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While gastric lymphoma has been known for a long time, the rare MALT/monocytoid lymphomas began to be described in 1983 as MALT, and 1984 as monocytoid, depending on presentation. When the lymphoma primarily involves lymph nodes, it has been called monocytoid, and when it is extranodal, it has been called MALToma. Some other terms used in the past: diffuse small lymphocytic lymphoma, small lymphocytic plasmacytoid, lymphocytic-plasmacytic, lymphocytic/histiocytic, and others. With the advent of a new classification scheme, called the R.E.A.L., both MALT and monocytoid lymphomas are subsumed under the heading of marginal zone lymphomas, along with a lymphoma of the spleen which continues to be discussed separately. Whether or not this designation will hold remains to be seen -- there seems to be some significant opposition to it, and various other proposals have been made.
Many researchers believe that monocytoid and MALT lymphomas are two different manifestations of the same disease, which ought to be called monocytoid lymphoma. This file reflects that perspective, and discusses both variations together, since they are phenotypically, morphologically and clinically similar. Monocytoid cells appear in MALT lesions, and extranodal disease frequently accompanies monocytoid presentation. Combining MALT and monocytoid lymphomas together also serves patient interests better: the recent significant advances made in understanding and treating gastric MALTomas may be useful for monocytoid lymphomas as well.
MALT lymphoma arises in a variety of body tissues, but most often in the stomach. These body tissues contain, or are infiltrated by, mucosa-associated lymphoid tissue (MALT for short) within which arise clonal populations of malignant B cells. This substrate is thought to result from chronic antigenic stimulation attendant to chronic infections and inflammations. Monocytoid lymphoma is first noted in the nodes but is often found in extranodal areas as well. And the term monocytoid was coined not because it is a cancer of the monocytes (those are non B cell leukocytes) but because these cells look similar to monocytes under the microscope.
MALT lymphomas arise in epithelium-lined mucosal sites, and show small to medium sized cells with irregular nuclei. Reactive germinal centers are almost always noted (these cells show changes under the influence of an infectious or allergic process, e.g. toxoplasmosis), as is the presence of monocytoid cells which have been described as of medium size with plentiful amounts of pale cytoplasm. The cells express the Bcl-2 anti-apoptotic protein. Large cells are often present in small quantities. Because of the presence of reactive centers and the very slow growing nature of the disease, many of these lymphomas were classifies as pseudolymphomas in the past, and considered largely benign. Only when molecular analysis showed clonal (identical twin) populations was the neoplastic nature of these lesions ascertained.
Some researchers think that the healthy counterpart to this NHL cell type is the marginal zone B cell lymphocyte about whose function not much is known. Another source says that the postulated normal counterparts are the "postgerminal center B memory cells with capacity to differentiate into marginal zone, monocytoid, and plasma cells." Immunophenotypically, these two lymphomas are indistinguishable. Tumor cells are positive for antigens CD19, CD20, CD22, and CD79a, and usually negative for CD5, CD10 and CD23. Immunophenotyping is important at diagnosis because of the similarity of these cells to other NHLs, particularly follicular, mantle cell, CLL/SLL, hairy cell leukemia, and also to non-malignant reactive hyperplasia. It is recommended that several opinions are sought as to the accurateness of the diagnosis, one of these from a recognized lymphoma expert in your area. Some specialists also do a PCR (polymerase chain reaction) analysis because it can be difficult to distinguish between gastritis with lymphoid infiltrates and MALT lymphoma. The PCR can identify the presence of a clonal population of cells. However, it has been noted that not all people who have a positive PCR will develop lymphoma.
Most MALT lymphomas are low grade tumors. MALTomas also occur as diffuse large cell tumors (described as intermediate in American usage, and high grade in European usage). These higher grade tumors often have some areas of low grade MALT in them, and it is thought that they may arise from low grade MALToma before the disease is diagnosed. (These diffuse large cell tumors will be dealt with in the future section on diffuse large cell lymphomas.)
MALT lymphomas have been described in almost all anatomic sites, but most frequently occur in the stomach, lung, thyroid, salivary gland and lacrymal gland. Less commonly they are noted in the orbit (eye area), breast, conjunctiva, bladder, kidney and thymus. Unlike in other low grade NHLs, patients most often present with localized disease, although regional node involvement is common, esp. in gastric and salivary gland MALT lymphomas. This involvement is believed by many to be monocytoid. One study mentions the following breakdown by stage: 57% at stage I, 9% at stage II, and 34% at stage III and VI. If there is recurrence after treatment, most patients' disease recurs in other sites. This recurrence is common in disseminated later stage disease but mortality is limited.
Histologic transformation into diffuse large cell does occur but the rate at which it happens is not known at present; some sources claim this is rare, while others think that some diffuse large cell lymphomas are a transformation from low grade MALT/monocytoid that went undiagnosed. MALT/monocytoid lymphoma also occurs not infrequently alongside another lymphoma, usually follicular.
Widespread nodal involvement is not common, and neither is spleen or bone marrow involvement (only about 10%). CNS involvement is very rare, and so is leukemic conversion. Clinical course is very slow -- these are probably the slowest growing lymphomas, termed "very favorable" in the literature -- and most patients are asymptomatic. Low grade MALT lymphoma often remains localized and stable for long periods of time; for example, one case study mentions a patient with conjunctival lesions that were present for 15 years without progression. Studies note a high percentage of complete remissions and long survival times. Commonly, the disease is perceptible but shows no sign of growth for many years.
There is a strong association between salivary MALTomas and Sjögren's syndrome and a history of autoimmune disease. MALToma of the thyroid is associated with Hashimoto's thyroiditis. Helicobacter pylori gastritis is very frequent in MALTomas of the stomach (90% or more cases). It is thought that antigen stimulation is critical not only to the development of this cancer but also for its continuation. Spontaneous remissions often occur after antibiotic treatment for H. pylori infection. It is hoped that many of these remissions are cures, but it will take many years of follow up to know for sure. Crohn's disease may also be implicated in GI MALT lymphomas.
Signs predictive of survival differences are probably the same as for other lymphomas. People with poor health, advancing age, high liver enzymes, and high beta2-microglobulin do not do as well as others.
The following is a list of problems reported in the literature for lymphomas. The list for MALT/monocytoid may be similar, with specific symptoms of the affected organ taking precedence.
All sources maintain that the median survival is very long, but so far, I have not found specific numbers. I am surmising that people with this disease have the longest median survival among low grade lymphomas. One source reports 80% survival at 15 years.
Roughly, about 1-2% of all B cell lymphomas are MALT/monocytoid. The incidence is increasing. Median age at diagnosis: about 65 years.
Very few trials have addressed the needs of people with MALT/monocytoid NHL because this lymphoma is rare. Patients have been treated with surgery, radiation, and single agent or combination chemotherapy, with CHOP and similar regimens being common. The modality known as "watch and wait" has been frequent after treatment if only partial regression was achieved. There are no studies comparing the survival of untreated patients (formerly diagnosed with "pseudolymphoma" incorrectly) and those of patients treated with the above three modalities. The extant studies pay very little attention to the effects of stomach removal and radiation to the abdomen on the patients' quality of life.
At present, treatment is still unsettled and controversial. Many sources recommend the removal of affected isolated lesions if possible. Gastrectomy is no longer recommended by most sources, but this treatment was very frequently used in times past. At present, some authorities have come to the conclusion that the high risk of mortality and morbidity of the procedure is not warranted in this slow growing cancer. Partial gastrectomy may still have a role in emergency situations (e.g. perforation).
Systemic chemotherapy has been recommended for widespread disease, and local radiation can be used to control localized masses. More recently, antibiotic therapy has been used with significant success in limited stages of gastric and some other MALT lymphomas. One source notes that "there is circumstantial evidence that a similar sequence of events [to the H. pylori infection] may be responsible for the growth of low-grade MALT lymphoma other than those arising in the stomach. The difficulty here lies in identifying the antigens responsible for initiating the disease that recruits the lymphoid tissue in the first instance."
Antibiotic therapy for gastric MALT lymphoma in people who have the H. pylori infection consists of double or triple antibiotic regimens of about 2 weeks' duration, with bismuth therapy following the antibiotic treatment for several months. This therapy has a great deal of success in early limited gastric MALT lymphomas. Studies have reported 60-90% of complete regressions following antibiotics. Complete regression can take up to 18 months. Some sources still consider this treatment experimental since more studies are needed, but the perspective taken in this document is that the results warrant widespread acceptance and the designation of antiobiotic therapy as first line therapy in limited gastric MALT lymphoma. It is not yet known if future data from many more patients will confirm the current about 80% rate of complete remissions in stage IE. A small subset of these patients may require a second antibiotic regimen. Complete remissions in later stages do not occur as readily but do occur. The stability of complete regressions following antibiotic therapy has not yet been researched adequately, but preliminary studies are encouraging.
Monocytoid lymphoma has in the past been treated as a generic low grade lymphoma, with watch and wait playing a role in non-symptomatic disease, local control achieved by radiation, and systemic control by chemotherapy. Treatment for relapsed MALT/monocytoid disease has been also followed that of other low grade lymphomas.
It is of interest to note that there is a rare disease called Mediterranean lymphoma (possibly a subset of MALToma) which is a highly lethal lymphoma of young people in less developed countries, in which encouraging results have been also reported following antibiotic therapy.
PCR is recommended to ascertain molecular remission of the disase in cases of CR. However, some studies have identified subsets of patients who achieved full remission after treatment, but whose PCR still showed residual monoclonal cells. It is not known at present if these clones may develop into full-fledged lymphoma, or if they perhaps represent benign memory B-cell precursors of the malignant clone. There is some evidence that patients who are PCR positive before treatment take longer to have their disease eradicated completely.
GASTRIC MALT LYMPHOMA
About 5% of all gastric cancers are NHL lymphomas, and the percentage is growing. If the stomach is exclusively or predominantly involved, then it is considered primary gastric lymphoma; if this requirement is not fulfilled, then it is seen as a secondary gastric involvement from systemic lymphoma. Peak incidence is in the 6th and 7th decade of a person's life. Common symptoms are: pain in the area of the stomach, weight loss, anorexia, nausea, and vomiting. Occult blood in the stool and anemia are also observed in many patients.
Endoscopy is the prefered diagnostic method, as it allows for biopsy samples. Combined with brush cytology and ultrasound, it provides the best results. CT scans of the chest and abdomen, bone marrow biopsy, and biopsy of any enlarged nodes are all used to determine the stage.
Partial or total gastrectomy (removal of the stomach) used to be the first stage of treatment. This approach has never been supported by controlled studies. It caught on because it allowed a more detailed examination of the disease, because it can be curative if all the cancer is cut out, and because it was thought that the risk of perforation in subsequent chemotherapy was great if the cancerous stomach was left in place.
More recently, this procedure has become controversial, with many specialists speaking against it for several reasons: gastric lymphoma is very rarely completely contained, and even total gastrectomies cannot be typically expected to get all the cancer out. Total gastrectomies have a high mortality and morbidity (severe long term side effects) rate. And the danger of perforation with chemo has been overstated. Sonography can be used to identify patients at danger of perforation.
In a limited number of patients with stage I disease, such a surgery has nevertheless been curative. For those at risk of recurrence, postoperative radiation has been used. In patients with stage II disease, the cancer will recur in about 30% despite surgery and radiation. In this lymphoma, only stage I is considered limited localized disease, all other stages are considered disseminated. Chemo has been recommended for patients with disseminated disease in addition to surgery and radiation. More currently, these patients have been treated with chemo alone. This treatment has been based on several retrospective reports; no controlled trials had been conducted. Several recent reports have suggested that there is no benefit to adding radiation to chemotherapy either.
In 1993, an exciting breakthrough was made by scientists in England who realized that Helicobacter pylori was implicated in the disease and decided to treat patients with antibiotic therapy. The majority of these patients saw their tumors disappear. Later studies have shown that some 90% of patients with gastric lymphoma suffer from H. pylori infection. This inffection is more common in areas of the world where it can be passed on by unhygienic conditions, by human contact or water contamination. It can be spread within families and local communities.
Early studies that followed assumed that only low grade MALT lymphoma would be responsive to H. pylori eradication. But more recently, when this assumption was put to the test, the researchers in a small study found that most of the higher grade MALT tumors completely cleared up after antibiotic therapy.
H. pylori eradication therapy is said to result in about 60-70% of durable regressions of tumors, but long term data are not available yet. H. pylori is a very tough microorganism and tends to reccur after treatment in perhaps 1/3 of cases. There are also reports of growing resistance to antibiotics. Patients are well advised to look for the latest news in H. pylori therapy. It may also help to grow the organism following biopsy, and test prospective antibiotic agents on the culture.
Some H. pylori infections will recede following a second course of antibiotic treatment. If no or limited results are obtained, patients are referred to other alternatives which include gastrectomy (but less and less), sometimes radiation (which can cause serious long term effects), and more commonly chemotherapy. Such patients might benefit from restaging since the reason for nonresponsiveness could be the presence of higher grade disease. There are at present no data on treatment with Rituxan.
Patiens are commonly reported to be alive 20-30 years after diagnosis.
LUNG MALT LYMPHOMA
This type occurs in about 4% of all extranodal presentations of lymphoma. In this cancer, the MALT tissue in the lung (bronchus-associated lymphoid tissue) undergoes transformation in patients with chronic infections, connective tissue disease, rheumatoid arthritis, and Sjögren's syndrome. This type is more commonly low grade. Some of these have been considered pseudolymphomas in the past. Some do occur in the diffuse large cell type. Majority of patients are asymptomatic. Cough, difficulty breathing, expectoration of bloody mucus (hemoptysis), chest pain, and venous inflammations with cryoglobulinemia are also noted at presentation.
Bronchoscopy is used for diagnosis. Sometimes, pleural effusions and mucous inflammation is found. Bronchoalveolar lavage is often enough to provide cells for biopsy. Sometimes percutaneous or open lung biopsy is needed. Low grade tumors are usually confined to the lung and mediastinal and hilar lymph nodes.
Tumors often remain stable for long periods of time. If treatment is inititated, recurrence in the lung or the GI tract is common. Treatment used to be surgical, but this is now less common, as surgery is not needed for diagnosis, and there is no significant indication that surgery improves outcome. Usually, single agent or non-anthracycline combination chemo is given. Radiation can also be used in small quantities. There is no indication that the treatment is curative, but long survival is common. Side effects to watch for: pulmonary fibrosis (from certain chemo agents), and radiation pneumonitis. 94% survival at 5 years, with median survival longer than 10 years has been reported.
THYROID MALT LYMPHOMA
About 3% of NHLs are thyroid lymphomas. Women are affected more than men. Patients usually present with fast-growing mass in the thyroid area on the neck, as well as enlarged nodes in the neck region. Biopsy is done from a tissue sample, and surgery is not indicated beyond this sampling. Most of these lymphomas are localized, and linked to Hashimoto's thyroiditis.
Low grade tumors are uncommon; most are diffuse large cell. MALT thyroid lymphomas have a better prognosis than non-MALT. Locoregional radiation is used for control. But relapses in more distant areas are common, and so more recently, radiation and chemotherapy used together are recommended. Survival at 5 years is about 75% for low grade tumors.
SALIVARY GLAND MALT LYMPHOMA
It occurs more commonly in women than men, and in people over 50. The parotid gland is involved in 80%, with the submandibular gland second. Presentation is typically with a nonsymptomatic swelling in the area. Sjögren's syndrome and connective tissue disorders are implicated. Low grade tumors are most common. It is important to rule out the possibility that the lymphoma arises in a node within the gland, and is some other B-cell lymphoma. These MALT lesions were formerly thought benign (myoepithelial sialadenitis).
Radiation provides local control in limited disease. Overall survival at 5 years is about 70-80%. Distant relapses are common, and part of the natural history of the disease. Chemotherapy is not recommended. At least one case report exists of regression of the tumor after antibiotic therapy in a person who had H. pylori infection.
LACRYMAL GLAND MALT LYMPOMA
Patients present with swelling, bulging, and eye movement disturbances. Bilateral involvement occurs in about 10-15%. Biopsy is mandatory for diagnosis. Imaging by MRI, CT and sonography are useful. Low grade disease is most common, and most patients are found to have stage I, localized disease. Bilaterality does not mean dissemination.
Low to moderate radiation is used for tumor control. Radiation of 40Gy or higher risks cataracts, keratitis, and sicca syndrome, as well as damage to the optic nerve and retina. Overall survival reported is about 75-80% at 10 years. There are very high CRs after radiation, some 90-95%. Relapse rates to other sites or to disseminated B cell lymphoma are about 20-50%, but the relapsed disease remains slow growing and long survival is common. One source indicates that perhaps cures are possible in this subset of MALT. Latest research indicates that local interferon treatment may be worth trying as first line therapy.
BREAST MALT LYMPHOMA
Maybe 2% of NHLs are in the breast as primary presentation. Occurs most commonly in the 6th decade of life. The low grade type often occurs in the right breast, for unknown reasons. It is commonly in the upper outer quadrant. It is very rare. Diagnosis is by breast biopsy. Radiologic appearance is similar to carcinoma, but calcifications are not usually there. CNS fluid should be examined in case of suspicion of higher grade tumors.
Mastectomy is not recommended because the completeness of excision does not affect outcome. Local surgery has often been used; local radiation results in local control, but with risk of edema to the affected arm if the lymph nodes are irradiated. The disease is so rare in low grade that no data is available on more up to date chemo results, or survival. But radiation alone is most recommended for low grade disease. MALT lymphomas of the breast tend to remain localized, and to relapse locally as well. This pattern remains stable independent of treatment (surgery, radiation, chemo singly or in combination).
SKIN MALT LYMPHOMA
Cutaneous lymphomas of low grade B cell origin may be the cutaneous counterpart of the MALT lymphomas of the gastrointestinal tract. If localized in the skin, they have a very long natural history. Watch and wait is used, with local radiation or modest chemo if needed, then back to watch and wait.
Since MALT/monocytoid lymphomas are positive for CD20, treatment with Rituxan, the monoclonal antibody treatment for low grade lymphomas of low toxicity, is an option. Using the antibiotic regimen for non-gastric MALTomas, for higher stages of gastric MALT lymphomas, and for monocytoid lymphomas is also experimental. Patient/dr teams who have success with such treatment should notify one of the MALT lymphoma research groups.
The Mayo Clinic's trial with phenylacetate accepts MALT lymphomas, and so does the trial with DaunoXome. There are other trials that accept all low grade lymphomas, and may be worth checking out. It seems that most if not all trials for MALT have occurred in Europe, possibly due to the fact that some areas there have an unusually high concentration of MALT lymphomas. To my knowledge, there has been no trial so far focused specifically on monocytoid lymphoma.
Please write if you know of trials or promising treatments in other countries. For detailed information on U.S. lymphoma trials, call 1-800-4CANCER and ask for their free printouts. Unfortunately, neither the 4CANCER service nor LRFA has any information on trials specific to MALT/monocytoid lymphomas (early 1999).
The literature mentions that the greatest experience in the dealing with MALT lymphomas has been gathered by the German multicenter MALT group. How to contact them: Prof. Andreas Neubauer M.D., Medizinische Klinik I, Hämatologie-Onkologie, Technische Universität, Fetscherstrasse 74, 01307 Dresden, Germany. Fax (49) 351-458-5362.
The team that pioneered the antibiotic treatment of MALT can be reached in England: Peter G. Isaacson DM, University College London Medical School, London WC1E 6JJ, United Kingdom.
Another MALT research group is at the University of New South Wales in Sydney, Australia.
www.micro.unsw.edu.au/!THEHELI.COP/helihome.html
The Dept. of Microbiology and Immunology can be reached by fax: 61-2-9385-1591.
Other future developments include telomerase research, antisense therapy, gene therapy, anti-angiogenesis therapies, next generation of monoclonal antibodies, tumor and bacterial vaccines, and hyperthermia.
Gastric lymphoma and Helicobacter pylori, editorial by Peter G. Isaacson. New England Journal of Medicine, vol 330, no.18 (May 5, 1994).
Gastroenterology, vol.113, no.6 (December 1997 supplement) contains a wealth of information on H. pylori and MALT lymphomas.
A great deal of information, including details on some very rare MALT lymphomas, can be gathered from the new book called The Lymphomas, George P. Canellos et al, editors. WB Saunders, 1998. Look for chapter 25, Primary Extranodal Lymphomas.
Before you do anything else, you must understand exactly what "median survival" means. I cannot stress this enough! Please see the unsurpassed file written on this topic by Steven Jay Gould (http://cancerguide.org/median_not_msg.html) when he was diagnosed some years back with a cancer with a bad prognosis. Then you can breathe a sigh of relief -- people with MALT/monocytoid lymphoma have rather excellent median survival rates. :-) This gives you plenty of time to see new and superior treatments come forth, even if antibiotic therapy either does not work for you or is not applicable.
MALT/monocytoid lymphoma is a fairly new entity. As such, and due to its unusual features (its close correlation with infectious agents and autoimmune disease), it presents an interesting and challenging puzzle to scientific minds. When people become intrigued, good ideas are not too far off.
Brand new agents (immunotherapies) are becoming available for the treatment of lymphoma that may considerably improve the odds, especially for people with resistant or advanced disease.
People with these rare lymphomas have the fortune to benefit from the fast advancing research connected with H. pylori. This recently-identified organism is providing original insights and therapeutic options for several diseases, and a great deal of energy is being invested in investigating it, partly because some of these diseases, such as gastric ulcers, have been quite common.
The integrative approach to lymphoma has not been studied, but it is common sense that patients in any chronic disease who undertake steps to a healthier lifestyle and who take good care of themselves will likely do better in the long run than those who do not. What is true for heart disease and diabetes is likely true for cancer as well. Lifestyle changes, supplements and judiciously chosen complementary therapies can be an integral part an optimal approach in a cancer apparently caused by infectious agents or inflammatory processes. By using an integrative approach, you are likely to increase your chances of shedding these irritants permanently, and give your body the support it needs to regress the tumors and repair the damage done.
Joining a support group will link you with other people with your lymphoma cell type, as well as with professionals with special interest in this form of cancer. Local groups may only be possible in large metropolitan areas but the nhl-malt list is open day and night and one need not travel anywhere. There you will hear about the newest therapies and how patients experience them from first person accounts. You will be able to draw strength from others in the same situation and share your own strengths as you learn to cope. This single step can make a big difference in your cancer experience and your survival. To find out how to subscribe, see the page on Links, Lists and Books.
Keep in mind that uppity patients have been shown to do better than passive patients over time. Question and fight: it is your life!
Look for the gifts that the cancer brings you, despite itself. Use it to bring good things into your life. Cancer is an adventure. Not one we would have chosen, I know. But an adventure nevertheless... Live it creatively, live it to the full.
This is important: you may not be able to heal the cancer, but you CAN heal you life.
Researched, compiled and written by Vera Bradova © 1998-2001
Updated 9-1-2001
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