Gastric MALT lymphoma

by Dr Andrew Wotherspoon

Andy Wotherspoon qualified at the Welsh National School of Medicine in 1984. He trained in Histopathology at University College Hospital, London. After a short appointment as a senior Lecturer in Histopathology at the Royal Postgraduate Medical School he became a Consultant Histopathologist at the Royal Marsden Hospital where he specialises in the diagnosis of haematological and gastrointestinal cancer. During his training he developed a research interest in lymphoma with particular emphasis on genetics of gastric MALT lymphoma and the association between gastric lymphoma and Helicobacter pylori. He has over 120 publications and was nominated as an Eminent Scientist of the Year 2003 by the International Research Promotion Council. 

What is MALT lymphoma?

MALT lymphoma is an indolent (commonly called low grade) type of B-cell non-Hodgkin lymphoma, first recognised as a specific type of lymphoma in 1983[1]. It occurs at sites that are outside lymph nodes or the spleen.  The organisation of the lymphoma cells, when viewed under the microscope, resembles the lymphoid tissue normally found in the gut, which is called ‘mucosa-associated lymphoid tissue’ (MALT).  MALT lymphoma most frequently arises within this type of lymphoid tissue after it has accumulated as part of a reaction to an infection or inflammation.

In the new World Health Organisation classification of lymphoid tumours[2], MALT lymphoma is more correctly called 'extra-nodal marginal zone B-cell lymphoma'.  This is because there is now strong evidence to suggest that the type of cell from which the lymphoma develops is a specific B-cell which is founding a specific compartment of the lymphoid tissue called the marginal zone.  

How common is MALT lymphoma and where does it occur? 

MALT lymphoma is the third most common type of non-Hodgkin lymphoma, although it only accounts for about 7-8% of these tumours.  MALT lymphomas have been described at almost all extra-nodal sites (sites other than lymph nodes), but are most commonly found in the gastrointestinal tract - the gut - (50% of all MALT lymphomas) within which the stomach is the most frequently involved area (34% overall; 50-70% of gastrointestinal MALT lymphomas). It appears to be a contradiction that MALT lymphomas are found least frequently in sites in which MALT is normally present, like the terminal part of the small intestine, and seem only to develop when the lymphoid tissue arises in response to infection or other cause of inflammation. 

Gastric MALT lymphomas account for up to 4% of all primary gastric tumours and 40-50% of all primary gastric lymphomas (the remaining being mostly the more aggressive (commonly called high grade) diffuse large B-cell lymphomas). 

MALT lymphomas are approximately equally distributed between men and women. This lymphoma is most frequent in late middle aged/elderly people although it may be found in any age-group.  

How do MALT lymphomas develop? 

MALT lymphomas arise at sites that have acquired some MALT-type lymphoid tissue due to some other disease/disorder or infection. For some MALT lymphomas this underlying condition remains a mystery, while for others more is known about predisposing factors. For example, in the thyroid and salivary glands, MALT lymphomas can develop due to autoimmune inflammatory conditions known respectively as Hashimoto’s thyroiditis and Sjogren’s syndrome.  

However, most is known about gastric MALT lymphoma, as this is the commonest site at which these lymphomas develop. In the stomach, the majority of these lymphomas are associated with infection by a bacterium called Helicobacter pylori (see below). This causes inflammation of the lining of the stomach which includes the development of MALT-type lymphoid tissue. Once the MALT-type tissue is acquired, there is continuous stimulation of the lymphocytes to replicate and increase in number as a result of the constant presence of bacteria (a normal immune reaction). However, in a small minority of people, this results in a mistake within the genetic material of a lymphoid cell and continuation of this faulty cell line leads to the development of a lymphoma. 

What is Helicobacter pylori? 

Helicobacter pylori is a spiral shaped bacterium that has adapted to survive in the adverse, acidic, conditions found in the stomach. The organism has a worldwide distribution, although more people are infected in some countries/regions than in others. People have been infected by Helicobacter pylori for many centuries.  Transmission of the organism is thought to be from person to person and close personal contact appears to facilitate this infection. Infection normally happens in childhood and, once acquired, is lifelong in most people, unless specific eradication therapies are undertaken. Many people have no symptoms, but the presence of the organism has been associated with various types of gastric and duodenal disease, including duodenal ulcer, gastric ulcer, gastritis unrelated to ulceration, gastric carcinoma and, of course, gastric lymphoma. 

Eradication of the organism can be quite complex and normally involves the use of a combination of antibiotics, together with a drug to suppress acid secretion in the stomach (eg a proton pump inhibitor, PPI).  The exact combination used may vary between treatment centres. In some patients initial attempts to eradicate the organism may fail, requiring different drug combinations before eradication is successful. 

How are gastric MALT lymphomas found? 

In the majority of people gastric MALT lymphoma is found during tests for persistent indigestion - although only a very small percentage of people with this symptom have lymphoma.  The indigestion is probably more related to the presence of the Helicobacter than the actual lymphoma and patients are often symptomatically better following its eradication, irrespective of whether the lymphoma is decreasing (regressing). 

A very few people go to their doctor with other symptoms including nausea and vomiting (possibly with specs of blood in the vomit) but severe abdominal pain or the finding of a mass in the abdomen are unusual. 

How is gastric MALT lymphoma diagnosed? 

Gastric MALT lymphoma is frequently an unsuspected diagnosis following an endoscopic examination (using an optical instrument to look inside) of the stomach during investigation of gastric symptoms such as indigestion. The lining of the stomach may look generally inflamed or swollen and the diagnosis may only become evident after biopsies taken at the time are examined under the microscope. In other cases there may be ulceration or a nodular mass. The distinction between lymphoma and carcinoma (cancer of the stomach lining cells) on the basis of direct inspection of these ulcers or nodules is very difficult and, in many cases, is impossible. 

In some cases the diagnosis may also be difficult at the microscopic level. The histopathologist (an expert who examines samples of cells under the microscope) will assess the size and shape of the lymphoid cells, their distribution in the stomach lining and their interactions with the other components that make up the stomach wall.  In the past patients frequently required multiple examinations of the stomach before a confident diagnosis of lymphoma could be made.  More recently, and particularly after MALT lymphomas were specifically  recognised in 1983, pathologists have become better at recognising the subtle features that are characteristic of this lymphoma, but there will still be instances when the confident distinction between lymphoma and an inflamed immune reaction is impossible, necessitating further endoscopic examinations. 

What happens after a diagnosis of MALT lymphoma is made? 

Once a diagnosis of MALT lymphoma has been made, several further studies may be required. Firstly, because the diagnosis is usually unsuspected, not enough samples may have been taken during the biopsy to check for the possible of aggressive (high grade) lymphoma cells. If this is the case, another endoscopic examination may be required so further biopsies can be taken from the area of lymphoma.  

It is very important that the presence of Helicobacter is established to enable confirmation of the diagnosis. In many cases this will have been possible at the time of the initial diagnostic investigation, but in some cases the organisms are very scanty and difficult to find. In these instances a blood test may be performed to look for evidence of infection. 

Several studies[3] [4] [5] have shown that the response of gastric MALT lymphoma to treatment is highly dependant on the depth of the stomach wall involved by the tumour. This is best assessed by endoscopic ultrasound.  By using an ultrasound probe, images of the stomach wall can be obtained from which a measurement of the extent of the lymphoma can be made. Alternatively, computerised tomography (CT) scanning can be used, but this is generally less ideal for determining wall thickness. 

As with all lymphomas, it is important to assess the degree of spread of the lymphoma through the body (staging). This would usually involve a CT scan to find if there is lymph node involvement in the chest, abdomen or pelvis. Although spread to the bone marrow is rare (about 10%) in MALT lymphoma, a bone marrow biopsy is usually performed. Unlike lymphomas that arise within the lymph node system, MALT lymphomas tend to spread to other extra-nodal sites, and these would normally be studied as part of the general assessment and staging of the lymphoma. 

There are some alterations within the lymphoma cells that may have a bearing on the response of the lymphoma to therapy. These include alterations in genes that may underlie the change from normal lymphocytes to abnormal lymphoma cells. These can normally be detected in the laboratory using the original biopsies, but the techniques are quite sophisticated and frequently take some time to complete.  

How is gastric MALT lymphoma treated?  

Until the early 1990's surgery was probably the most commonly used treatment for gastric MALT lymphoma. However, with the recognition of the common association between gastric MALT lymphoma and Helicobacter infection and following some laboratory-based studies[6] [7] on cells derived from lymphomas, it was suggested that eradication of Helicobacter alone might have a therapeutic effect.  Further studies[8]^-15, some of which now have follow-up extending to over ten years, have shown that eradication of Helicobacter alone can induce tumour regression in 50-70% of cases.  The cases that respond the best are those that have not extended very far through the gastric wall and have not spread to lymph nodes. An initial antibiotic-based regime for eradication is usually prescribed, followed by endoscopies to confirm eradication of the organism and to assess tumour response.  

The interval between Helicobacter eradication and regression of the tumour is highly variable between patients. A proportion of patients will not respond to eradication therapy alone and will go on to more conventional anti-lymphoma therapies such as chemotherapy or radiotherapy.  There is, at present, no clear agreement between doctors as to when eradication therapy can be assessed as having failed in an individual, but while there are sequential improvements in biopsies taken during endoscopies, it may be worth delaying the use of other therapies. Some cases have been reported where there has been regression of the lymphoma many years after eradication and in the absence of other therapies (Savio A, personal communication to the author). 

When Helicobacter eradication has been deemed to have failed, more conventional therapies can be used. While surgery has, in the past, been the mainstay of treatment for gastric lymphoma, this is no longer the case. Several studies have shown that, although the lymphoma is usually concentrated in one part of the stomach, there are small deposits all over the stomach lining16,17  

Both radiotherapy and chemotherapy have been shown to be highly effective in the treatment of gastric MALT lymphoma.  Single-agent chemotherapy with alkylating agents (substances which are used to treat some cancers by interfering with cell metabolism and growth) such as cyclophosphamide or chlorambucil or nucleoside analogues (other drugs used to check the growth of lymphoma cells) such as cladribine appear to have equal activity. 

The role of rituximab (MabThera®) is currently being assessed in clinical trials. The role of combination, multi-drug, chemotherapy is uncertain but should probably not be used in the first instance in the absence of more aggressive, large cell disease. If combination chemotherapy is used to treat gastric lymphoma, it should be combined with acid suppression by a proton pump inhibitor (PPI). Radiotherapy with well targeted fields can be equally successful. 

Can we tell whether Helicobacter eradication will be successful? 

It is impossible to predict with 100% accuracy which cases will and which will not respond to eradication therapy. Nor is it possible to predict how long regression of the lymphoma will take if the therapy is successful. There are, however, certain features that are associated with a decreased likelihood of response: 

• cases in which Helicobacter cannot be identified and in which there is no evidence of previous infection, are unlikely to respond to eradication therapy
   

• the frequency of response decreases in cases that have extended more deeply through the stomach wall and if there is spread to local or distant lymph nodes.

There are also some features in the MALT lymphoma cells that, if they are present, make it easier to predict a likely decreased response to eradication therapy. Certain abnormalities in the genetic make-up of the lymphoma cell are likely to mean a poorer response.  Additionally, an increased number of large cells detected in the biopsy when examined under the microscope also indicates that there will be a poor response and may be a factor in deciding to adopt a more conventional chemotherapy/radiotherapy approach at an earlier stage than in those cases where these abnormalities are absent. 

How are people with gastric MALT lymphoma monitored and what is their outlook? 

The most important investigation in the follow-up of patients with gastric MALT lymphoma involves direct inspection of the gastric wall through an endoscope, together with the examination of any abnormal areas, as well as the area previously involved by lymphoma. The exact frequency of the endoscopic investigations remains controversial. After confirmation of Helicobacter eradication, assessment endoscopies would normally occur initially every 3-4 months, extending to 6 monthly intervals and eventually to annual examinations. The exact regime will depend on many factors, including the time at which complete regression of the lymphoma at both endoscopic and microscopic levels has occurred.   

The required duration of monitoring of patients in complete remission remains uncertain. The excellent outlook for people with these lymphomas means that some centres will discharge patients after a fixed time of maintained remission, while other clinicians may choose to follow-up their patients indefinitely as our knowledge about these lymphomas remains rather iincomplete at present. 

In a small proportion of cases initially treated by Helicobacter eradication, relapse is detected at follow up endoscopies. In some patients this is associated with recurrent Helicobacter infection and this usually responds to further antibiotic-based therapy. In a few cases, microscopic relapse has spontaneously regressed with no further treatment. In cases where there is a clear relapse of gastric MALT lymphoma, this can be treated with chemotherapy and/or radiotherapy in the same way as for those patients who don’t respond to eradication therapy with a similar response rate. Transformation of the lymphoma to a more aggressive form (diffuse large B-cell lymphoma) occurs in less than 10% of cases and when this does happen it would normally be treated with intravenous multi-agent chemotherapy with the aim of curing the aggressive disease. 

The outlook for people with gastric MALT lymphoma is usually good with about 80% of people surviving beyond the 5 year milestone and 77% going on to have disease free survival at 10 years. 

References 

1          Isaacson PG, Wright DH.  Malignant lymphoma of mucosa associated lymphoid tissue. A distinctive type of B-cell lymphoma. Cancer. 1983; 52: 1410-1416.

 

2          Jaffe ES, Harris NL, Stein H, Vardiman JW.  Pathology & Genetics: Tumours of hematopoietic and lymphoid tissues.  2001; IARC Press, Lyon

 

3          Ackmann M, Morgner A, Rudolph B et al. Regression of gastric MALT lymphoma after eradication of Helicobacter pylori is predicted by endosonographic staging. MALT Lymphoma Study Group. Gastroenterology.  1997; 113: 1087-1090.

 

4.         Ruscone-Fourmestraux A, Lavergne A, Aegerter PH et al. Predictive factors for regression of gastric MALT lymphoma after anti-Helicobacter pylori treatment. Gut. 2001; 48: 297-303.

 

5.         Nakamura S, Matsumoto T, Suekane H et al. Predictive value of endoscopic ultrasonography for regression of gastric low grade and high grade MALT lymphomas after eradication of Helicobacter pylori. Gut. 2001; 48: 454-460.

 

6.         Hussell T, Isaacson PG, Crabtree JE, Spencer J. The response of cells from low-grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue to Helicobacter pylori.  Lancet. 1993; 342: 571-574.

7.         Hussell T, Isaacson PG, Crabtree JE, Spencer J. 1996. Helicobacter pylori specific tumour infiltrating T cells provide contact dependant help for the growth of malignant B cells in low grade gastric lymphoma of  mucosa associated lymphoid tissue. J. Pathol. 1996; 178: 122-127.

 

8.         Wotherspoon AC, Doglioni C, Diss TC,  et al.  Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet. 1993; 342: 575-577.

 

9.         Stolte M, Eidt S.  Healing gastric MALT lymphomas by eradicating H pylori? Lancet. 1993; 342: 568.

 

10.        Wotherspoon AC, Doglioni C, de Boni M, et al. Antibiotic treatment for low-grade gastric MALT lymphoma. Lancet. 1994; 343: 1503.

 

11.        Weber DM, Dimopoulos MA, Anandu DP, et al. Regression of gastric lymphoma of mucosa-associated lymphoid tissue with antibiotic therapy for Helicobacter pylori. Gastroenterol. 1994; 107: 1835-1838.

 

12.        Bayerdorffer E, Neubauer A, Rudolf B, et al. Regression of primary gastric lymphoma of mucos-associated lymphoid tissue type after cure of Helicobacter pylori infection. Lancet. 1995; 345: 1591-1594.

 

13.        Montalban C, Manzanal A, Bioxeda D, et al. Treatment of low-grade gastric MALT lymphoma with Helicobacter pylori eradication. Lancet. 1995; 345: 798-799.

 

14.        Roggero E, Zucca E, Pinotti G, et al. Eradication of Helicobacter pylori infection in primary low-grade gastric lymphoma of mucosa-associated lymphoid tissue. Ann. Int. Med. 1995; 122: 767-769.

 

15.        Please contact Helpline for a further four references to these studies

 

16.        Wotherspoon AC, Doglioni C, Isaacson PG. Low-grade gastric B-cell lymphoma  of mucosa-associated lymphoid tissue (MALT): a multifocal disease. Histopathology. 1992; 20: 29-38.

 

 17.       Du M-Q, Diss TC, Ye H-T, Aiello A, Wotherspoon AC, Pan L-X, Isaacson PG.  Clone specific PCR reveals wide dissemination of gastric MALT lymphoma to the gastric mucosa. J Pathol 2000: 192; 488-493