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Gastric MALT lymphoma MALT lymphoma is a slow-growing cancer of the lymphatic system, which is part of the body's immune system. It is a type of non-Hodgkin lymphoma. MALT lymphomas usually affect people in their 50s and 60s, but they can occur in younger and older people too. MALT lymphomas can develop almost anywhere in the body but the most common place for MALT lymphoma to develop is in the stomach – gastric MALT lymphoma. Gastric MALT lymphomas account for fewer than 1 in 20 of all primary gastric tumours (cancers that start in the stomach), so it is an unusual type of stomach cancer. In this article we aim to answer the questions you might have about gastric MALT lymphoma: • What is MALT lymphoma? (see below) • What causes gastric MALT lymphoma? (page 3) • What are the symptoms of gastric MALT lymphoma? (page 4) • What tests will I need? (page 5) • How is gastric MALT lymphoma treated? (page 6) • What happens after the treatment is finished? (page 8) If you have a MALT lymphoma that has started somewhere else (ie not in the stomach), our information on non-gastric MALT lymphoma would be more suitable for you. Please ring our helpline on 0808 808 5555 if you would like this to be sent to you, or download the information from our website (www.lymphomas.org.uk).

What is MALT lymphoma? What is lymphoma? A lymphoma is a cancer of cells called lymphocytes, which are white blood cells that normally help the body to fight infections. There are two kinds of lymphocyte, B lymphocytes (usually just known as 'B cells') and T lymphocytes (T cells). B cells are made in the bone marrow, which is a spongy tissue found in the middle of some of our bigger bones. T cells start their life in the bone marrow but they mature in the thymus, a gland in the chest which lies behind the sternum or breastbone. Lymphocytes collect particularly in lymph nodes (glands). Lymph nodes are found in groups, particularly under the arms, in the neck and in the groin. We also have groups of lymph nodes internally, around our organs. Lymphocytes can also be found in other parts of the body, such as in the spleen and the thymus. These places are all part of our lymphatic system (see Figure 1 on page 2). The cells and organs that make up the lymphatic system are also called lymphoid tissue. Gastric MALT lymphoma

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If lymphocytes start to divide and multiply uncontrollably or if they don’t die off after their normal lifespan, they can build up and form a lymphoma. Figure 1: The lymphatic system

Neck (cervical) lymph nodes Lymph vessels

Thymus Diaphragm (muscle that separates the chest from the abdomen)

Armpit (axillary) lymph nodes

Spleen Liver

Groin (inguinal) lymph nodes

What types of lymphoma are there? Lymphomas can develop from either type of lymphocyte. There are therefore B-cell lymphomas and T-cell lymphomas. If a lymphoma develops and grows quickly it is called a ‘high-grade’ or 'aggressive' lymphoma. If it is slow-growing it is described as a ‘low-grade’ or ‘indolent’ lymphoma. There are over 60 types of lymphoma but there are two main kinds, Hodgkin lymphoma and non-Hodgkin lymphoma. These look different when they are examined under the microscope in the laboratory and they affect people differently.

What kind of lymphoma is MALT lymphoma? MALT lymphomas are low-grade B-cell non-Hodgkin lymphomas and they represent about 8% of all non-Hodgkin lymphomas. Their official name is ‘extranodal marginal Gastric MALT lymphoma

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zone lymphoma of mucosa-associated lymphoid tissue’. They are described as extranodal lymphomas because, unlike most lymphomas (which develop in lymph nodes), MALT lymphomas form outside the lymph nodes – in what are known as extranodal sites. They are called marginal zone lymphomas because, looking at specimens under the microscope, the cancerous lymphoma cells appear to have grown from B cells that are normally found in an area of lymphoid tissue called the 'marginal zone'. MALT is short for mucosa-associated lymphoid tissue. Mucosa is a soft, moist protective tissue that lines many parts of our body, such as our mouth and gut, breathing passages and other internal organs. Lymphocytes can be found in mucosa, attracted there as part of a reaction to an infection or to inflammation. When lymphocytes collect in mucosa they form patches of what is called 'mucosa-associated lymphoid tissue' or MALT – this is a normal immune reaction. MALT lymphomas look similar to MALT tissue when they are looked at under the microscope. MALT lymphomas can develop almost anywhere in the body, including the gut, the salivary glands, the lung, the thyroid gland, the skin and around the eye. The most common place for MALT lymphoma to be found is the stomach. Gastric (stomach) MALT lymphomas account for roughly a third of all MALT lymphomas. MALT lymphomas tend to stay near to where they first develop in the body, though in a third to a half of people they are found in more than one extranodal site when they are diagnosed. They are low-grade lymphomas, so they develop slowly. They generally have a good outlook, even if they are in more than one place in the body when they are first diagnosed – the majority of people with MALT lymphomas survive for 10 years or longer.

What causes gastric MALT lymphoma? Lymphocytes start to grow out of control and form a lymphoma because something happens to change or damage their genes. If their genetic make-up changes they might not be able to control how quickly they divide or die off. With most types of lymphoma it is not known why these genetic changes happen in the lymphocytes. With some of the MALT lymphomas, however, research has shown possible causes for the genetic changes and the formation of the lymphoma. It has been noticed that some MALT lymphomas develop where MALT tissue has formed in response to inflammation caused by a chronic (long-lasting) infection or an autoimmune condition (a condition in which the body’s immune system reacts against its own tissue instead of protecting it). For some MALT lymphomas this underlying inflammatory condition remains a mystery. For others, more is known about the factors that might have played a part in the development of the lymphoma. Gastric MALT lymphoma has been strongly linked to an infection by a bacterium called Helicobacter pylori. People with a gastric MALT lymphoma will quite commonly be found to have had this infection. Helicobacter pylori causes gastritis, which is inflammation of the mucosa or lining of the stomach. Lymphoid tissue develops in the stomach mucosa as part of this inflammatory reaction. Once this MALT tissue has formed, there is continuous Gastric MALT lymphoma

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stimulation of the lymphocytes within it to divide and increase in number as a result of the constant presence of the bacteria. This is a normal immune reaction, but in a small number of people this constant stimulation results in a mistake occurring within the genetic material of a lymphocyte. These faulty cells go on to multiply and they do not die off as they would normally. This eventually leads to a build-up of cells and the development of a lymphoma. Not everyone who has this infection will develop a gastric MALT lymphoma, however. This means that there must be other reasons for the lymphocytes losing control of their growth. Researchers are trying to find out more about why MALT lymphomas develop in some people with inflammation and not in others. But be assured that nothing you have done – or not done – will have caused the lymphoma to develop. Also, although the lymphoma forms when the genes in the lymphocytes change in some way, MALT lymphoma is not a disease that you can inherit or pass on to your family.

What is Helicobacter pylori? Helicobacter pylori, which is often shortened to H. pylori, is a spiral-shaped bacterium that we know has been around for many centuries. It is unusual in that it has become adapted to survive in the acid conditions found in the stomach, conditions that would destroy most other organisms. The bacterium has been found all over the world, although more people are infected in some countries or regions than in others. The bacterium is thought to be passed on from person to person and close personal contact appears to make this infection spread more easily. Infection normally happens in childhood and most people will then have it for their whole life unless it is treated. It can be quite difficult to treat this infection and eradication (complete removal) of the bacterium normally involves the use of a combination of antibiotics, together with a drug that cuts down the amount of acid that is secreted in the stomach. The exact combination used varies between treatment centres. In some people, the first attempt to eradicate the organism fails and different drug combinations might have to be tried before eradication is successful.

What are the symptoms of gastric MALT lymphoma? In most people gastric MALT lymphoma is found during tests for persistent indigestion – although only a very small percentage of people with indigestion or heartburn will have lymphoma. The indigestion is probably more related to the presence of the H. pylori infection than to the lymphoma and people often feel better after they have had treatment to eradicate the infection, whether or not the lymphoma is regressing (decreasing). A few people with gastric MALT lymphoma go to their doctor with other symptoms, such as abdominal pain, nausea (feeling sick), vomiting (possibly with specks of blood in the vomit) and weight loss. Some people will have symptoms of anaemia, such as tiredness and shortness of breath, because the stomach lining has been bleeding, but this is quite rare. Severe abdominal pain or the finding of a lump or mass in the abdomen would also be unusual. Gastric MALT lymphoma

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What tests will I need? How is gastric MALT lymphoma diagnosed? For a gastric MALT lymphoma to be diagnosed, the stomach lining has to be examined and biopsied. Tests for H. pylori infection are also needed to confirm the diagnosis. Endoscopy: Gastric MALT lymphoma is usually discovered unexpectedly during an endoscopy examination of the stomach. This is a test in which a flexible tube with a light and a tiny camera in its tip is passed down through the mouth into the stomach. You would normally be offered a sedative when you have this test. The lining of the stomach might just look generally inflamed or swollen. It is quite common to see ulcers. In a few people a nodular (lumpy) mass might be seen in the stomach during endoscopy. Biopsy: It is very difficult, and often impossible, to tell the difference between lymphoma and the much more common kind of stomach cancer just by looking at these ulcers or nodules during the endoscopy examination, so small samples of the stomach lining – biopsies – will be taken during the endoscopy. The biopsies will be examined under the microscope, when the pathologist will assess: • the size and shape of the lymphoid cells • where the cells are positioned within the stomach lining • how the cells interact with the other parts of the stomach wall. Sometimes, reaching a diagnosis can even be difficult when the samples are examined under the microscope. Biopsies are therefore often put through more detailed tests, sometimes in another laboratory, and this can take up to 2–3 weeks. These tests are done to look at the types of proteins on the surface of the lymphoma cell (immunohistochemistry tests) and at the genetic make-up of the lymphoma cells (cytogenetics tests). These specialised tests help the doctors to predict how well the lymphoma is likely to respond to therapy (see page 7). Sometimes, even using the latest sensitive techniques, it will not be possible to distinguish confidently between a lymphoma and inflammation in the stomach and several biopsies and more than one endoscopy are needed. Testing for H. pylori organisms: It is very important that the presence of the H. pylori organism is confirmed so that a firm diagnosis can be made. This has often already been tested for before the endoscopy. There are several ways of testing for this. In one method a stool sample is collected and tested. Sometimes the organisms are very scanty and difficult to find and you might have other tests done to look for evidence of the infection.

How is gastric MALT lymphoma assessed? Tests will also be done to find out whether the lymphoma is in one place or in more than one place. Assessing how much of the body is affected like this is called 'staging', and the results of these tests help the doctors to plan the most suitable treatment.

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In order to assess the gastric MALT lymphoma, you are likely to have: •  blood tests – to check your blood counts and the levels of certain chemicals in your blood, and to check that your kidneys and liver are working well. • scans: – CT scan (computed tomography) – this the most usual scan that is done. This kind of scan produces pictures of your internal organs in cross-section, from top to bottom, and will show if any of the lymph nodes in the chest, abdomen or pelvis are affected by the lymphoma –e  ndoscopic ultrasound – a scan using high-frequency sound waves (ultrasound) will also be done during the initial endoscopy or during a later endoscopy in order to assess how far the lymphoma has spread through the stomach wall. In this test a tiny ultrasound probe is attached to the tip of the endoscope and scan images will be seen on a monitor. The ultrasound scan will show up the tissues that lie deep to the stomach lining and will also show whether there is any lymphoma in lymph nodes near the stomach. Other tests that you might have are: •  bone marrow biopsy – this test involves taking a sample of bone marrow through a needle. The needle is usually inserted through your skin into your hip bone after the skin has been numbed using local anaesthetic. This test takes around 15 minutes. The bone marrow is only involved in about 1 in 10 people with gastric MALT lymphoma, however, and a bone marrow biopsy might only be done if the lymphoma does not regress (go away) with the initial treatments. •  PET scan (positron-emission tomography) – some people will have this kind of scan if their specialist feels this would be helpful in planning the treatment. Unlike lymphomas that start in the lymph nodes, MALT lymphomas tend to spread to other extranodal sites rather than to lymph nodes. MALT lymphoma can be found in places like the thyroid gland or other parts of the bowel, for example. These other extranodal sites would therefore normally be examined and tested as part of your general assessment and the staging of the lymphoma.

How is gastric MALT lymphoma treated? The initial treatment for gastric MALT lymphoma is a course of treatment to eradicate the H. pylori infection. This will successfully treat the lymphoma in most people who showed evidence of H. pylori infection in their tests. Some people will need to have this eradication treatment more than once and a few people will go on to need other treatments such as chemotherapy or radiotherapy.

H. pylori eradication Treatment of the H. pylori infection leads to regression of the lymphoma in about 8 out of every 10 people with gastric MALT lymphoma who showed evidence of an H. pylori infection. The treatment is most successful when the tumour has not extended very far through the stomach wall and has not spread to the lymph nodes. Gastric MALT lymphoma

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You would normally be prescribed an initial course of antibiotic treatment for H. pylori eradication – clarithromycin together with either amoxicillin or metronidazole. These antibiotics are usually given with a drug that cuts down the amount of acid the stomach produces (a proton pump inhibitor or 'PPI' drug such as omeprazole). This combination of three drugs is often called ‘triple therapy’ and is taken for 10–14 days. A few weeks after the eradication treatment has finished you will be tested again for H. pylori infection. This is sometimes done using a simple 'breath test', in which a sample of your breath is analysed after you have had a special drink. If tests show that the infection is still there, you will be given another course of antibiotics, usually using different drugs from those used in your first course. Then you would be tested for the infection again. The interval of time between eradication of the H. pylori infection and regression (disappearance) of the lymphoma is very variable. In some people the lymphoma might be found to have regressed at the first follow-up biopsy (see page 8). In other people it can take a year or more for the lymphoma to go away completely. If the H. pylori treatment is successful you will not need any other treatment.

Why does H. pylori eradication not work in some people? It is impossible to predict with 100% accuracy whether a lymphoma will or will not respond to H. pylori eradication therapy. Also, as we have seen, it is not possible to predict how long the lymphoma will take to decrease in size or disappear altogether, even if the therapy is successful. There are, however, certain features that make it less likely that the lymphoma will respond well to antibiotic eradication therapy. In general, eradication therapy is usually less successful if: • the H. pylori organism cannot be identified in the tests and there is no evidence of previous infection • the lymphoma has extended deeply through the stomach wall • the lymphoma has spread to lymph nodes. There are also some features in the MALT lymphoma cells that, if they are present, make it easier to predict that there will be a poorer response to antibiotic eradication therapy. For example, eradication therapy is less likely to be successful if the cytogenetics tests report that the lymphoma is ‘t(11;18)-positive’. If the tests showed this the medical team might suggest treatment with more conventional lymphoma treatments – chemotherapy or radiotherapy (see below).

What happens if the treatment if H. pylori eradication doesn’t work? Some people do not respond to eradication therapy alone and need to have more conventional anti-lymphoma therapies such as chemotherapy or radiotherapy. These are very effective treatments for gastric MALT lymphoma. MALT lymphomas are very sensitive to radiotherapy and the doses needed are not very high, so this is a safe treatment. Radiotherapy is used to treat the lymphoma if it is localised (in one place).

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If the lymphoma is in more than one place, it would be treated with chemotherapy. You might be prescribed cyclophosphamide, chlorambucil, cladribine or fludarabine. The doctors will choose the drug that is most suitable for you on the basis of the tests you had to assess your general health and your lymphoma. These drugs all appear to work equally well. Another treatment for gastric MALT lymphoma that is being assessed in clinical trials is antibody treatment. In this treatment you are given a specially manufactured protein antibody called rituximab (MabThera®), which works by attaching itself to the abnormal lymphoma cells. This targets the lymphoma cells so that your own immune system can then find them more easily and kill them. When rituximab is used it is usually given together with a chemotherapy drug such as chlorambucil. Gastric MALT lymphoma is not treated by surgery. One reason for this is that, although the lymphoma tends to be concentrated in one part of the stomach, there are usually small areas of lymphoma spread all over the stomach lining. This means that removing a small part of the stomach would not remove it all.

What happens after the treatment is finished? Follow-up after your treatment After your course of eradication therapy you will have a test (usually a breath test) to check for H. pylori about 4–6 weeks after the treatment has finished. About 3–6 months after the treatment has finished you will have another endoscopy. A biopsy is usually taken during this endoscopy to make sure that the infection has been eradicated and to assess whether the lymphoma is decreasing. After that you might expect to have endoscopy examinations about every 4–6 months at first, dropping eventually to once a year. Biopsies might be taken at these later endoscopies if the medical team feel this would be helpful. The timing of your follow-up visits and examinations will depend on many factors, such as how long it has taken for the lymphoma to regress completely and what treatments you had. The outlook for people with gastric MALT lymphoma is good, so some clinics discharge patients after a fixed time of being in remission (when there is no sign of the lymphoma). Other doctors follow up their patients with gastric MALT indefinitely. Your team will give you information on what to expect.

What happens if gastric MALT lymphoma comes back? In a small proportion of people a follow-up endoscopy will show that the lymphoma has relapsed (come back). If the H. pylori infection has also come back, this usually responds to further antibiotic-based therapy. In a small number of people, relapse detected on microscopic examination of a biopsy clears spontaneously with no further treatment at all, so it is quite common to monitor this situation without giving further treatment. A few people whose lymphoma has clearly come back will be treated with chemotherapy and/or radiotherapy in the same way as people who do not respond to the initial eradication therapy are treated (see pages 7–8). These are very effective treatments in these circumstances too. Gastric MALT lymphoma

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In around 1 in 10 people the lymphoma turns into a faster-growing form of lymphoma called 'diffuse large B-cell lymphoma’. This is called ‘transformation’. When this happens the lymphoma is usually treated with intravenous chemotherapy using a combination of drugs, with the aim of curing this more aggressive disease. We have separate information on radiotherapy, chemotherapy and antibody treatments. We also have information on transformation. Please ring our helpline if you would like to talk to someone about your treatment or if you would like any of this information sent to you (0808 808 5555). The information is also available to download from our website (www.lymphomas.org.uk).

Acknowledgement We are grateful to Dr Andrew Wotherspoon, Consultant Histopathologist at The Royal Marsden Hospital, London for reviewing this information.

Useful organisations Macmillan Cancer Support  0808 808 0000 (Monday–Friday, 9am–8pm) www.macmillan.org.uk CancerHelp UK CancerHelp UK is the patient information section of Cancer Research UK.  0808 800 4040 (Monday–Friday, 9am–5pm) www.cancerresearchuk.org

Sources used in this information Our information is written using the most up-to-date published research available and current nationally recognised guidelines. If you want to know which textbooks, guidelines and research papers we used as sources for this information, please contact us by emailing the publications team on [email protected] or ring us on 01296 619409.

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How you can help us We continually strive to improve our information resources for people affected by lymphoma and we would be interested in any feedback you might have. Please visit www.lymphomas.org.uk/feedback or email [email protected] if you have any comments. Alternatively please phone our helpline on 0808 808 5555.

We make every effort to ensure that the information we provide is accurate but it should not be relied upon to reflect the current state of medical research, which is constantly changing. If you are concerned about your health, you should consult your doctor. The Lymphoma Association cannot accept liability for any loss or damage resulting from any inaccuracy in this information or third party information such as information on websites which we link to. Please see our website (www.lymphomas.org.uk) for more information about how we produce our information. © Lymphoma Association PO Box 386, Aylesbury, Bucks, HP20 2GA Registered charity no. 1068395 Updated: January 2014 Next planned review: 2016

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