Extranodal marginal zone lymphomas (EMZLs) are a form of MZL in which malignant marginal zone B-cells initially infiltrate MALT tissues of the stomach (50–70% of all EMZL) or, less frequently, the
esophagus,
small intestine,
large intestine,
rectum,
conjunctiva of the eye,
nasal passages,
pharynx, lung
bronchi,
vulva,
vagina,
skin,
breast,
thymus gland,
meninges (i.e.
membranes) that envelop the
brain and
spinal cord, or other organs. These EMZLs are classified into subtypes based on the organ(s) involved. For example, EMZL of the stomach is termed primary gastric EMZL. Regardless of subtype, these EMZLs share similar
pathophysiological (i.e. disordered
physiological processes that cause the disease) and
histopathological (i.e.
microscopic features of diseased
tissues). However, the subtypes differ in presentation, progression, severity, treatment, and instigating factors. The following two sections describe the common pathophysiologic and histopathologic features found in all EMZL subtypes. Features specific to each EMZL subtype follow these two sections.
Pathophysiology , with marginal zone annotated at bottom. Numerous factors appear to be involved in the development of EMZL. In a small number of cases where there is a family history of a
blood cancer particularly leukemia, or a number of autoimmune diseases such as Sjögren syndrome and
lupus erythematosus, there is seen to be an increased frequency. Inherited genetic, shared environmental, and other as yet unidentified factors may underlie these increased risks of developing an EMZL. Another key factor in the initiation of many EMZL cases is chronic inflammation caused by a chronic infection or autoimmune reaction. The chronic inflammation stimulates B-cells to rearrange their
immunoglobulin heavy chain locus so that they encode
B-cell receptors that recognize unnatural antigens presented by the injured issues and/or infectious agents that underlie the inflammation. This rearrangement results in the B-cells responding to the abnormal antigens by taking on features of marginal B-cells and proliferating excessively. In consequence, these B cells progressively acquire in a step-wise fashion
chromosome abnormalities, gene
mutations, and/or dis-regulated genes that contribute to their becoming malignant. The acquired genomic abnormalities found in EMZL along with the frequency of occurrence in specific EMZL subtypes include the following. •
Chromosome translocations: 1) A translocation of the long (or "q") arm of
chromosome 11 at position 21 with the q arm of chromosome 18 at position 21 (notated as a t(11;18)(q21;q21) translocation) occurs in 24% of gastric, 38% of lung, and rarely other EMZL subtypes. This translocation places a part of the
API2 gene with a part of the
MALT1 gene to create a
fusion gene that encodes an Api2-Malt1
fusion protein. This
chimeric protein promotes the continuous activation of a
transcription factor,
NF-κB. NF-κB controls the expression of various genes which increase the survival,
cytokine production, and other potentially malignant behaviors of cells. 2) A t(14;18)(q32;q21) translocation occurs in 7% of ocular adnexa, 6% of lung, and rarely if at all in other cases of EMZL. It causes the overexpression of Malt1. This protein indirectly inhibits
programmed cell death to prolong cell survival and also promotes activation of NF-κB. 3) A t(1;14)(p22;q32) ("p" stands for a chromosome's short arm) translocation occurs in ~9% of lung, ~4% of stomach, and rarely if at all in other cases of EMZL. This translocation causes the overexpression of the
BCL10 gene. Bcl10 protein contributes to the activation of NF-κB. 4) A t(3;14)(p13;q32) translocation occurs in rare cases of EMZL and is thought to cause overexpression of the
FOXP1 gene. FoxP1 protein stimulates production of
transcription factors such as
PRDM1,
IRF4, and
XBP1 which promote the maturation of B-cells to plasma cells. 5) Three translocations, t(1;14)(p21;q32), t(5;14)(q34;q32), t(9;14)(p24;q32), and t(X;14)(p11.4;q32), occur in rare cases of EMZL but their effects on promoting malignancy are unknown. • Gene inactivations and mutations: 1)
Inactivation or the
TNFAIP3 gene due to its deletion on chromosome 6 about position 23 (i.e. a 6q23 deletion) or its mutation occur mainly in ocular adnexa, salivary gland, and thyroid gland EMZL.
TNFAIP3 inactivation generally takes place in cases which do not have any of the above chromosome translocations. This gene's product, tumor necrosis factor, alpha-induced protein 3, functions to impair the activation of NF-κB. 2)
Gain-of-function mutations in the
MYD88 gene occur in ~5% of ocular adnexa EMZL cases. The product of this gene, myeloid differentiation primary response 88, continuously activates NF-κB as well as the
STAT3 and
AP1 transcription factors. Many EMZL subtypes are associated with infectious agents or autoimmune diseases that may contribute to their malignant development. The following Table reports on these EMZL subtypes; the tissues they involve; the infectious agents/autoimmune diseases that may underlie the development of the EMZL subtypes; the strength of evidence linking these infectious agents/autoimmune diseases to their malignancy; the incidence (i.e. percentage) of cases with the EMZL subtype associated with the infectious agent/autoimmune disease; and some of the
chimeric genes expressed by the neoplastic B-cells of the EMZL subtype.
Histopathology The
histopathologic (i.e. microscopic) examination of EMZL
lesions typically reveals a vaguely nodular or diffuse pattern of cells. The malignant cells in these lesions have, in varying proportions, the
morphology of small-to-medium-sized lymphocytes,
centrocyte-like B cells,
centroblast-like B cells,
monocyte-like B cells,
plasma cell-like B cells, and/or large B cells. When the large B cells form prominent sheets that are clearly separated from cells with the other, low-grade malignant morphologies, the disease may be transforming to the far more aggressive malignancy,
diffuse large B-cell lymphoma. This transformation occurs in ~18% of patients at a median of 4–5 years after the original diagnosis of EMZL.
Immunophenotyping or the neoplastic large B cells in these lesions shows that they express
CD20 but not
CD3 surface membrane B cell marker proteins. The cells almost always express
BCL2 and may express
MNDA (~70% of cases),
CD23 (~33% of cases) and
CD5 (~20% of cases) marker proteins but do not express the
cyclin D1 marker protein., with various symptoms such as
nausea, vomiting, indigestion, upper abdominal pain, and gastric bleeding as indicated by coughing up blood,
bloody bowel movements, and/or
iron deficiency anemia. Rarely, patients present with
perforation of the stomach or
B symptoms such as fever and
night sweats. Individuals with chronic
Helicobacter pylori infection may also have
halitosis.
Endoscopic inspection and biopsy of lesions
Helicobacter heilmannii sensu lato designates at least 11 different
Helicobactor species of which 5 are known to infect the human stomach. It has been more difficult to determine that
Helicobacter heilmannii sensu lato is responsible for human gastric disease because the urea breath test is less often positive in infestations by these species, antibodies directed against them are generally not available, and they are difficult to grow in culture. The diagnosis of
Helicobacter heilmannii sensu lato therefore depends upon detecting the organism in tissues or fecal material histologically using special silver staining methods and then sequencing certain genes (i.e. urease A, urease B, heat shock protein 60, and/or gyrase subunit B) in the organisms DNA and/or the organisms 23sRNA.) plus any one of several different
antibiotic combinations (e.g.
Clarithromycin +
Amoxicillin or
levofloxacin +
nitazoxanide +
doxycyclin). While generally a progressive disease, patients with early stage primary small intestinal MZL may have spontaneous and complete remissions. is a variant and by far the most common form of small intestinal MZL. The following sections further describe these two EMZL subtypes.
Primary colonic Primary colonic EMZL, also termed primary colonic MALT lymphoma, usually presents at an early stage of disease with evidence of lower GI tract bleeding (e.g. tarry bowel movements and/or iron deficiency anemia), less commonly with lower abdominal pain, and rarely with
bowel perforation or
intussusception. Endoscopic examination most often reveals a single
polyp or rarely multiple polyps, a mucosal ulcer, or a mucosal nodule. Diagnosis is passed on biopsy of the lesions showing a histology typical of EMZL, e.g. diffuse infiltrates composed of small to medium-sized lymphocytes that may show morphological features of monocytes and/or plasma cells. The lymphocytes in these lesions express B cell markers (e.g. CD19 and CD79a) typical of EMZL lesions. The best treatment regimen for this lymphoma is debated. Surgical resection, endoscopic resection, radiation, and chemotherapy have been employed. Surgery followed by chemotherapy (
mitoxantrone +
chlorambucil +
prednisone or
cyclophosphamide +
vincristine + prednisone combined with either chlorambucil or
rituximab) have been regarded as first-line treatment for the disease. More recently, rituximab alone as a single agent has also been found successful in treating primary colonic MALT lymphoma. Finally, rare cases of primary colonic EMZL have been completely resolved using
Helicobacter pylori antibiotic therapy. On examination, >90% of cases present with localized (i.e. stage I or II) disease. The lymphomas' lesions are characterized by reactive lymphoid follicles infiltrated with centrocyte-like or monocyte-like B cells (the latter cells may show features of
plasma cells). The malignant cells in these lesions may contain the t(11;18) translocation and therefore express the API2-MALT1 chimeric protein (11% of cases). Some 22–45% of casests are associated with
Helicobactor pylori GI tract infection. Treatments for the disease have included radiotherapy, surgical resection, endoscopic mucosal resection, various chemotherapies, and antibiotic-based eradication of
Helicobactor pylori. Eradication therapy for
Helicobactor pylori-positive cases using currently recommended standard antibiotic regimens has given complete responses in 12 of 19 cases and therefore is regarded as proper treatment for such cases. Surgical resection for localized disease has achieved long-term survivals in individual cases. or, more commonly, a linear central indentation or ridge in the esophagus. In a 2017 review, 6 of 18 patients with EMZL of the esophagus had evidence of concurrent
Helicobacter pylori infection. The histopathology of the lesions in EMZL of the esophagus is typical of EMZL in showing the presence of centrocyte-like cells, monocyte-like cells, and small lymphocytes that express CD20 but not CD10.
Primary ocular adnexa Primary ocular
adnexa EZML (also termed primary EMZL of the ocular adnexa, primary ocular adnexa MALT lymphoma, or primary MALT lymphoma of the ocular adnexa) occurs primarily in older patients (median age 65 years). Individuals may be predisposed to the disease by having a long history of exposure to livestock, mainly cattle and pigs or working with meat from these animals; autoimmune diseases, particularly autoimmune thyroid disease; and infections, particularly
Clamydophelia psittaci, a communicable
intracellular bacterium that infects feral birds, farm animals, and humans. In humans, it causes respiratory
psittacosis and eye infections, particularly chronic
conjunctivitis.
Clammydophelia psittaci has been detected in the lesions of 47–80% of patients with primary ocular adnexa EMZL with the highest rates of this detection occurring in Italy, Austria, Germany, and Korea. Much lower detection rates are reported in the United Kingdom and Southern China while there has been little or no evidence of this organism in cases from the United States and Japan. A variable percentage of patients with primary ocular adnexa MZL may concurrently be affected by
Hashimoto's thyroiditis,
Sjögren syndrome, or
IgG4-related disease. Some studies have also found that the disease is associated with
Helicobactor pylori infection of the stomach (45% of cases) or EMZL in other tissues (25% of cases). The lesions in primary ocular adnexa EMZL are typical of EMZL: they contain
centrocyte-like B-cells, monocyte-like B-cells, and/or small lymphocytes many of which express CD20, CD791, PAZ5, and BCL2 but not CD10 or cyclin D1 proteins. The t(1:14)(p22:q320 chromosome translocation, which leads to the over expression of the
MALT1 gene, trisomy 3, trisomy 18, and deletions at position 23 on the long arm of chromosome 6 are also often found in primary ocular adnexa EMZL. The B-cells in these lesions express the B-cell markers commonly seen in EMZL. The
DNA of
Borrelia burgdorferi, the causative agent of
Lyme disease, has been detected in the lesions of 10%–42% of patients in Germany, Italy, Japan, and Turkey but not of patients from Spain, Finland, the Netherlands, or the United States. While the disease almost always has a highly indolent course, it is subject to repeated relapses that are usually limited to the skin. Rarely, primary cutaneous EMZL disseminates to other tissues and becomes a systemic disease.
Achromobacter xylosoxidans is a
betaproteobacteria that is routinely isolated from the lungs of
cystic fibrosis patients; it has a low
virulence but is extremely resistant to antibiotics. include surgery, radiotherapy, chemotherapy,
immunotherapy, and
watchful waiting. Patients with this syndrome have a 40- to 80-fold increased risk of developing a thyroid lymphoma, 25% of which are primary thyroid EMZLs. Hashimoto's thyroiditis patients who develop this lymphoma are typically women (median age 70 years) who have had the thyroiditis for 20–30 years and present with a rapid increase in the thyroid gland's size and, in association with this, have developed
hoarseness, high-pitched
breath sounds, and/or difficulty in swallowing and/or breathing. Patients with primary thyroid EMZL are at an increased risk of developing a more disseminated lymphoma, particularly diffuse large B-cell lymphoma or, alternatively, nodal MZL, or splenic MZL.) and/or
immunotherapy (i.e.
rituximab or disease that has progressed to a more malignant lymphoma and
autoimmune hemolytic anemia are similarly susceptible to developing an EMZL. While the exact reasons for these associations are unclear, it is generally considered that the chronic inflammation involved in each disease promotes the malignant behavior of B-cells and thereby the development of EMZL. Histologically, lesions in the disorder were typical of EMZL in that they consisted of small to medium-sized B-cells that express CD19, CD20, and CD79a) but not CD10, CD23, or cyclin D1 marker proteins along with some plasma cells and a variable number of reactive T-cells. Fifty percent of cases tested for trisomy of chromosome 3 were positive. Histopathological findings are typical for EMZL: lesions consist of small- to medium-sized B cells,
centrocyte-like B-cells, small lymphoid cells with some features of
plasma cells or
monocytes, and mature plasma cells with the lymphoid cells in these lesions expressing CD20 and CD79a but usually not CD10, CD43 or BCL6 marker proteins. Moderate doses of local radiation therapy are recommended to treated localized EMZL of the breast. This treatment has achieved overall survival rates of >90%. Given these results and the high sensitivity of EMZL to radiation therapy,
mastectomy is not recommended and wide excision is not usually necessary to treat localized disease. For patients with disseminated disease, treatment options include
watchful waiting and chemotherapy (typically employing a
CHOP or CHOP-like regimen) with or without radiation therapy and/or excision. These approaches have attained complete disease remissions in 9 of 9 patients followed for 6–74 months and one death due to progressive disease in a patient followed for 107 months. Other drugs used to treat the disease include rituximab,
tamoxifen, and
oxaliplatin. However, this lymphoma commonly occurs as a disseminated disease involving other organs and tissues. Radiological and cystoscopy examinations reveal one or more mucosal masses in, or diffuse thickening of, the bladder wall. Patients may present with signs and symptoms of a kidney mass (e.g. low pack pain and/or abnormal kidney function as determined by elevation in serum
creatinine). The best treatment for kidney EMZL is unclear. Reported cases have been subjected to
nephrectomy and/or chemotherapy.
Primary gallbladder Primary
gallbladder EMZL (i.e. extranodal marginal zone lymphoma of the gallbladder, primary MALT lymphoma of the gall bladder) is an extremely rare disease with only 17 cases being reported in the literature as of 2017. Only 47 cases of primary hepatic EMZL were reported in the English literature as evaluated by a 2019 review. Based on this review, individuals with primary hepatic EMZL had concomitant liver disease ( principally
hepatitis B viral hepatitis or
hepatitis C viral hepatitis, less commonly,
primary biliary cirrhosis or
hepatocellular carcinoma, and, rarely, other liver diseases Rarely EMZL associated with hepatitis C virus infection presents as single or multiple soft, mobile sub-cutaneous nodules. Treatment of this disease had relied on eradicating the virus using
peginterferon-alfas,
interferon-alpha-like drugs to mobilize the hosts' immune systems. This treatment cured the viral infection in ~50% and produced lymphoma remissions in <50% of cases. More recently, drugs (e.g.
simeprevir,
daclatasvir,
sofosbuvir, and
dasabuvir) that directly inhibit the virus's reproduction have cured the infection and achieved lymphoma responses in up to 100 and 73%, respectively, of patients with one year overall and progression-free survival rates of 98 and 75%, respectively. For patients whose lymphoma fails to respond to this therapy (~25% of cases), recommended treatments include
rituximab or rituximab + a peginterferon-alfa. Since
chemotherapy regimens are highly toxic in patients with liver disease, they should be avoided, where possible, in treating EMZL associated with hepatitis C virus infection. == Splenic marginal zone lymphoma ==