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Paediatric non-Hodgkin lymphoma

By Dr Mary Gerrard BSc MB ChB FRCPCH

Mary Gerrard qualified from the University of Manchester in 1977 and did her postgraduate training in paediatrics and paediatric oncology in Manchester, London, Bristol and Edinburgh. She has been a Consultant Paediatric Oncologist at Sheffield Children’s Hospital since 1988 and has always had a major research interest in non-Hodgkin lymphoma. Dr Gerrard has been actively involved in the development and running of clinical trials for NHL in the UK for many years.

Introduction

Lymphomas are the third commonest group of malignancies in childhood (after leukaemia and brain tumours).  Approximately 60% of lymphomas seen in childhood are non-Hodgkin lymphoma (NHL); the remainder are Hodgkin lymphoma¹ (formerly known as Hodgkin’s disease). However, NHL is a relatively rare disease in children; fewer than 100 children aged less than 15 years develop the disease each year in the United Kingdom.  NHL also occurs in young people, and some types are most common in late teenage or early adult life.  NHL is rare in children under the age of four years. Improvements in treatment mean that nowadays most children with NHL will be cured.

What causes NHL in children?

In most cases of childhood NHL there is no known cause.  However, children with underlying immunological problems such as a congenital immunological deficiency or acquired immune deficiency syndrome (HIV-AIDS) have an increased risk of developing NHL. 

How does NHL develop?

NHL develops in the lymphatic system. The lymphatic system includes a network of very thin tubes known as ducts that branch, just like blood vessels, into all parts of the body. These lymphatic ducts carry lymph: a colourless, watery fluid containing blood cells called lymphocytes. In addition to the lymphatic ducts, the lymphatic system also includes small, bean-shaped structures called lymph nodes; these are often referred to as ‘glands’. Lymph nodes are located on both sides of the neck, the underarms, and in the groin and abdomen. In addition the spleen (in the abdomen), the thymus (located in the chest just below the breastbone) and the tonsils are part of the lymphatic system.  Lymph nodes make and store particular blood cells that combat infection.  It is the transformation of these cells into malignant (cancerous) cells that results in the development of lymphoma. Because lymphatic tissue occurs throughout the body, NHL may develop in almost any part of the body. In addition, NHL can spread to involve almost any organ or tissue in the body, including the liver, bone marrow and the central nervous system.

Is NHL in children the same disease as in adults?

Many of the NHL types that are common in adults occur very rarely, if at all, in children.  These include low grade or ‘indolent’ lymphomas such as follicular lymphoma.  Most of the lymphomas seen in childhood are classified as ‘aggressive’ or high grade disease.  However, despite this, the majority of children with non-Hodgkin lymphoma can be cured with treatment. In general, the outcome for children with NHL is much better than for adults. 

Classification of childhood NHL

Determining the exact subtype of NHL is important as treatment varies for the different types. 

The classification is based on the histological (microscopic) appearances of the tumour.  The classification of lymphoma has over recent years become much more sophisticated and, in addition to standard histological examination, will now include tests to determine the precise immunophenotype of NHL, and may also include cytogenetic examination of the tumour material – as the chromosomes of the malignant cells often have specific abnormalities.  There are two main types of NHL seen in children.  These are T cell and B cell lymphomas.  There are normal white blood cells in the body which are known as T cells and B cells.  Both T cells and B cells are lymphocytes (a type of white blood cell) and they form part of the body’s defences, particularly against infection.

There are different subtypes within each of these two main categories of NHL (if you would like to receive a copy of the fact file ‘Lymphoma classification – why does it matter’, please call the Helpline).  For example, included amongst the B cell lymphomas are small non-cleaved cell lymphomas which are often referred to as Burkitt's and Burkitt-like lymphomas. Burkitt's lymphomas are more common in children than in adults.  They are particularly common in equatorial Africa, where Dennis Burkitt was working in 1965 when he described an unusual type of lymphoma, which occurred frequently amongst children in the region. Later research showed that the B-lymphocytes in these children were infected with the virus known as the Epstein-Barr virus (EBV). Infection with EBV causes glandular fever (also known as infectious mononucleosis).  This is relatively common, and usually does not cause serious problems, but in central Africa many children have chronic malarial infection, which reduces resistance to EBV. This can then allow the virus to change the infected B-lymphocytes into malignant or cancerous cells, which results in the development of the lymphoma. This is known as endemic Burkitt's lymphoma.  The Burkitt's lymphoma that occurs in western countries such as Europe and the USA looks very similar under the microscope to the African form, but is rarely associated with infection with EBV. Another type of B cell lymphoma which occurs in both children and adults is known as diffuse large B cell lymphoma.  T cell NHL includes lymphoblastic lymphomas and also the large cell anaplastic lymphomas. 

How does NHL present?

The presentation of lymphoma in children and young people depends on the subtype.  In general most lymphomas that develop in the abdomen are B cell lymphomas, and most that develop in the chest are T cell lymphomas.  However, B cell NHL can also occasionally develop in the chest; if it does it is nearly always of the diffuse large B cell type. Lymphomas in the head and neck may be either B or T cell disease.  Large cell anaplastic lymphomas can present in the chest or the abdomen or at other sites such as the head and neck. Skin and bone involvement may occur with this type of lymphoma.  B cell lymphomas account for around 50% of the NHL seen in children. T cell lymphoblastic  NHL make up around 20-25% and anaplastic lymphoma around 15-20%. 

T cell lymphoblastic lymphomas most commonly cause enlargement of a gland inside the chest, in an area known as the mediastinum.  Enlargement of these glands can cause pressure on the trachea (windpipe) and result in coughing or breathlessness.  Sometimes there is also pressure on the blood vessels inside the chest and this can lead to swelling of the neck, redness of the face, and prominence of the neck veins. These symptoms, particularly of coughing and breathlessness, may be mistaken for asthma.  B cell lymphoma often involves glands in the abdomen which may cause abdominal pain and vomiting and sometimes the abdomen becomes distended. Some children present with unusual sites of involvement such as skin lumps. Symptoms such as unexplained fever, weight loss and night sweats may also occur.

Investigations to diagnose and stage NHL

If lymphoma is suspected there are a number of investigations that are required. These are firstly to confirm the diagnosis and in addition to assess the extent of the disease.  To make the diagnosis a biopsy of the ‘primary’ tumour (the site in the body where the tumour first occurred) is required.  In addition to this it is necessary to examine the bone marrow (where the blood cells are produced) by aspirate and biopsy, and the cerebrospinal fluid (the clear fluid which flows around the brain and spinal cord) by lumbar puncture. It is important to know whether lymphoma is present in the bone marrow or cerebrospinal fluid before treatment is given, because if either is involved additional treatment is required.

Blood tests to estimate the blood count and blood chemistry are also required before treatment starts.  In addition to these investigations, the full staging assessment may involve x-rays of the chest, and CT or MRI scans of the chest, abdomen and pelvis. Ultrasound scans are often also done, particularly for examining the abdomen or pelvis.  The information obtained from these investigations is used to determine the stage of the lymphoma (see below) and this, along with the information from the biopsy regarding the precise subtype of NHL, is used to plan the most appropriate treatment. 

Staging of non-Hodgkin lymphoma

There are a number of different staging systems but the one most frequently used for NHL in children and young people is called the St Jude classification. 

Stage 1            The lymphoma involves a single site or group of lymph nodes, but this does not include tumours arising within the abdomen or chest

Stage 2            Any of the following means the disease is stage 2

Lymphoma involves a single site and the lymph nodes associated with that site.

Lymphoma is found in two or more groups of lymph nodes or other areas on the same side of the diaphragm (the sheet of muscle below the lungs that separates the chest from the abdomen).

Lymphoma involves the digestive tract but has been removed by an operation.

Stage 3            Any of the following means the disease is stage 3

There is lymphoma in lymph nodes on both sides of the diaphragm.

Lymphoma that arises in the chest -  mediastinal lymphoma.

Extensive lymphoma in the abdomen – that cannot be removed by operation.

Lymphoma involves the area adjacent to the spine, or on or around the outermost covering of the brain.  These are paraspinal and epidural tumours. 

Stage 4            Lymphoma involves the bone marrow, or is found within the central nervous system – either in the cerebrospinal fluid, or within the brain or spinal cord.  The bone marrow or central nervous system may be the only sites of disease, or may be involved in addition to other sites in the body. 

Stage 1 and 2 are sometimes referred to as localised NHL.  Similarly stages 3 and 4 may be referred to as extensive NHL. The majority of children with NHL are found to have stage 3 or 4 disease when they are diagnosed.  This is because NHL in children tends to develop and spread quickly.

Treatment of NHL

The outlook for children and young people with NHL has improved considerably over the last 30 years² and today most are cured with chemotherapy. Radiation therapy is also sometimes used in addition to chemotherapy, but much less so than in treatment of adult lymphomas. The role of surgery is limited to biopsy, or occasionally resection of localised abdominal tumours. High dose chemotherapy with stem cell transplantation (from peripheral blood or bone marrow) is sometimes used, mainly for patients who have had a relapse of their disease. Most children with NHL will have a central line such as a Hickman or Broviac line or portacath inserted into the chest (please contact the Helpline if you would like more information about central lines) during a small operation before treatment starts.  This can be left in place for many months, and is used to give intravenous chemotherapy without having to keep putting in a new intravenous cannula. 

Most children with NHL are referred to a paediatric oncologist or paediatric haematologist working in one of the specialist centres in the UK. There are 22 paediatric oncology centres located throughout the UK and Ireland.  Doctors working in paediatric oncology and haematology are members of the UK Children’s Cancer Study Group (UKCCSG), an organisation set up in 1977 to develop and carry out treatment trials with the aim of improving outcome and quality of long-term survival in children’s cancer. Many children with NHL will be offered the choice of taking part in a clinical trial if available.     

The improvement in survival results have nearly all happened because of clinical trials of treatment.  Over recent years, because of the rarity of childhood NHL, groups of doctors from several countries have worked together to develop treatment trials.  In 1977 the overall survival was around 55%. Currently more than 85% of children with NHL are cured.  Chances of cure are better with localised disease. However, even children with extensive disease can be cured with intensive chemotherapy.

For a number of years the UKCCSG have developed trials for paediatric NHL in collaboration with colleagues in Europe, and also the USA.  Trials examine whether one treatment is better than another, or sometimes whether treatment can be safely reduced for children with a better outlook. The hope is to minimise the toxicity of treatment both in the short term, and also, which is particularly important for children, in the longer term.

Treatment of NHL by subtype

Lymphoblastic lymphoma is treated with combination chemotherapy, using a course of treatment similar to that used for children with acute lymphoblastic leukaemia.  The course of treatment usually lasts for 2 years, with intensive blocks of treatment given over the first 6 months, followed by a less intensive 'continuation treatment' for a further 18 months.  Children who have less advanced disease – stage 1 or 2 - receive fewer blocks of intensive chemotherapy than children with more advanced disease i.e. stage 3 or 4. 

The first part of treatment may be referred to as the ‘induction block’. It is given over about two months, and involves a number of different drugs – many are intravenously administered, some are tablets. In addition, some chemotherapy is injected directly into the spinal fluid by lumbar puncture – this is known as intrathecal treatment.  Tests such as scans to assess response to treatment are carried out during this block, and it is expected that the disease should have responded well by the completion of this block.  If the response to treatment is not satisfactory, different treatment will be discussed.  A clinical trial for lymphoblastic lymphoma opened in September 2004 in the UK.

The trial also involves doctors and patients from a number of other European countries, including France, Germany, Spain and Italy.  The purpose of the trial is to investigate whether the length of continuation treatment can be reduced from 18 to 12 months.  The reason it is thought this should be possible is that results from a previous German study using this type of approach are very good, with 90% success rate.  As the relapses in the German study occurred within the first few months, it appears likely that such a prolonged course of treatment with the risk of additional complications is not required for the majority of patients.    

Most children and young people with lymphoblastic lymphoma treated in this way will not relapse.  If relapse occurs then treatment options are more limited, and usually involve further chemotherapy.  Depending on the type of relapse and the previous treatment given, this may involve using high dose chemotherapy and radiotherapy with stem cell transplantation using blood stem cells harvested from a donor. This is done by using either the donor’s peripheral blood stem cells or stem cells harvested from bone marrow. 

Small non-cleaved cell lymphoma (Burkitt’s, Burkitt-like) is treated with chemotherapy.  At the present time there is no open trial of treatment in this country for this type of paediatric NHL. Treatment is recommended to follow guidelines produced by the UKCCSG, based on results obtained from the FABLMB trial: a large international trial (involving the UK, France and the USA) which ran from 1996 until 2001.  The results of this trial confirmed that the amount of treatment that needs to be given varies depending on the stage of the illness.  Very localised disease, stage 1 or 2, which has been removed by surgery, can be successfully treated with only two courses of a combination of four drugs. More extensive disease will be treated with between five and nine courses of several different chemotherapy drugs depending on the extent of disease. Prolonged continuation (also referred to as ‘maintenance’) treatment is not required for this type of lymphoma. Detailed assessment of the response to treatment is carried out at regular intervals. Previous experience has shown that those children who have an inadequate response to the very first course of treatment should have treatment intensified to improve their chance of cure. In addition it is known that children who have persisting evidence of disease (usually determined by scans) after the first four courses of treatment, should undergo surgery to remove this if possible, or biopsy if surgery is not possible.  If the biopsy shows evidence of active tumour then more intensive treatment should be given.

Once treatment has been successfully completed for this type of lymphoma, most children do not relapse.  If relapse does occur, this tends to happen within 18 months of diagnosis and is unusual after this time.  Treatment for relapsed disease depends on what previous treatment has been used.  If very intensive treatment has already been given, the options for curative treatment are limited.  Further treatment may involve further chemotherapy, including high dose chemotherapy and bone marrow/peripheral blood stem cell transplantation. This might use the patient’s own stem cells if the bone marrow is not involved with disease, or stem cells from a donor if the relapse involves the bone marrow.  Relapsed disease may also be treated using immunotherapy with a drug called rituximab which can ‘recognise’ tumour cells and destroy them.  Rituximab has been used for some time in treatment of adults with NHL, but there is so far only limited experience of its use in children.  There are a small number of trials being conducted in Europe and the USA in children, and it is hoped these trials will determine what role this drug has in the treatment of paediatric NHL. 

Diffuse large B cell lymphoma is usually treated in a similar way to other B cell lymphomas such as Burkitt’s lymphoma.  There is a sub-group of this type of lymphoma which arises in the chest and is most often seen in teenagers and seems to be more common in girls.  This type of lymphoma seems to be less responsive to standard treatment and it is not yet clear whether these patients benefit from more intensive treatment, or radiotherapy.   

Large cell anaplastic lymphoma is treated with chemotherapy in a broadly similar way to B cell NHL.  A European clinical trial for paediatric anaplastic NHL is investigating whether the two methods of treating the central nervous system are equally effective at controlling the disease in that system.  Also, for patients at higher risk of relapse, the trial is examining whether the addition of another drug (vinblastine) results in fewer relapses. This trial, which opened in 2000 and is anticipated to remain open for another 2-3 years, involves groups from several European countries, including the UK.  

Side-effects of treatment

Short-term side-effects

Because chemotherapy drugs work by killing dividing cells, they affect normal dividing cells as well as the malignant cells, and this causes side-effects.  The normal cells in the body that are dividing include those in the bone marrow, the gut and the hair follicles.  These side-effects include bone marrow suppression leading to a low blood count, and increased susceptibility to infection and problems with bleeding or anaemia.  Hair loss is usual with treatment for NHL.  For children with lymphoblastic NHL the hair starts to regrow once treatment changes to the oral continuation therapy, ie after the initial intensive treatment.   Loss of appetite is common with the chemotherapy used for NHL; in addition mucositis – sore mouth and throat - is a common problem, making it difficult for a child to eat and drink.  Your child’s weight will be checked regularly, and if he or she loses too much weight then he/she may need to be fed through a naso-gastric tube (a thin tube passed through the nose into the stomach), or intravenously through the central line.  

Longer-term side-effects.  Following treatment for NHL most children will not have serious long-term health problems.  However the drugs that are used may cause effects which may not be apparent for some time.  Part of the follow up that is done involves assessment for these, which may include specific scans and blood tests. The main long-term effects that may arise following treatment for NHL include cardiac toxicity (affecting the heart) and effects on pubertal development and fertility.   

Cardiac toxicity may arise as a result of treatment with the anthracycline family of drugs.  These include doxorubicin and daunorubicin both of which are used in the treatment of NHL. They are very effective drugs in the treatment of lymphoma so currently it is not possible to avoid their use.  The risk of cardiac damage is increased if higher total doses of these drugs are used, and so the total dose is kept as low as possible. Your child’s doctor will regularly check the health of his/her heart at follow-up visits by doing regular echocardiograms (ultrasound scans of the heart). 

Fertility can be particularly affected by the group of drugs known as alkylating agents which include the drugs cyclophosphamide and ifosfamide, both of which are used in the treatment of NHL.  The risk of infertility is increased if higher doses of these drugs are used, and so the total dose is kept as low as possible.   

The FABLMB trial for B cell NHL was able to demonstrate that the outcome in terms of survival and freedom from relapse was as good for those with so called ‘standard risk’ disease who were given lower doses of both anthracycline and cyclophosphamide.  This means that the risk of long-term toxicity from these drugs can be reduced by using these lower doses, without reducing the chance of cure. 

Paediatric NHL - future considerations

With current treatment the majority of children with NHL survive. Because childhood NHL is a relatively rare disease, in order that successful clinical trials can continue, it is essential that these involve other national groups both in Europe and also in the United States. Over the last few years collaboration between Europe and the USA has led to improvements in outcome for children with NHL.   

The challenge for the future lies in refining treatment so that children who do have a potentially better outcome receive the least intensive treatment required to control their disease. A major challenge also remains to define treatment strategies for the patient who relapses.  

Improvements in survival for adult patients with NHL using a combination of chemotherapy and targeted monoclonal antibody therapy such as rituximab suggest that immunotherapy may be a possible future treatment strategy for children with NHL. How best to use this and other similar agents is the subject of current investigation.

Glossary 

Antibody                       any of a large number of proteins that are produced normally by specialized B cells (lymphocytes) after stimulation by an antigen and act specifically against the antigen in an immune response. They can also be produced abnormally by some cancer cells 

Biopsy                          a sample of affected tissue which is taken to see if abnormal cells are present and to confirm a diagnosis. Examination of the cells and their arrangement in the sample, as seen under the microscope, indicates the exact type of lymphoma 

Chromosomes              the self-replicating genetic structures of cells containing the cellular DNA

Cytogenetics                 the study of the structure of chromosomes. Cytogenetic tests are carried out on samples of tumour tissue and/or bone marrow to detect any chromosomal abnormalities associated with the disease. These can help in the more precise diagnosis of the type of lymphoma and so the selection of the optimal treatment 

Immunophenotype         A more precise way of describing the type of tumour cell based on the cell’s immunochemical (the proteins which are present within the cell and on the surface) and immunohistological characteristics (what the cell looks like). The immunophenotype varies depending on the type of tumour cell  

Immunotherapy             Treatments which use antibodies to fight specific cancers in the same way as the immune system fights infections 

Lumbar puncture (LP)   this provides a route through which a sample of the cerebrospinal fluid can be taken for examination, or through which treatment can be administered if necessary 

Small non-cleaved cell   Description of the microscopic appearance of a type of B cell NHL; includes Burkitt’s and Burkitt-like lymphomas

References

¹ Parkin DM, Kramarova E, Draper GJ, et al; eds: International incidence of childhood cancer, vol 2. IARC Scientific Publications No 144, 1998.

²Percy CL, Smith MA, Linet M, et al: Lymphomas and reticuloendothelial neoplasms. In: Ries LA, Smith MA, Gurney JG, et al, eds: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999.