eMedicine Specialties > Hematology > Stem Cells and Disorders

Mucosa-Associated Lymphoid Tissue

Sara J Grethlein, MD, Associate Dean for Graduate Medical Education, Professor, Department of Internal Medicine, Division of Hematology and Oncology, State University of New York Upstate Medical University
Jose A Perez Jr, MD, MSEd, MBA, Consulting Physician, Department of Internal Medicine, Residency Director, Vice Chair of Education Department of Medicine, The Methodist Hospital, Houston; Associate Professor of Clinical Medicine, Weill Cornell Medical College

Updated: Oct 14, 2008

Introduction

Background

A significant quantity of lymphoid tissue is associated with human mucosa. Mucosa-associated lymphoid tissue (MALT) is scattered along mucosal linings, measuring roughly 400 m².^{1 2,3,4} It is the most extensive component of human lymphoid tissue. These surfaces protect the body from an enormous quantity and variety of antigens. The tonsils, Peyer patches within the small intestine, and the vermiform appendix are examples of mucosa-associated lymphoid tissue (MALT).

The nomenclature incorporates location; therefore, mucosa-associated lymphoid tissue (MALT) includes gut-associated lymphoid tissue (GALT), bronchial/tracheal-associated lymphoid tissue (BALT), nose-associated lymphoid tissue (NALT), and vulvovaginal-associated lymphoid tissue (VALT). Additional mucosa-associated lymphoid tissue (MALT) exists within the accessory organs of the digestive tract, predominantly the parotid gland.

Mucosa-associated lymphoid tissue (MALT) may consist of a collection of lymphoid cells, or it may include small solitary lymph nodes. Lymph nodes contain a light-staining region (germinal center) and a peripheral dark-staining region. The germinal center is key to the generation of a normal immune response. The location of mucosa-associated lymphoid tissue (MALT) is key to its function. Stimulation of B lymphocytes leads to the production of immunoglobulin A (IgA) and IgM within the Peyer patches, preventing adherence of bacteria and viruses to the epithelium, thus blocking entry to the subepithelial layers of the intestine.^1,2,3,4,5

Mucosal epithelial surfaces contain M cells, which are specialized cells that are so named because they exhibit microfolds on their luminal surface and because of their membranous appearance. The role of the M cells is absorption, transport, processing, and presentation of antigens to subepithelial lymphoid cells.^6,7 These subepithelial cells include CD4⁺ type 1 T-helper cells (THCs) and IgD/IgM⁺ B lymphocytes, the latter of which are antigen-presenting cells (APCs) and function as memory cells interacting with type 1 THCs.

Under these M cells and in close proximity, B lymphocytes, CD4⁺ T lymphocytes, and APCs are found, of which dendritic follicular cells (DFCs) are one type.⁸ Together, this group of cells constitutes a "pocket" of M cells. Within this pocket, an area of follicles associated with the epithelium (follicle-associated epithelium) is observed. These follicles, having true germinal centers, are similar to the follicles of the spleen and lymph nodes.

The direct secretion of secretory IgA onto mucosal epithelia represents the major effector mechanism of mucosa-associated lymphoid tissue (MALT). Major accumulations of lymphoid tissue are found in the lamina propria of the intestine. M cells in the intestinal epithelium overlying Peyer patches allow transport of antigens to the lymphoid tissue beneath it.

Another APC is the DFC, which activates some clones of type 1 THCs, although less potently than B lymphocytes. Stimulation of CD28 on type 1 THCs by B7 co-stimulatory molecules results in the secretion of interleukin 2 (IL-2) and gamma-interferon by type 1 THCs. Regulation of the immune response involves the suppression of type 2 THCs (involved in humoral immunity) by gamma-interferon and production of IL-10 by type 2 THCs, which inhibits type 1 THCs. Tolerance to antigens results from the lack of a T-lymphocyte response. Often, this is due to failed involvement of B-lymphocyte co-stimulatory molecules or cytokines. Signaling requires more than just receptor stimulation.

The activity of the germinal centers in the follicle-associated epithelium is key to the immune response. The germinal center provides an area where a large number of cells important in the immune response congregate. Early on in the T-cell–dependent immune response, B lymphocytes known as founder cells concentrate in the germinal center, forming the dark zone, where rapid division of these cells occurs.^9,10,11,12

Selection of B lymphocytes for participation in the immune response occurs based on their interaction with antigen-antibody complexes on the surface of DFCs. This involves a series of steps that result in expression of complexes of major histocompatibility complex II (MHC II) and peptides resulting from processed antigens. This then begins a process of somatic hypermutation in the dark zone and, later, immunoglobulin class-switching and generation of memory cells and plasma cell precursors in the apical light zone of the germinal center.

The complex interplay among antigens, cells, and cytokines results in a very efficient immune response. The efficiency of mucosa-associated lymphoid tissue (MALT) also depends on the adequate function of IgA. Individuals with selective IgA deficiency are prone to infections along mucosal surfaces in the respiratory, gastrointestinal, and genitourinary tracts. Adequate function of IgA depends on the production and acquisition of a joining (J) chain. This glycoprotein is produced by plasma cells and is important in the formation of IgA dimers and IgM pentamers. It has been shown that in children who have recurrent tonsillitis, B lymphocytes in tonsillar crypts do not produce the J chain. The J chain is key in permitting secretory IgA and IgM to function as the first line of defense in mucosal epithelium.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Lymphoma.

Pathophysiology

In selective IgA deficiency, the capability of the mucosal barrier is weakened and a second line of defense is activated. This consists of the participation and recruitment of large numbers of immune-competent cells, resulting in the onset of an inflammatory process that eradicates the antigen and restores functionality to the mucosa. If this process is constant and intense, it may result in a chronic inflammatory process.

Malignancies that occur in mucosa-associated lymphoid tissue (MALT) are called MALT lymphomas or MALTomas. MALTomas are extranodal manifestations of marginal-zone lymphomas. Most MALTomas are a low grade, although a minority either manifest initially as intermediate-grade non-Hodgkin lymphoma (NHL) or evolve from the low-grade form. Most of the MALTomas occur in the stomach, and roughly 70% of gastric MALTomas are associated with Helicobacter pylori infection. Several cytogenetic abnormalities have been identified, the most common being trisomy 3 or t(11;18). The specific gene abnormalities responsible for the pathogenesis of MALTomas have not yet been identified. Mutations commonly identified in NHLs are not commonly present in MALTomas, although both BCL2 and TP53 have been reported.

Frequency

United States

MALTomas account for approximately 5% of NHLs diagnosed annually. NHL represents only 4% of non–skin cancer malignancies.

International

NHL accounts for 2-3% of all malignancies, and MALTomas comprise approximately 5% of all NHLs. Although extensive studies have not been performed, no particular ethnic group or geographic area shows a strong predilection for MALTomas.

Mortality/Morbidity

• Morbidity and mortality occur when neoplastic transformation into a MALToma develops.
• Most MALTomas are responsive to available treatment modalities, including radiation and chemotherapy. In addition, H. pylori – associated tumors may respond to antibiotics.¹³
• The most common morbidities associated with gastrointestinal MALTomas include abdominal pain, gastrointestinal bleeding, and gastrointestinal obstruction. Gastric or intestinal perforation is rare.

Race

No significant racial differences of mucosa-associated lymphoid tissue (MALT) distribution are known; however, some epidemiologic studies indicate a slight increase in MALTomas in whites relative to blacks.

Sex

Although no sex differences are known regarding mucosa-associated lymphoid tissue (MALT) distribution, males usually have a more extensive distribution of lymphoid tissue. However, according to some epidemiologic studies, MALTomas are slightly more common in females than in males.

Age

The peak incidence of MALTomas is during the seventh and eighth decades of life. However, MALTomas have been noted in children, adolescents, and young adults.

Clinical

History

The median age of onset of MALTomas is 65 years. According to some epidemiologic studies, MALTomas are slightly more common in females than in males and are more common in whites than in blacks.

• Symptoms of MALTomas are nonspecific and are related to the organs involved.
  • Gastric MALToma symptoms may mimic peptic ulcer disease or gastritis.
  • Chronic fatigue, low-grade fevers, nausea, constipation, tarry stool, epigastric pain, weight loss, anemia, and shortness of breath are some of the more nonspecific symptoms that may occur in patients with gastric MALTomas.
  • Recurrent respiratory infections may be observed in some patients, especially in patients with pulmonary MALTomas.
  • Patients with conjunctival MALTomas may present with blurry vision or visual-field defects.
  • Patients with MALTomas often have a history of an associated autoimmune disease.

Physical

Most patients with MALTomas have no physical findings; lymphadenopathy is rare.

Causes

Although the cause of MALTomas and most other tumors is still unknown, accumulated evidence indicates a strong association between autoimmune diseases and MALTomas. A clear causal association exists between H. pylori infection and gastric MALTomas.

• Continued massive antigen stimulation is postulated to represent a critical step in the development and progression of MALTomas.
• MALTomas of the salivary glands are often associated with Sjogren syndrome.
• MALTomas of the thyroid are associated with Hashimoto thyroiditis.
• Crohn disease or celiac disease may be involved in the genesis of intestinal MALTomas.
• In contrast to weaker etiologic associations, infection with H. pylori has been definitively established as a cause of MALTomas. H. pylori gastritis is common in individuals who develop gastric lymphomas.

Differential Diagnoses

Helicobacter Pylori Infection
Lymphoma, B-Cell
Lymphoma, Diffuse Large Cell
Lymphoma, Non-Hodgkin

Other Problems to Be Considered

Extranodal lymphoma
Gastric lymphoma
Low-grade NHL

Workup

Laboratory Studies

• Complete blood cell (CBC) counts and blood chemistries may provide important information about the tissues and organs affected by MALTomas.
• Immunologic phenotyping of circulating lymphocytes, bone marrow lymphocytes, or biopsy specimens of MALTomas can be determined by flow cytometric analysis.
  • MALTomas have an immunophenotype that is similar to marginal-zone lymphomas.
  • MALTomas are almost always negative for CD10, CD5, and CD23, but they do express CD20. They also express surface immunoglobulin that is restricted to one type of light chain (kappa or lambda) and, often, both CD21 and CD35. Low-grade MALTomas are usually positive for BCL2, whereas intermediate-grade MALTomas are usually negative for BCL2.
• Cytogenetic studies may show chromosomal abnormalities in the malignant cells of MALTomas. The most common abnormalities detected are trisomy 3, t(11;18), and, less frequently, t(1;4).

Imaging Studies

• Staging MALTomas can be a challenge (see Staging). Imaging studies are not helpful for visualizing normal mucosa-associated lymphoid tissue (MALT), but they may be useful in diagnosing and staging MALTomas.
• Barium contrast studies of the upper gastrointestinal tract, small bowel, or colon may demonstrate the presence of masses or infiltration of the bowel wall in mucosa-associated lymphoid tissue (MALT). However, the results from these studies are often nonspecific and may be insensitive.
• Computed tomography (CT) scanning and magnetic resonance imaging (MRI) findings may help document the extent of the primary lesion and possible distant disease, but they cannot help differentiate malignant from benign lesions in mucosa-associated lymphoid tissue (MALT).
• Positron-emission tomography (PET)/CT scans are becoming more widely accepted as useful in the management of MALToma. Gastric disease is less likely to be detected by this imaging modality. In one case series, only 42% of early mucosa-associated lymphoid tissue (MALT) was identified, but 100% of stage III-IV patients had positive studies.¹⁴

Procedures

• Endoscopy may reveal mucosal rigidity and hyperplasia in patients with MALTomas. The diagnosis requires a biopsy. Endoscopic ultrasonography can be performed for gastrointestinal tract lesions, but its applicability is limited. H. pylori infection can also be detected in samples obtained via endoscopy.
• Bone marrow aspiration and biopsy findings can show evidence of bone marrow involvement by the MALToma.

Histologic Findings

Mucosa-associated lymphoid tissue (MALT) is characterized by large amounts of immune-competent cells in the lamina propria of the mucosal layer of many organs.

Intercalated among the mucosal epithelial cells are the M cells, which have a membranous appearance and several external microfolds. Lymphoid tissue occupying the lamina propria of digestive, genitourinary, and respiratory mucosae contains an outer, dense-staining region that contains small T lymphocytes (dark zone) and a lighter-staining region that contains large cells (B lymphocytes and plasma cells). Together, these areas constitute the germinal center, consisting of a mesh of DFCs that support rapidly dividing B cells. The mantle zone surrounds the germinal center and contains small, resting B cells. Germinal centers also contain CD4⁺ T cells and macrophages.

In the ileum, the lamina propria may contain hundreds of aggregated nodules that form Peyer patches. In the tonsils, epithelium is distributed over lymphoid tissue. Small indentations in the tonsillar tissue form tonsillar crypts. Lymphoid tissue in the tonsils is dense and more nodular. Mucosal glands may be scattered among the surface epithelium of tonsillar tissue. Stratified squamous epithelium is seen in palatine and lingual tonsils, and pseudostratified and ciliated columnar epithelium is seen in the pharyngeal and tubaric tonsils, respectively.

MALTomas are B-cell lymphomas composed of small- to medium-sized lymphocytes that have irregular nuclear contours and abundant cytoplasm. Intermediate-grade MALTomas are distinguished from low-grade MALTomas by the presence of clusters or sheets of transformed blastlike cells with or without a background of low-grade MALToma. If no background of low-grade MALToma is present, the intermediate-grade form is morphologically indistinguishable from diffuse large B-cell lymphoma.

The unifying theme in MALTomas is the production of a diffuse infiltrate that invades epithelial structures and disrupts epithelium, resulting in a lymphoepithelial lesion. Reactive lymphoid follicles are present and become infiltrated and colonized by neoplastic lymphocytes. Thus, most MALTomas are low-grade B-cell lymphomas that express the B-cell antigens CD19 and CD20 and monotypic surface immunoglobulin (usually IgM without IgD). The CD23 marker, which is negative in almost all MALTomas, is useful for distinguishing MALTomas from mantle cell lymphomas.

Limited reports describe chromosomal anomalies that may have significant prognostic significance. The presence of trisomy 3 may indicate a low likelihood of response to anti-Helicobacter antibiotic therapy. The translocation t(11;18)(q21;q21) results in the API2-MALT1 fusion transcript, but it does not appear to have a negative prognostic impact.

Staging

The staging of MALTomas uses the same definitions as other NHLs; MALTomas are, by definition, extranodal in origin.

• Stage IE: Lymphoma is present in only 1 area or organ outside the lymph nodes.
• Stage IIE: Lymphoma is present in only 1 area or organ outside the lymph nodes and in the lymph nodes around it. Other lymph nodes on the same side of the diaphragm may also be involved.
• Stage IIIE: Lymphoma is present on both sides of the diaphragm. It may also have spread to an area or organ near the lymph nodes and/or the spleen.
• Stage IV: Lymphoma is widespread to several organs, with or without lymph node involvement.

Treatment

Medical Care

MALTomas have been reclassified as extranodal marginal-zone lymphomas of mucosa-associated lymphoid tissue (MALT)-type.¹³ Management is different for gastric and nongastric MALTomas.

Nongastric MALTomas are most common in the head and neck,^15,16,17 lung,¹⁸ and orbit.^14,19 These nongastric MALTomas are not associated with H. pylori and are treated using standard modalities that include radiation, chemotherapy, and monoclonal antibodies. In general, patients with stage IE-II disease can be treated with locoregional radiation therapy and/or surgery.

Patients whose condition subsequently recur, as well as patients with stage III/IV disease at presentation, are treated with regimens typically used for follicular lymphoma (ie, rituximab, CVP [chlorambucil, vincristine, prednisone], fludarabine, FND [fludarabine, mitoxantrone, dexamethasone], etc). However patients who have nongastric MALToma that is transformed to large B-cell lymphoma should be treated with regimens that are appropriate for the latter disease, (eg, R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone]).

Gastric MALTomas are the most common and well-studied MALTomas. These neoplasms are intimately associated with H. pylori, with the organism present in more than 90% of pathologic specimens of MALTomas.

• Proton pump inhibitors (PPIs) and antibiotics
  • Treatment with a PPI and antibiotics to eradicate H. pylori is the most important modality used in the therapy of gastric MALTomas, resulting in regression in up to 75% of cases of the low-grade form and some, but a minority, of the intermediate-grade forms of MALToma.
  • Treatment with a combination of amoxicillin, clarithromycin, and PPIs results in eradication rates of 90%. An alternate regimen of metronidazole, clarithromycin, and PPIs achieves the same result.
  • The presence of t(11;18)(q21;q21) translocations has been shown to predict a poor response to therapy.
  • Because most gastric MALTomas are of a low grade, they may remain localized and may not progress for several years.
  • Treatment with chemotherapy, surgery, or radiotherapy (alone or in combination) has not been demonstrated to be superior to antibiotic treatment. Because of this, a conservative approach, with oncologic and endoscopic follow-up, is advisable.
  • In cases in which no initial response to anti-Helicobacter therapy is observed, an alternative regimen is recommended for use during the second course of treatment.
  • Locally advanced disease that has infiltrated the muscularis mucosa, serosa, or perigastric lymph nodes has a significantly lower response rate.
  • Patients who have stage IE-II disease who are H. pylori– negative typically receive radiation therapy or rituximab.
• Chemotherapy
  • Chemotherapy for MALTomas has not been studied extensively, but historically, the treatment used has been the chemotherapy used for low-grade NHLs.
  • Several traditional monotherapy regimens have been used for MALTomas, including chlorambucil, cyclophosphamide, or fludarabine. In addition, standard combination regimens such as CHOP (cyclophosphamide, Adriamycin [hydroxydaunomycin], Oncovin [vincristine], and prednisone) have been used successfully.
  • Conjunctival MALTomas have been treated with interferon alfa-2a.
  • Gastrointestinal MALTomas are first treated with an antibiotic regimen designed to eradicate H. pylori.
    • In cases in which antibiotic regimens fail, chemotherapy should be used, although it has not been extensively studied. The treating physician's clinical judgment is crucial in this circumstance; he or she should choose secondary regimens that work in other NHLs.
    • A small, nonrandomized study evaluated single agents (chlorambucil and cyclophosphamide) in the treatment of low-grade gastric MALTomas. Complete remissions were achieved in 75% of patients.
    • Rituximab, an anti-CD20 monoclonal antibody, has been reported to achieve remissions in patients with gastric MALTomas whose conditions were either not responsive to anti– H. pylori therapy or who were not infected with H. pylori.
  • The large-cell, intermediate-grade forms of MALToma require standard chemotherapy similar to that used in other intermediate-grade NHLs (eg, diffuse large B-cell lymphoma).
• Radiation therapy
  • The efficacy of radiation therapy for gastric MALTomas has been demonstrated in several small trials.
  • Patients with gastric MALToma who will receive the maximal benefit from radiation therapy are those whose disease is in a limited area that could be incorporated in a single radiation treatment field and whose cases antibiotic treatment has failed.
  • Treatment with radiation therapy has achieved long-term remissions (>8 y in one series) in selected patients with gastric MALToma.
  • The optimal dose, patient characteristics, and role in the treatment armamentarium for gastric MALToma are not well delineated, but the dose generally recommended is in the range of 3000-3600 cGy.
  • Radiotherapy may be very effective for orbital soft-tissue MALTomas.
  • Caution is warranted in patients with tumor infiltration into the serosa; successful treatment may lead to gastric perforation, requiring immediate surgical intervention.
  • Secondary malignancies may occur in a small fraction of patients with gastric MALToma treated with radiation.

Surgical Care

• Surgery has an important, although limited, role in the treatment of gastric MALTomas. The morbidity associated with a partial or total gastrectomy is considerable, and, in most cases, neither is necessary. The efficacy of antibiotics, chemotherapy, and monoclonal antibody therapy has dramatically reduced the need for these procedures. Similarly, debulking is only rarely performed.
• Surgery for nongastrointestinal MALToma is predominantly used for excisional biopsy of the lungs or orbital soft tissue. The presence of microscopic disease in other sites and the efficacy of other treatment modalities have made surgical therapy an adjunctive rather than curative component of treatment.

Consultations

A gastroenterologist is an integral member of the treatment team for follow-up of the results of therapy for gastric MALTomas.

Diet

No special diet is required for patients with MALTomas.

Medication

In patients with H. pylori infection in association with a MALToma, especially gastric MALToma, the first line of therapy is treatment for the H. pylori infection. In patients with low-grade MALTomas who are not infected with H. pylori or whose MALToma does not respond to H. pylori treatment, options in asymptomatic patients include observation versus active intervention.

If treatment is required, treatments similar to those used for other low-grade NHLs are used. Examples are single-agent therapy such as chlorambucil, cyclophosphamide, fludarabine, or rituximab. Combinations of chemotherapy agents with or without rituximab may also be used. Patients with large-cell MALTomas are treated with combination chemotherapy (usually the CHOP regimen), with or without rituximab.

Antineoplastics

Antineoplastics interrupt proliferative activity and induce programmed cell death in proliferating B lymphocytes of MALTomas.

Cyclophosphamide (Cytoxan)

Transformed primarily in the liver to active alkylating metabolites. Metabolites interfere with the growth of susceptible rapidly proliferating malignant cells. The mechanism of action is thought to involve cross-linking of tumor cell DNA.

Dosing

Adult

400-1200 mg/m² IV as single dose q21d

Pediatric

Administer as in adults.

Interactions

Causes marked and persistent inhibition of cholinesterase activity and potentiates the effect of succinylcholine chloride; if the patient is treated with cyclophosphamide within 10 d of general anesthesia, alert the anesthesiologist

Contraindications

Documented hypersensitivity, severe bone marrow suppression

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Myelosuppression and alopecia are common; hemorrhagic cystitis is infrequent with adequate hydration; neutropenia should be anticipated, and an increased risk of infection begins at an absolute neutrophil count of <1000/µL; platelets should be 100,000/µL before subsequent treatment.

Doxorubicin (Adriamycin, Adriamycin PF)

Results in a conformational change of DNA and interferes with RNA polymerase, causing inhibition of protein synthesis.

Dosing

Adult

50-60 mg/m² IV q3wk (most common regimen, several others exist)

Pediatric

Administer as in adults.

Interactions

Phenobarbital increases elimination; patients on anticoagulant treatment may have an increased risk of bleeding; blood concentrations of phenytoin may be decreased.

Contraindications

Documented hypersensitivity; because of potential cardiac and hepatic toxicity, use caution in patients with cardiac and/or liver disease

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Induces both acute and chronic cardiotoxicity and must be used cautiously in patients with cardiac disease; half-life may be decreased (up to 30-50%) in patients who are obese; subcutaneous infiltration can cause chemical burns and necrosis; the long-term risk of development of myelodysplastic syndrome and/or acute myeloid leukemia ranges from 2% to 5%

Vincristine (Oncovin)

Vinca alkaloid extracted from the plant Catharanthus rosea. Exerts therapeutic effects on cells by interfering with microtubules of mitotic spindle fibers, causing metaphasic cell cycle arrest.

Dosing

Adult

2 mg IV on day 1 q21d

Pediatric

1.4 mg/m² (not to exceed 2 mg) IV push

Interactions

Because of hepatic metabolism due to the activity of CYP 3A4 (cytochrome P-450 isoenzyme 3A4), simultaneous use of drugs using the same pathway (eg, phenobarbital) may interfere with the metabolism and bioavailability.

Contraindications

Documented hypersensitivity; tumor lysis syndrome related to therapeutic effects may cause hyperuricemia that could cause or aggravate gout or urate nephrolithiasis

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May cause sensory and motor neurotoxicity, including paresthesias and foot drop, respectively; constipation, jaw pain, and alopecia also may occur; SC infiltration may result in extensive necrosis

Biologic Response Modifiers

Biologic response modifiers suppress immune cells involved in MALTomas.

Prednisone (Deltasone, Orasone, Meticorten)

Metabolized by liver to active metabolite prednisolone. Binds extensively to albumin and transcortin. Unbound portion crosses cell membranes and binds to specific cytoplasmic receptors, inducing a response by modifying transcription and, ultimately, protein synthesis.
Prednisolone is further metabolized to inactive compounds. Used as a component of the CHOP combination chemotherapy regimen.

Dosing

Adult

100 mg/m² PO on days 1-5 q2wk

Pediatric

Not established; for other lymphomas, 40 mg/m²

Interactions

Hepatic microsomal enzyme inducers (eg, phenobarbital, phenytoin, rifampin) may affect the metabolism, increasing the clearance; drugs such as troleandomycin and ketoconazole may inhibit metabolism

Contraindications

Documented hypersensitivity, systemic fungal infections

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in patients with frank psychosis, emotional instability, ocular infections due to HSV, renal disease, diverticulitis, hypertension, osteoporosis, diabetes mellitus, hypothyroidism, and seizure disorders; abrupt discontinuation in patients on long-term treatment may be associated with the development of adrenal insufficiency.

Fludarabine (Fludara)

Nucleotide analogue of vidarabine converted to 2-fluoro-ara-A that enters the cell and is phosphorylated to form the active metabolite 2-fluoro-ara-ATP, which inhibits DNA synthesis.

Dosing

Adult

25 mg/m²/d IV over 30 min qd for 5 d; repeat 5-d course q28d; adjust dose based on hematologic or nonhematologic toxicity

Pediatric

Not established

Interactions

Combination with other purine analogues (eg, pentostatin) is contraindicated, because the rate of pulmonary toxicity is unacceptably high when they are used together.

Contraindications

Documented hypersensitivity; breastfeeding; bone marrow suppression

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Perform frequent peripheral blood cell counts to detect the development of anemia, thrombocytopenia, and neutropenia; monitor for tumor lysis syndrome; adjust the dose for renal impairment, severe bone marrow suppression, severe neurologic effects, or life-threatening and fatal autoimmune hemolytic anemia.

Etoposide (Toposar, VePesid)

Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in the late S or early G2 portion of the cell cycle.

Dosing

Adult

120 mg/m² IV on days 1-3 or 100 mg/m² IV on days 1-5

Pediatric

Not established

Interactions

May prolong the effects of warfarin and increase the clearance of methotrexate; cyclosporine and etoposide have additive effects in the cytotoxicity of tumor cells

Contraindications

Documented hypersensitivity; IT administration may cause death

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Bleeding and severe myelosuppression may occur.

Mitoxantrone (Novantrone)

Inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II.

Dosing

Adult

12-14 mg/m² IV q3-4wk

Pediatric

18-20 mg/m² IV q3-4wk

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in patients with impaired hepatic function and preexisting cardiac disease (cardiotoxicity is commonly seen after a cumulative dose of 120-160 mg/m²); perform baseline and follow-up cardiac function tests (2-dimensional echocardiography and ejection fraction measurements)

Bleomycin (Blenoxane)

Glycopeptide antibiotic that inhibits DNA synthesis. For palliative measure in the management of several neoplasms.

Dosing

Adult

0.25-0.5 U/kg (10-20 U/m²) IV/IM/SC 1-2 times/wk; reconstitute 15-U vial with 1-5 mL of sterile water or NS for injection

Pediatric

Not established

Interactions

May decrease the plasma levels of digoxin and phenytoin; cisplatin may increase the toxicity when administered systemically

Contraindications

Documented hypersensitivity; significant renal function impairment; compromised pulmonary function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in the presence of renal impairment; possibly secreted in breast milk; may cause mutagenesis and pulmonary toxicity (10%); idiosyncratic reactions similar to anaphylaxis may occur (1%); monitor for adverse effects during and after treatment; vasoocclusive phenomenon may occur with distal necrosis of digits; permanent damage to nail matrix may occur

Chlorambucil (Leukeran)

Alkylates and cross-links strands of DNA, inhibiting DNA replication and RNA transcription

Dosing

Adult

0.1-0.2 mg/kg/d PO or 3-6 mg/m²/d PO q3-6wk; adjust dose depending on the patient's blood cell counts

Pediatric

Administer as in adults.

Interactions

None reported

Contraindications

Documented hypersensitivity; previous resistance to medication

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in patients with a history of seizure disorders; bone marrow suppression

Monoclonal Antibodies

Monoclonal antibodies are genetically engineered chimeric murine/human monoclonal antibodies directed against proteins involved in cell cycle initiation.

Rituximab (Rituxan)

Genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen that is found on the surface of normal and malignant B lymphocytes. The antibody is an IgG1-kappa immunoglobulin containing murine light- and heavy-chain variable region sequences and human constant region sequences.

Dosing

Adult

375 mg/m² IV qwk for 4 doses (days 1, 8, 15, and 22)

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hypotension, bronchospasm, and angioedema may occur; discontinue treatment if life-threatening cardiac arrhythmias occur.

Antibiotics

Antibiotics are the mainstay in the eradication of H. pylori, the major etiologic agent in gastric MALToma.

Clarithromycin (Biaxin, Biaxin XL)

Inhibits bacterial growth, possibly by blocking the dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Dosing

Adult

250-500 mg PO q12h for 7-14 d

H. pylori eradication: 250 mg bid PO clarithromycin in combination with 400 mg bid metronidazole and 20 mg bid omeprazole for 1 wk

Pediatric

15 mg/kg PO divided bid

Interactions

The toxicity increases with the coadministration of fluconazole and pimozide; the effects decrease and adverse GI effects may increase with the coadministration of rifabutin or rifampin; may increase the toxicity of anticoagulants, cyclosporine, tacrolimus, digoxin, carbamazepine, ergot alkaloids, triazolam, and HMG-CoA reductase inhibitors; plasma levels of certain benzodiazepines may increase, prolonging CNS depression; arrhythmias and increases in QTc intervals occur with disopyramide; coadministration with omeprazole may increase the plasma levels of both agents

Contraindications

Documented hypersensitivity; coadministration of pimozide

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Coadministration with ranitidine or bismuth citrate is not recommended when CrCl <25 mL/min; give a half dose or increase the dosing interval if CrCl <30 mL/min; diarrhea may be a sign of pseudomembranous colitis; superinfections may occur with prolonged or repeated antibiotic therapies

Metronidazole (Flagyl)

Imidazole ring-based antibiotic that is active against various anaerobic bacteria and protozoa. Used in combination with other antimicrobial agents (except for Clostridium difficile enterocolitis).

Dosing

Adult

Loading dose: 15 mg/kg or 1 g for 70-kg adult IV over 1 h

Maintenance dose: 6 h following loading dose; infuse 7.5 mg/kg or 500 mg for 70-kg adult over 1 h q6-8h; not to exceed 4 g/d

H. pylori eradication: 400 mg PO bid metronidazole in combination with clarithromycin 250 bid and omeprazole 20 mg bid for 1 wk

Pediatric

Administer as in adults, using weight-based dosing.

Interactions

May increase the toxicity of anticoagulants, lithium, and phenytoin; cimetidine may increase the toxicity of metronidazole; disulfiram reaction may occur with orally ingested ethanol

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adjust the dose in patients with hepatic disease; monitor for seizures and the development of peripheral neuropathy.

Proton Pump Inhibitors

Proton pump inhibitors are used in combination with antibiotics for H. pylori eradication.

Omeprazole (Prilosec)

Decreases gastric acid secretion by inhibiting parietal cell H⁺/K⁺ -ATP pump.

Dosing

Adult

40 mg/d PO for 4-8 wk for gastric ulcer

Eradication of H. pylori: 20 mg bid omeprazole in combination with metronidazole 400 mg bid and clarithromycin 250 bid for 1 wk

Pediatric

Not established

Interactions

May decrease the effects of itraconazole and ketoconazole; may increase the toxicity of warfarin, digoxin, and phenytoin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

The bioavailability may increase in elderly individuals.

Follow-up

Further Outpatient Care

• Patients with MALToma should continue to receive serial examinations at increasing frequencies for several years following the successful completion of therapy.

Prognosis

• Generally, low-grade MALTomas are indolent neoplasms with a fairly good prognosis.
• MALTomas that are not eradicated by treatment of H. pylori infection are incurable but are associated with a long course.
• Although the intermediate-grade, diffuse, large B-cell MALTomas are more aggressive malignancies, the cure rate may be as high as 90% for stage IE disease and is approximately 30-40% for extensive stage IIIE or IVE disease. These outcomes are similar to non-MALT intermediate-grade NHLs.
• Gastric MALTomas have a stage-dependent prognosis. The survival rate for stage IE disease is 93% at 5 years and 58% at 10 years.²⁰ Long-term responses to anti– H. pylori treatment alone have been reported.
• Nongastrointestinal MALTomas are most common in the head and neck, ocular adnexa, and lungs.
• Several small studies have reported that observation alone may be appropriate in selected patients with ocular adnexal MALToma.
  • The prognosis depends on the grade of the tumor, with long-term survival possible for patients with low-grade tumors. However, achieving a cure is more difficult in patients with MALTomas in advanced stages.
  • Use of the International Prognostic Index — taking into account age, Ann Arbor stage, lactate dehydrogenase (LDH) levels, the number of extranodal sites, and performance status — has better characterized low-, intermediate-, and high-risk groups. Five-year survival rates in these groups are 99% for the low-risk groups; 85-88%, intermediate-risk groups; and 72%, for high-risk groups. Patients with early-stage MALToma may be curable with chemotherapy.
  • The risks and benefits of surgical or radiation therapy for MALTomas should be considered before proceeding.

Miscellaneous

Medicolegal Pitfalls

• Failure to diagnose cancer is one of the most frequent reasons for medical malpractice actions. Suggestive symptoms should be thoroughly investigated.
• Failure to diagnose the correct subtype of lymphoma and subsequent use of treatment for another type of lymphoma or other malignancy that is not optimal therapy for MALToma is a medicolegal hazard.
• Inappropriately aggressive surgical, radiation, or medical therapy that results in serious injury or long-term disability is a potentially serious medicolegal hazard in the management of MALTomas.

References

1. Johnson RM, Brown EJ. Cell-mediated immunity in host defense against infectious diseases. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Disease. 5^th ed. Philadelphia, Pa: Churchill Livingstone; 2000:131-4.

2. Greer JP, Macon WR, McCurley TL. Non-Hodgkin lymphoma. In: Lee GR, Foerster J, Lukens J, et al, eds. Wintrobe's Clinical Hematology. 10^th ed. Baltimore, Md: Lippincott, Williams & Wilkins; 1999:2471-3.

3. Bufo P. The MALTomas. Academic lesson; 1999.

4. Santacroce L. Anatomy, physiology and surgical pathophysiology of the MALT. Academic lesson; 1997.

5. Beagley KW, Elson CO. Cells and cytokines in mucosal immunity and inflammation. Gastroenterol Clin North Am. Jun 1992;21(2):347-66. [Medline].

6. Featherstone C. M cells: portals to the mucosal immune system. Lancet. Oct 25 1997;350(9086):1230. [Medline].

7. Hamzaoui N, Pringault E. Interaction of microorganisms, epithelium, and lymphoid cells of the mucosa-associated lymphoid tissue. Ann N Y Acad Sci. Nov 17 1998;859:65-74. [Medline].

8. Dubois B, Barthélémy C, Durand I, et al. Toward a role of dendritic cells in the germinal center reaction: triggering of B cell proliferation and isotype switching. J Immunol. Mar 15 1999;162(6):3428-36. [Medline]. [Full Text].

9. Delves PJ, Roitt IM. The immune system. First of two parts. N Engl J Med. Jul 6 2000;343(1):37-49. [Medline].

10. Delves PJ, Roitt IM. The immune system. Second of two parts. N Engl J Med. Jul 13 2000;343(2):108-17. [Medline].

11. Chin YH, Cai JP, Hieselaar T. Lymphocyte migration into mucosal lymphoid tissues: mechanism and modulation. Immunol Res. 1991;10(3-4):271-8. [Medline].

12. Keren DF. Intestinal mucosal immune defense mechanisms. Am J Surg Pathol. 1988;12 suppl 1:100-5. [Medline].

13. Cavalli F, Isaacson PG, Gascoyne RD, Zucca E. MALT Lymphomas. Hematology Am Soc Hematol Educ Program. 2001;241-58. [Medline]. [Full Text].

14. Perry C, Herishanu Y, Metzer U, et al. Diagnostic accuracy of PET/CT in patients with extranodal marginal zone MALT lymphoma. Eur J Haematol. Sep 2007;79(3):205-9. [Medline].

15. Chen Y, Inobe J, Marks R, et al. Peripheral deletion of antigen-reactive T cells in oral tolerance. Nature. Jul 13 1995;376(6536):177-80. [Medline].

16. Bachert C, Möller P. [The tonsils as MALT (mucosa-associated lymphoid tissue) of the nasal mucosa] [German]. Laryngorhinootologie. Oct 1990;69(10):515-20. [Medline].

17. Kracke A, Hiller AS, Tschernig T, et al. Larynx-associated lymphoid tissue (LALT) in young children. Anat Rec. Jul 1997;248(3):413-20. [Medline].

18. Lugton I. Mucosa-associated lymphoid tissues as sites for uptake, carriage and excretion of tubercle bacilli and other pathogenic mycobacteria. Immunol Cell Biol. Aug 1999;77(4):364-72. [Medline].

19. Ferreri AJ, Assanelli A, Crocchiolo R, et al. Therapeutic management of ocular adnexal MALT lymphoma. Expert Opin Pharmacother. Jun 2007;8(8):1073-83. [Medline].

20. Fung CY, Grossbard ML, Linggood RM, et al. Mucosa-associated lymphoid tissue lymphoma of the stomach: long term outcome after local treatment. Cancer. Jan 1 1999;85(1):9-17. [Medline]. [Full Text].

21. Babcock GJ, Thorley-Lawson DA. Tonsillar memory B cells, latently infected with Epstein-Barr virus, express the restricted pattern of latent genes previously found only in Epstein-Barr virus-associated tumors. Proc Natl Acad Sci U S A. Oct 24 2000;97(22):12250-5. [Medline]. [Full Text].

22. Brandtzaeg P, Sollid LM, Bjerke K, et al. Interactions of lymphoid cells with the epithelial environment. Monogr Allergy. 1988;24:51-9. [Medline].

23. Dürkop H, Anagnostopoulos I, Bulfone-Paus S, Stein H. Expression of several members of the TNF-ligand and receptor family on tonsillar lymphoid B cells. Br J Haematol. Sep 1997;98(4):863-8. [Medline].

24. Fasano A. Physiological, pathological, and therapeutic implications of zonulin-mediated intestinal barrier modulation. Living life on the edge of the wall. Am J Pathol. Oct 2 2008;epub ahead of print. [Medline].

25. González-Fernández A, Gilmore D, Milstein C. Age-related decrease in the proportion of germinal center B cells from mouse Peyer's patches is accompanied by an accumulation of somatic mutations in their immunoglobulin genes. Eur J Immunol. Nov 1994;24(11):2918-21. [Medline].

26. Greiner A, Knörr C, Seeberger H, Schultz A, Müller-Hermelink HK. Tumor biology of mucosa-associated lymphoid tissue lymphomas. Recent Results Cancer Res. 2000;156:19-26. [Medline].

27. Hammel P, Haioun C, Chaumette MT, et al. Efficacy of single-agent chemotherapy in low-grade B-cell mucosa-associated lymphoid tissue lymphoma with prominent gastric expression. J Clin Oncol. Oct 1995;13(10):2524-9. [Medline].

28. Harris A, Misiewicz JJ. ABC of the upper gastrointestinal tract. Management of Helicobacter pylori infection. BMJ. Nov 3 2001;323(7320):1047-50. [Medline]. [Full Text].

29. Harris NL, Isaacson PG. What are the criteria for distinguishing MALT from non-MALT lymphoma at extranodal sites?. Am J Clin Pathol. Jan 1999;111(1 suppl 1):S126-32. [Medline].

30. Hein WR. Organization of mucosal lymphoid tissue. Curr Top Microbiol Immunol. 1999;236:1-15. [Medline].

31. Husson H, Lugli SM, Ghia P, et al. Functional effects of TNF and lymphotoxin alpha1beta2 on FDC-like cells. Cell Immunol. Aug 1 2000;203(2):134-43. [Medline].

32. Isaacson PG. Extranodal lymphomas: the MALT concept. Verh Dtsch Ges Pathol. 1992;76:14-23. [Medline].

33. Iwasaki A, Kelsall BL. Localization of distinct Peyer's patch dendritic cell subsets and their recruitment by chemokines macrophage inflammatory protein (MIP)-3alpha, MIP-3beta, and secondary lymphoid organ chemokine. J Exp Med. Apr 17 2000;191(8):1381-94. [Medline]. [Full Text].

34. Jain SL, Michael JG. The influence of antigen digestion on orally induced immunity and tolerance. Adv Exp Med Biol. 1995;371B:1245-50. [Medline].

35. Kuo SH, Yeh PY, et al. Overexpression of B cell-activating factor of TNF family (BAFF) is associated with Helicobacter pylori-independent growth of gastric diffuse large B-cell lymphoma with histologic evidence of MALT lymphoma. Blood. Oct 1 2008;112(7):2927-34. [Medline].

36. Köhne G, Schneider T, Zeitz M. Special features of the intestinal lymphocytic system. Baillieres Clin Gastroenterol. Sep 1996;10(3):427-42. [Medline].

37. Langkamp-Henken B, Glezer JA, Kudsk KA. Immunologic structure and function of the gastrointestinal tract. Nutr Clin Pract. Jun 1992;7(3):100-8. [Medline].

38. Liu YJ, Barthélémy C, de Bouteiller O, et al. Memory B cells from human tonsils colonize mucosal epithelium and directly present antigen to T cells by rapid up-regulation of B7-1 and B7-2. Immunity. Mar 1995;2(3):239-48. [Medline]. [Full Text].

39. López-González MA, Sánchez B, Mata F, Delgado F. Tonsillar lymphocyte subsets in recurrent acute tonsillitis and tonsillar hypertrophy. Int J Pediatr Otorhinolaryngol. Feb 1998;43(1):33-9. [Medline].

40. Miki H, Kobayashi S, Harada H, et al. Early stage gastric MALT lymphoma with high-grade component cured by Helicobacter pylori eradication. J Gastroenterol. Feb 2001;36(2):121-4. [Medline].

41. Moretó M, Pérez-Bosque A. Dietary plasma proteins, the intestinal immune system and the barrier functions of the intestinal mucosa. J Anim Sci. Sep 26 2008;epub ahead of print. [Medline].

42. Mosby. Schoefer J, Nissen D, eds. Mosby's GenRx 2001: A Comprehensive Reference for Generic and Brand Prescription Drugs. St. Louis, Mo: Mosby-Year Book; 2001.

43. Owen RL. Mid-life crisis for M cells. Gut. Jan 1998;42(1):11-2. [Medline]. [Full Text].

44. Pabst R. Lymphocyte migration to the gut: oversimplifications and controversial aspects. Immunol Res. 1991;10(3-4):279-81. [Medline].

45. Patrick MK, Gall DG. Protein intolerance and immunocyte and enterocyte interaction. Pediatr Clin North Am. Feb 1988;35(1):17-34. [Medline].

46. Richards JW Jr. Cryptic tonsillitis. J Fam Pract. Nov 1996;43(5):502. [Medline].

47. Rothkötter HJ, Geist M, Fritz FJ, Pabst R. Age-dependence of lymphocyte production in Peyer's patch follicles in contrast to the other Peyer's patch compartments and the thymus. Adv Exp Med Biol. 1988;237:81-5. [Medline].

48. Sierro F, Pringault E, Assman PS, Kraehenbuhl JP, Debard N. Transient expression of M-cell phenotype by enterocyte-like cells of the follicle-associated epithelium of mouse Peyer's patches. Gastroenterology. Sep 2000;119(3):734-43. [Medline].

49. Syrjänen S, Syrjänen K, Horsmanheimo M. Structure and function of salivary glands in psoriatics. Arch Dermatol Res. 1982;274(3-4):295-301. [Medline].

50. Yamamoto M, Rennert P, McGhee JR, et al. Alternate mucosal immune system: organized Peyer's patches are not required for IgA responses in the gastrointestinal tract. J Immunol. May 15 2000;164(10):5184-91. [Medline]. [Full Text].

51. Zinzani PL, Magagnoli M, Galieni P, et al. Nongastrointestinal low-grade mucosa-associated lymphoid tissue lymphoma: analysis of 75 patients. J Clin Oncol. Apr 1999;17(4):1254. [Medline]. [Full Text].

Keywords

mucosa-associated lymphoid tissue, lymphoid tissue, MALToma, MALT lymphoma, MALT, marginal zone B-cell lymphoma, lymph node, mucus membrane, mucus, mucosal tissue, tonsils, Peyer patches, Peyer's patches, vermiform appendix, non-Hodgkin lymphoma, non-Hodgkin's lymphoma, NHL, lymphoma, malignancy, malignancies, cancer, Hashimoto thyroiditis, Hashimoto's thyroiditis, Crohn disease, Crohn's disease, celiac disease, Sjögren syndrome,
gut-associated lymphoid tissue, GALT, bronchial/tracheal-associated lymphoid tissue, BALT, nose-associated lymphoid tissue, NALT, vulvovaginal-associated lymphoid tissue, VALT, gastric MALT lymphoma, nongastric MALT lymphoma, gastric MALToma, nongastric MALToma, human mucosa

Contributor Information and Disclosures

Author

Sara J Grethlein, MD, Associate Dean for Graduate Medical Education, Professor, Department of Internal Medicine, Division of Hematology and Oncology, State University of New York Upstate Medical University
Sara J Grethlein, MD is a member of the following medical societies: American Society of Hematology
Disclosure: Nothing to disclose.

Coauthor(s)

Jose A Perez Jr, MD, MSEd, MBA, Consulting Physician, Department of Internal Medicine, Residency Director, Vice Chair of Education Department of Medicine, The Methodist Hospital, Houston; Associate Professor of Clinical Medicine, Weill Cornell Medical College
Jose A Perez Jr, MD, MSEd, MBA is a member of the following medical societies: American College of Physician Executives, American College of Physicians, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Medical Editor

Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, and American Society of Hematology
Disclosure: Novartis Honoraria Speaking and teaching; Schering Honoraria Speaking and teaching; Cephalon Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Troy H Guthrie, Jr, MD, Director of Cancer Institute, Baptist Medical Center
Troy H Guthrie, Jr, MD is a member of the following medical societies: American Federation for Medical Research, American Medical Association, American Society of Hematology, Florida Medical Association, Medical Association of Georgia, and Southern Medical Association
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
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