Overview of anaplastic large cell lymphoma (ALCL)
Lymphomas are a group of cancers of the lymphatic system. Lymphoma occurs when lymphocytes, which are a type of white blood cell, gain a DNA mutation. The role of lymphocytes is to fight infection, as part of the body’s immune system. There are B-lymphocytes (B-cells) and T-lymphocytes (T-cells) that play different roles.
The lymphoma cells then divide and grow uncontrollably or do not die when they should. Lymphoma has a build up of abnormal lymphocytes. There are two main types of lymphoma. They are called Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Lymphomas are further divided into:
- Indolent (slow growing) lymphoma
- Aggressive (fast-growing) lymphoma
- B-cell lymphoma are abnormal B-cell lymphocytes & are the most common. B-cell lymphomas account for around 85% of all lymphomas
- T-cell lymphoma are abnormal T-cell lymphocytes. T-cell lymphomas account for around 15% of all lymphomas
Anaplastic large cell lymphoma (ALCL) is an aggressive (fast growing) T-cell non-Hodgkin lymphoma. It develops when mature T- lymphocytes grow abnormally and in an uncontrolled manner.
The abnormal T-lymphocytes usually build up in the lymph nodes of the neck but can emerge from the chest, abdomen, skin, lungs or bone. Anaplastic Large Cell lymphoma can affect any other part of the body including the bone marrow, the spleen, the blood and almost any organ or tissue.
Why is it called ‘anaplastic large cell’ lymphoma?
When cells are examined under a microscope, they have different markers that identify them to the doctors and pathologist. This is one-way pathologists can tell the difference between B-cell lymphoma and T-cell lymphoma. The cells have different identifying markers. When a marker is present it is considered positive, the absence of a marker is referred to as a negative.
One of the major identifiers of anaplastic large cell lymphoma, is the presence of two different protein markers on the surface of the T-lymphocytes. CD30 and ALK (Anaplastic Lymphoma Kinase).
Anaplastic large cell lymphoma is known as CD30 positive and can be either ALK negative or ALK positive. CD30 is usually strongly expressed while ALK is only positive in roughly 90% of cases in children. ALK negative expressed anaplastic large cell lymphoma is more common in older adults diagnosed with this lymphoma.
There are two distinctive subtypes of anaplastic large cell lymphoma (ALCL)
- Primary cutaneous anaplastic large cell lymphoma – can be ALK positive or negative and is CD30 positive
- Systemic anaplastic large cell lymphoma – can be ALK positive or negative and is CD30 positive
Who is affected by anaplastic large cell lymphoma?
Lymphoma accounts for 7% of childhood cancers, it is the third most common cancer in children aged 0-14 years, behind leukaemia and brain or central nervous system cancers.
Anaplastic large cell lymphoma (ALCL) accounts for around 10% of childhood all non-Hodgkin lymphoma cases. Whilst the incidence of ALCL is low, it is one of the most common childhood lymphomas. ALCL accounts for 30–40% of all large cell lymphomas in children.
ALCL can occur at any age and to either gender. ALCL commonly occurs between the ages of 1-10 years of age, with a second prevenance in the 11- 15-year-old age group. Overall, the average age at diagnosis is 10 years in children. ALCL is more common in boys than girls.
Anaplastic Large Cell lymphoma is one of the four most common types of non-Hodgkin lymphomas in children, the other types are:
- Diffuse large B-cell lymphoma – comprising approximately 15% of childhood NHL
- Burkitt’s lymphoma – accounting for roughly 40% of childhood NHL
- Lymphoblastic lymphoma – around 25% – 30% of childhood NHL
What are the causes of anaplastic large cell lymphoma (ALCL)?
In most cases of anaplastic large cell lymphoma (ALCL), the cause is not known. There is nothing that you have done or have not done that has caused this for your child. It is not infectious and cannot be passed onto other people. What we do know is that special proteins or genes are damaged (become mutated) and then the cells grow uncontrollably.
While the possible causes of ALCL are not obvious, there have been some factors that have been linked to its development, these can include (although the risk is still very low):
- Previous infection with Epstein-Barr virus (EBV) – this virus is the cause of the common glandular fever
- Weakened immune system due to an inherited immune deficiency disease (autoimmune disease)
- HIV infection
- Immunosuppressant medication that is taken to prevent rejection after an organ transplant or allogeneic (donor) stem cell transplant
Types of anaplastic large cell lymphoma (ALCL)
Anaplastic large cell lymphoma (ALCL) can be divided into two types:
- Primary cutaneous anaplastic large cell lymphoma
- Systemic anaplastic large cell lymphoma
One of the major identifiers of anaplastic large cell lymphoma (ALCL), is the presence of two different protein markers that are on the surface of the T-lymphocytes. CD30 and ALK (Anaplastic Lymphoma Kinase).
Anaplastic large cell lymphoma (ALCL) is known as CD30 positive and can be either ALK negative or ALK positive. CD30 is usually strongly expressed while ALK is only positive in around 90% of cases in children.
Primary cutaneous anaplastic large cell lymphoma
- Less common in children and can be either ALK negative or ALK positive but is always CD30 positive.
- Generally present with a single lump or ulcerating tumour in the skin
- Often confined to the skin and the lesions can spontaneously self-resolve. This natural remission, however, is often short as the disease inevitably returns.
- Primary cutaneous ALCL follows a less aggressive course than systemic ALCL.
- It is usually managed as an indolent (slow growing) lymphoma as long as it remains confined to the skin. If it extends beyond the skin, to the lymph nodes or organs, the management of the lymphoma will shift to that of systemic ALCL.
- The shift of managing this as an indolent lymphoma to an aggressive lymphoma occurs in about 10% of patients diagnosed with primary cutaneous ALCL.
Systemic anaplastic large cell lymphoma (ALCL)
- More common than primary cutaneous ALCL
- An aggressing (fast growing) lymphoma which requires treatment immediately
- Can be either ALK positive or ALK negative with 90% of paediatric ALCL cases being systemic ALCL which is ALK positive
- The name ‘systemic’ means that the lymphoma can affect all organs in the body including bones, skin, bone marrow, the lungs and the liver.
Symptoms of anaplastic large cell lymphoma (ALCL)
The first symptoms can be a lump or several lumps that don’t go away after several weeks. You might feel one or more lumps on your child’s neck, armpit or groin. These lumps are swollen lymph nodes, where abnormal lymphocytes are growing. These lumps often start in one part of a child’s body, usually the head, neck or chest and then tend to spread in a predictable manner from one part of the lymphatic system to the next. In advanced stages, the disease can spread to the lungs, liver, bones, bone marrow or other organs.
The common symptoms of anaplastic large cell lymphoma include:
- Persistent infections
- Painless swelling of lymph nodes in the neck, underarm, groin or chest
- Shortness of breath – due to enlarged lymph nodes in the chest or mediastinal mass
- Cough (usually dry cough)
- Fatigue
- Difficulty recovering from an infection
- Itchy skin (pruritus)
B symptoms are what doctors call the following symptoms that some children may have and can include:
- Night sweats (especially at night, where you might need to change their sleepwear and bedding)
- Persistent fevers
- Unexplained weight loss
It is important to note that many of these symptoms can also relate to causes other than cancer and be difficult sometimes for doctors to diagnose.
Diagnosis of anaplastic large cell lymphoma (ALCL)
A biopsy is always required for a diagnosis of anaplastic large cell lymphoma (ALCL). 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 is usually done under general anaesthetic for children to help reduce distress.
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. It may help to talk to your family, friends or a specialist nurse.
Staging of anaplastic large cell lymphoma (ALCL)
Once a diagnosis of anaplastic large cell lymphoma (ALCL) is made, further tests are required to see where else in the body the lymphoma is located or has been affected. This is called staging. The staging of the lymphoma helps the doctor to know what the best treatment for your child.
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 lymphomas. This may also be called ‘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 lymphoma. In most cases, the lymphoma has spread to parts of the body that are far from each other.
‘Advanced’ stage lymphoma does sound concerning, but lymphoma is what is known as a systematic cancer. It can spread throughout the lymphatic system and nearby tissue. This is why systemic treatment (chemotherapy) is needed to treat anaplastic large cell lymphoma.
Staging tests and scans needed can include:
- Blood tests (such as: full blood count, blood chemistry and erythrocyte sedimentation rate (ESR) to look for evidence of inflammation)
- Chest x-ray – these images will help identify presence of disease in the chest
- Positron emission tomography (PET) scan – done to understand all sites of disease in the body before treatment starts
- Computed tomography (CT) scan
- Bone marrow biopsy (only usually done if evidence of advanced disease)
- Lumbar puncture – If lymphoma is suspected in the brain or spinal cord
Your child may also undergo a number of baseline tests prior to any treatment commencing to check organ function. These are often repeated during and after treatment has completed to assess whether the treatment has affected organ function. Sometimes treatment and follow-up care may need to be adjusted to help manage any adverse side effects. These may include:
- Physical examination
- Vital observations (Blood pressure, temperature, & pulse rate)
- Heart scan
- Kidney scan
- Breathing tests
Many of these staging and organ function tests are done again after treatment to check whether the lymphoma treatment has worked and to monitor the effect treatment has had on the body.
Prognosis of anaplastic large cell lymphoma (ALCL)
The long-term survival rate for limited (early stage) anaplastic large cell lymphoma is between 80% – 90%. The long-term survival for advanced (stage III and IV) anaplastic large cell lymphoma is around 60% – 75%.
Those who do not respond completely to first-line standard treatment or relapse, still have treatments available to potentially achieve long-term remission.
Long-term survival and treatment options can also depend on a range of factors, including:
- Age of your child at diagnosis
- Extent or stage of the cancer
- The type of ALCL
- How the lymphoma responds to treatment
Talk to your child’s doctor about your child’s individual disease, treatment options and prognosis.
Treatment of anaplastic large cell lymphoma (ALCL)
Once all of the results from the biopsy and the staging scans have been completed, the doctor will review these to decide the best possible treatment for your child. At some cancer centres, the doctor will also meet with a team of specialists to discuss the best treatment option. This is called a multidisciplinary team (MDT) meeting.
The doctors will take into consideration many factors about your child’s lymphoma and general health to decide when and what treatment is required. This is based on:
- The stage and grade of the lymphoma
- Symptoms
- Age, past medical history & general health
- Current physical and mental wellbeing
- Social circumstances
- Family preferences
Since anaplastic large cell lymphoma is a fast-growing lymphoma, treatment may need to start within a few days or weeks after a diagnosis is made.
Chemotherapy protocols and common agents used include:
Stage I or Stage II localised disease can be treated with a short 9-week course of chemotherapy:
- CHOP chemotherapy regimen: (cyclophosphamide, doxorubicin, vincristine and prednisolone)
For advanced (Stage III and IV) disease, there are several effective treatment protocols including:
- APO: Adriamycin (Doxorubicin), Methotrexate, Vincristine, 6-mecaptipurine and Prednisolone. This protocol is generally administered over one year as an outpatient.
- ALCL 99: Dexamethasone, Cyclophosphamide, Methotrexate, Ifosphamide, Cytarabine, Etoposide and Doxorubicin. This protocol generally requires a hospital admission for its administration, but patients can go home between protocol cycles.
- NHL – BFM90: High dose Methotrexate, Cyclophosphamide, Ifosfamide, Etoposide, Doxorubicin
Common side effects of treatment:
The treatment for Anaplastic Large Cell lymphoma comes with the risk of developing many different side effects. Each treatment regime has individual side effects and the treating doctor and/or specialist cancer nurse will explain these to you and your child prior to starting treatment. For further information on some of the most common side effects and ways to help manage these in your child, see the section on common side-effects.
Some of the more common side effects of treatment for anaplastic large cell lymphoma (not all) include:
- Anaemia (low red blood cells)
- Thrombocytopenia (low platelets)
- Neutropenia (low white blood cells)
- Nausea and vomiting
- Bowel problems such constipation and diarrhoea
- Fatigue
- Reduced fertility
The medical team, doctor, cancer nurse or pharmacist, should provide you with information about the treatment, the common side effects, what symptoms to report and who to contact. If not, please ask these questions.
For more information contact the lymphoma care nurse support line on 1800 953 081 or email us at nurse@lymhpoma.org.au
Follow-up care
Once treatment has completed, your child will have post treatment staging scans. These scans are to review how well the treatment has worked. The scans will show the doctors:
- 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)
Your child will then need to be followed up by their doctor with regular follow-up appointments, usually every 3-6 months. These appointments are important so that their medical team can check how well they are recovering from treatment. They are also a good opportunity for you to talk to their doctor or nurse about any concerns you may have. Their medical team will want to know how they and you are feeling both physically and mentally, and to:
- 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
They are likely to have a physical examination and blood 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 particular reason for them. If they stay well, the appointments may become less frequent over time.
Relapsed or Refractory treatment for ALCL
Relapsed lymphoma is when the cancer has come back, refractory lymphoma is when the cancer is not responding to first line treatments. For some children and young people, Anaplastic Large Cell lymphoma returns and in some rare cases it does not respond to initial treatment (refractory). For these patients there are other treatments that can be successful, and may include:
- High dose combination chemotherapy followed by autologous (own cells) stem cell transplant or an allogeneic (donor) stem cell transplant
- Combination chemotherapy
- Single agent chemotherapy with vinblastine
- Immunotherapy
- Radiotherapy
- Clinical trial participation
When a relapse is suspected, often the same staging exams are done, which include the tests that were stated above in the ‘diagnosis and staging’ section.
Treatment under investigation
The prognosis of paediatric anaplastic large cell lymphoma has remained rather stagnant at 60% – 75% for advanced disease so there are ongoing investigations into the role of novel targeted therapies, such as ALK inhibitors and anti-CD30 antibody drug conjugates, in trials to try and improve outcomes.
There are many treatments that are currently being tested in clinical trials and some of these treatments include:
- Brentuximab Vedotin – anti CD30 antibody drug conjugate
- Crizotinib – ALK inhibitor
- Single agent chemotherapy with vinblastine
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.
Children and adolescents may have treatment-related side effects that can appear months or years after treatment, including problems with bone growth and development of sex organs in males, infertility, and thyroid, heart and lung diseases. Many current treatment regimens and research studies now focus on trying to decrease the risk for these late effects.
For these reasons it is important the survivors of anaplastic large cell lymphoma have regular heck ups.
