Key Terms: Antigen, Autoimmune disease, Bone marrow biopsy, Indolent lymphoma.
Definition
MALT lymphomas are solid tumors that originate from cancerous growth of immune cells that are recruited to secretory tissue such as the gastrointestinal tract, salivary glands, lungs, and the thyroid gland.
Description
The digestive tract is generally not associated with lymphoid tissue, with the exception of small collections of lymphocytes such as Peyer's patches. A specific kind of white blood cell, B lymphocytes, can accumulate in response to infections of the digestive tract and other secretory tissues, or as a result of autoimmune conditions such as Sjögren's syndrome. When the growth of these lymphocytes is maintained through continued infection or autoimmune disease, a malignant cell can arise and replace the normal lymphocytes. These lymphomas, derived from mucosa-associated lymphoid tissue (MALT), most commonly arise in the stomach. Their growth seems to be dependent upon continuous stimulation of the immune system by an infectious agent, such as H. pylori, or some other entity, termed an antigen, that the body recognizes as foreign. This antigen-driven growth permits these tumors to be treated by eliminating the stimulus that generated the original, normal immune response. In the stomach they are associated, in greater than 90% of all cases, with the bacteria called Helicobacter pylori (H. pylori). This bacteria is also associated with peptic stomach irritation, ulcers, and gastric cancer. MALT lymphomas are generally indolent, that is, they grow slowly and cause little in the way of symptoms. Those MALT lymphomas that arise in the stomach in response to H. pylori infections are generally successfully treated with antibiotics, which eliminate the bacteria.
Demographics
MALT lymphomas occur at a frequency of about 1.5 per 100,000 people per year in the United States and account for about 10% of all non-Hodgkin's lymphomas. The frequency varies among different populations. For example, in parts of Italy the frequency of MALT lymphomas is as high as 13 per 100,000 people per year. This can in part be attributed to different rates of infection with H. pylori. However, other hereditary, dietary, or environmental factors are almost certainly involved.
Causes and Symptoms
The majority of MALT lymphomas appear to be the result of infectious agents, most commonly H. pylori in the stomach. It is not known if infectious agents also cause MALT lymphomas outside of the stomach. In some cases, such as in the thyroid, MALT lymphomas seem to arise in patients who have autoimmune diseases, which make their immune systems treat their own tissue as foreign or antigenic. It is believed that there must be additional factors, in addition to infection or autoimmunity, that influence the development of MALT lymphomas. For example, in the United States, where infections with H. pylori are quite common, less than 1 in 30,000 people who have H. pylori in their stomachs develop MALT lymphomas. In addition, individuals who develop MALT lymphomas are more likely to develop other forms of cancer. This would suggest that there might be genetic factors predisposing individuals to develop MALT lymphomas or other tumors in response to environmental or infectious agents.
In general, patients have stomach pain, ulcers, or other localized symptoms, but rarely do they suffer from systemic complaints such as fatigue or fever.
Diagnosis
The indolent nature of most MALT lymphomas means that the majority of patients are diagnosed at early stages with relatively nonspecific symptoms. In the case of gastric MALT lymphomas, the physician will then have a gastroenterologist perform an endoscopy to examine the interior of the stomach. MALT lymphomas are then recognized as areas of inflammation or ulceration within the stomach. It is unusual for masses recognizable as tumors to be seen upon examination. Definitive diagnosis of MALT lymphoma requires a biopsy, in which a bit of tissue is removed from the stomach or other involved site. Examination of this tissue by a pathologist is the first step in distinguishing among the possible diagnoses of inflammation, indolent lymphoma, or a more aggressive form of cancer, such as gastric cancer or a rapidly growing non-Hodgkin's lymphoma. The pathologist evaluates the type of lymphoid cells that are present in the biopsy to establish the nature of the lesion. In addition, it is essential that the pathologist determine whether the lymphoma has grown beyond the borders of the mucosa, which lines the stomach or other gland.
Clinical Staging, Treatments, and Prognosis
The best staging system to employ for MALT lymphomas is still the subject of discussion. However, it is standard practice that patients diagnosed with MALT lymphomas should be evaluated in a similar manner to individuals with nodal lymphomas, the more common type of lymphoma that originates at sites within the lymphoid system. These procedures include a complete history and physical, blood tests, chest x rays, and bone marrow biopsy. This evaluation will permit the oncologist to determine if the disease is localized or if it has spread to other sites within the body.
In general, the prognosis for patients with MALT lymphomas is good, with overall five-year survival rates that are greater than 80%. The features that are most closely related to the outlook for newly diagnosed individual patients are: whether the primary site is in the stomach or is extra-gastric; if the disease has spread beyond the initial location; and whether the histologic evaluation of the initial tumor biopsies is consistent with a low-grade, slowly growing lesion, as compared to a high-grade lesion that is more rapidly growing. In general, the histologic grade is the most important feature, with high-grade lesions requiring the most aggressive treatment.
Treatment of MALT lymphomas differs from that of most lymphomas. In the most common type of MALT lymphomas—low-grade lesions originating in the stomach—treatment with antibiotics to eliminate H. pylori leads to complete remissions in the majority of patients. The effectiveness of this treatment is indistinguishable from surgery, chemotherapy, radiation therapy, or a combination of surgery with drugs or irradiation. Approximately one-third of patients in this group have evidence of disseminated disease, where lymphoma cells are detected at sites in addition to the gastric mucosa. The response of these patients to antibiotic treatment is not significantly different from that for individuals with localized disease. For both groups a complete remission is achieved in about 75% of patients, who remain, on average, free of disease for about five years.
Patients with MALT lymphomas arising outside of the digestive tract also have good prognoses. Effective treatment for these lymphomas has been achieved with local radiation, chemotherapy, and/or interferons. Surgery followed by chemotherapy or radiation is also effective with nongastrointestinal MALT lymphomas. Overall these patients have five-year survival rates greater than 90%.
While the outlook for patients with MALT lymphomas is good, difficulties in diagnosis and staging have left the optimal treatment a matter of continued study. This is an especially open question for those patients who fail to respond to antibiotic therapy, or whose disease recurs. It may be the case that in these patients, the MALT lymphoma may have already progressed to a point where high-grade lesions, not observed in the original biopsies, were resistant to the initial treatment. The best treatment for these patients remains to be established. In general, these patients are treated with chemotherapy in a similar manner to patients with other types of lymphoma. Given the success of antibiotics, and the good prognosis for gastric MALT lymphomas in general, no sufficient body of evidence exists to determine the best chemotherapy for patients who fail to achieve a complete and lasting remission upon initial treatment. At present, a chemotherapeutic regime designated CHOP includes the anti-cancer drugs cyclophosphamide, doxorubicin, vincristine, and prednisone. Similar drug combinations are being used for patients whose MALT lymphomas do not respond to antibiotic treatment.
Clinical trials are underway and mostly concentrate upon optimizing treatment of gastric MALT lymphomas that involve H. pylori. The aspects of treatment being addressed are the most effective antibiotics and the use of antacids to modulate irritation in the stomach. These protocols have been designed to follow the natural history of gastric lymphomas and to establish the biological features that predict treatment response to antibiotics and duration of remission.
Questions to Ask the Doctor
- When will I know the results of the biopsies?
- Where does the lymphoma seem to be growing?
- Is there any evidence that it has spread?
- Does the pathology report indicate that this lymphoma is indolent? Will you treat me with antibiotics? Do you think chemotherapy or radiation is needed? Why?
- How long will I take the antibiotics or undergo chemotherapy before I am re-examined to see if the lymphoma is in remission?
Prevention
There are currently no commonly accepted means to prevent MALT lymphomas. While the H. pylori infections are associated with this and other gastric disease, the eradication of H. pylori in asymptomatic individuals is not currently recommended for prevention of MALT lymphomas or stomach cancer.
Resources
Periodicals
Thieblemont, C., et al. "Mucosa-associated Lymphoid Tissue Lymphoma is a Disseminated Disease in One-third of 158 Patients Analyzed." Blood 95 (February 2000): 802-6.
Zucca, E., et al. "The Gastric Marginal Zone Lymphoma of MALT Type." Blood 96 (July 2000): 410-19.
Other
"Low-Grade Non-Hodgkin's Lymphoma: A Year 2000 Perspective." Medscape. June 2000. .
—Warren Maltzman, Ph.D.
