.
Staging of lymphoma
Once a diagnosis of grey zone lymphoma (GZL) is made, further tests are required to see where else in the body the lymphoma has affected or is located. This is called staging. The staging of lymphoma helps the doctor to determine the best treatment management for the patient.
There are four stages from stage 1 (lymphoma in one area) through to stage 4 (lymphoma that is widespread).
- Early stage means stage 1 and some stage 2 lymphoma. This can also be referred to as ‘localised’. Stage 1 or 2 means that the lymphoma is found in one area or a few areas close together.
- Advanced stage means the lymphoma is stage 3 and stage 4, and it is widespread. In most cases, the lymphoma has spread to many parts of the body that are far from each other.
What is the ‘grade’ of lymphoma?
Lymphomas are also often grouped as either indolent or aggressive. Indolent lymphomas are usually slow growing and aggressive lymphomas are fast growing. The grade is also referred to as the clinical behaviour of the lymphoma. GZL is a high- grade lymphoma
It is important to know the stage and grade of your lymphoma
Staging scans and tests
The scans and tests needed for staging and before treatment can start may include:
- Positron emission tomography (PET) scan
- Computed tomography (CT) scan
- Bone marrow biopsy
- Lumbar puncture & magnetic resonance imaging (MRI) – If lymphoma is suspected in the brain or spinal cord
Patients may also undergo a number of baseline tests prior to any treatment commencing to check organ functions. These are often repeated during and after the treatment has completed to assess whether the treatment has affected the functioning of organs. Sometimes the treatment and follow-up care may need to be adjusted to help manage side effects. These may include:
- Physical examination
- Vital observations (blood pressure, temperature, & pulse rate)
- Heart scan
- Kidney scan
- Breathing tests
- Blood tests
It may take some time for all the necessary biopsies and tests to be done (an average of 1-3 weeks), but it is important for the doctors to have a complete picture of the lymphoma and the general health of the patient in order to make the best treatment decisions
Many of the staging and organ function tests are done again after treatment to check whether the lymphoma treatment has worked and the effect this has had on the body.
It is important to note that lymphoma is what is known as a systemic cancer. It can spread throughout the lymphatic system and nearby tissue and organs. Many patients are diagnosed at an advanced stage and the lymphoma can still be successfully treated. Lymphoma is very unlike advanced stage solid tumour cancers, such as bowel or lung cancer.
Prognosis of grey zone lymphoma (GZL)
Patients with any stage of grey zone lymphoma (GZL) are potentially curable with standard treatments and most generally respond (either completely or partially) to treatment.
GZL has an aggressive course. While there are high rates of relapse, radiotherapy and autologous stem cell transplants have shown encouraging results for patients with refractory or relapsed disease.
Treatment for grey zone lymphoma (GZL)
Once all the results from the biopsy and the staging scans have been completed, the doctor will review these to decide the best possible treatment for a patient. At some cancer centres, the doctor will also meet with a team of specialists to discuss the best treatment and this is called a multidisciplinary team (MDT) meeting.
Doctors take into consideration many factors about the lymphoma and the patient’s general health to decide when and what treatment is required. This is based on:
- The stage of lymphoma
- Symptoms (including the size and location of the lymphoma)
- How the lymphoma is affecting the body
- Past medical history & general health
- Current physical and mental wellbeing
- Patient preferences
Before treatment is started it is important that adequate information is provided about the treatment that is planned, the possible side effects and what to expect. Education from the cancer nurses prior to receiving treatment, can be extremely helpful and should include instructions about becoming unwell or needing medical or nursing assistance.
The standard first-line treatment for grey zone lymphoma (GZL) is still under consideration as researchers are still learning more about the condition. Most specialists will assess whether the GZL is acting more like Hodgkin lymphoma (HL) or more like primary mediastinal B-cell lymphoma (PMBCL).
GZL is a fast-growing lymphoma and treatment needs to start soon after diagnosis and may include:
- DA-EPOCH-R (dose adjusted etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin and rituximab)
- +/- Radiotherapy (after chemotherapy)
- Autologous stem cell transplant (AuSCT) after first-line chemotherapy to reduce the risk of the lymphoma coming back
- Clinical trial participation
Common side effects of treatment
There are many different side effects of the treatment and these are dependent on the treatment that has been given. The treating doctor and/or cancer nurse can explain the specific side effects prior to the treatment. Some of the more common side effects of treatment may include:
- Anaemia (low red blood cells that carry oxygen around the body)
- Thrombocytopenia (low platelets that help with clotting and bleeding)
- Neutropenia (low white blood cells that help fight infection)
- Nausea and vomiting
- Fatigue (tiredness or lack of energy)
- Reduced fertility
The medical team, doctor, cancer nurse or pharmacist, should provide information about:
- What treatment will be given
- What are the common and possible side effects for the treatment
- What side effects do you need to report to the medical team
- What are the contact numbers, and where to attend in case of emergency 7 days a week and 24 hours per day
Some treatments for lymphoma can reduce fertility and this is more likely with certain chemotherapy regimens (combinations of drugs) and high-dose chemotherapy used before a stem cell transplant. Radiotherapy to the pelvis also increases the likelihood of reduced fertility. Some antibody therapies may also affect fertility, but this is less clear.
Your doctor should advise you on whether fertility may be affected and whether fertility preservation should bedonebefore the start of treatment.
Once treatment has completed, post treatment staging scans will be used to review how well the treatment has worked. The scans will show the doctors if thre has been a:
- Complete response (CR or no signs of lymphoma remain) or a
- Partial response (PR or there is still lymphoma present, but it has reduced in size)
If all goes well regular follow-up appointments will be made for every 3-6 months to monitor the below:
- Review the effectiveness of the treatment
- Monitor any ongoing side effects from the treatment
- Monitor for any late effects from treatment over time
- Monitor signs of the lymphoma relapsing
These appointments are also important so that the patient can raise any concerns that they may need to discuss with the medical team. A physical examination and blood tests are also standard tests for these appointments. Apart from immediately after treatment to review how the treatment has worked, scans are not usually done unless there is a reason for them. For some patient’s appointments may become less frequent over time
Relapsed or refractory grey zone lymphoma (GZL)
Grey zone lymphoma (GZL) usually responds well to immunochemotherapy, but in some people the lymphoma comes back (relapses) or in rare cases does not respond to initial first-line treatment (refractory). If this happens there are other treatments that can be successful. These treatments can include:
- Combination chemotherapy
- Autologous stem cell transplant (although not suitable for everyone)
- Pembrolizumab (Keytruda)
Treatments under investigation
There are many treatments that are currently being tested in clinical trials in Australia and around the world for patients with both newly diagnosed and relapsed lymphoma. The treatments that are currently being investigated for your grey zone lymphoma (GZL) will depend on whether the doctor is treating “a more like” Hodgkin lymphoma or primary mediastinal B-cell lymphoma. For more information on the current treatments that are being investigated for these subtypes, please see these subtype sections.
What happens after treatment?
Sometimes a side effect from treatment may continue or develop months or years after treatment has completed. This is called a late effect.
This can be a challenging time for many people and some of the common concerns can be related to:
- Mental wellbeing
- Emotional health
- Work, study and social activities
Health and wellbeing
A healthy lifestyle, or some positive lifestyle changes after treatment can be a great help after the treatment has been finished. Making small changes such as eating and increasing fitness can improve health and wellbeing and help the body to recover. There are many self-care strategies that can help during the recovery phase.