Primary gastric

Helicobacter pylori is the bacteria that often causes gastric ulcers and is a main cause of primary gastric EMZL

Primary gastric EMZL, also termed primary gastric MALT lymphoma or, more often, just gastric MALT lymphoma, is usually an indolent disease that in ~10% of cases also involves other GI tract and/or non-GI tract sites. Patients commonly present at an early stage of the disease^[22] 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.^[23] Endoscopic inspection and biopsy of lesions^[15] and endoscopic-based ultrasound^[22] inspection of the upper GI tract show lesions, most often in the stomach's pyloric antrium, that are superficial mucosal erosions, shallow ulcers, nodules, enlarged rugae, and/or thickenings of the stomach wall.^[15] The histopathology of primary gastric MALT lesions and the marker proteins and genomic abnormalities expressed by the malignant cells in these lesions are given in the Histopathology section. Primary gastric EMZL is associated with infection of the stomach with Helicobacter pylori in >80% of cases or with Helicobacter heilmannii sensu lato in <1% of cases.^[14] Indications that gastric Helicobactor pylori is the causes for gastric EMZL include: a positive urea breath test; a positive stool test that detects an antigen of the pathogen in the patient's feces; a positive urease test in a biopsied tissue specimen; a positive serum or whole blood test using specific antibodies directed against the pathogen; and growth of the pathogen in tissue cultures of a biopsied tissue.^[24] 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.^[16] The 'Treatment of localized (i.e. Ann Arbor stage I and II) Helicobactor pylori-positive primary gastric EMZL employs any one of several different Helicobacter pylori eradication protocols. These protocols include a proton-pump inhibitor (e.g. omeprazole or lansoprazole^[25]) plus any one of several different antibiotic combinations (e.g. Clarithromycin + Amoxicillin or levofloxacin + nitazoxanide + doxycyclin).^[15] The exact drug regimen is chosen based on the known or suspected resistance of the pathogen to these antibiotics in individual cases. The regimen is given for 7–14 days and followed-up by testing within 4 weeks for the presence of the pathogen by the urea breath or stool antigen test. If the initial regimen fails to eradicate the pathogen, patients are treated with a second regimen using a combination of three or four drugs (e.g. a proton-pump inhibitor + bismuth subcitrate + tetracycline + metronidazole).^[15] Eradication of the pathogen is successful in 70–95% of cases. Recently, a sequential treatment regimen (i.e. a proton-pump inhibitor + amoxicillin followed by a proton-pump inhibitor + clarithromycin + Tinidazole) has been reported to eradicate the pathogen in >90% of cases.^[15] Patients who have lesions that harbor a t(11;18) or t(1;14) chromosomal translocation and therefore express the BIRC3-MALT1 or IGH-BCL10 chimeric protein, respectively, have an increased incidence of being resistant to Helicobactor pylori eradication protocols.^[14] Some 50-80% of patients who have experienced eradication of the pathogen develop within 3–28 months a remission and long-term clinical control of their lymphoma. Radiation therapy to the stomach and surrounding (i.e. peri-gastric) lymph nodes has been used to successfully treat: a) localized Helicobactor pylori-positive primary gastric EZML in which the pathogen has not been eradicated by the cited drug protocols; b) localized Helicobactor pylori-negative primary gastric EZML cases; and c) Helicobactor pylori-positive and -negative EZML cases in elderly or frail patients. Patients with systemic (i.e. Ann Arbor stage III and IV) primary gastric EMZL who are free of symptoms have been treated with watchful waiting or if symptomatic been treated with the immunotherapy drug, rituximab (given for 4 weeks) combined with chlorambucil given for 6–12 months; 58% of these patients attain a 58% progression-free survival rate at 5 years. Frail stage III/IV patients have been successfully treated with rituximab or cyclophosphamide alone.^[1] While the treatment of Helicobactor heilmanni sensu lato depends on far fewer studies, it generally follows the recommendations used for the treatment of Helicobactor pylori.^[16]

Primary small intestinal

Primary small intestinal MZL, also termed primary small intestinal MALT lymphoma, commonly presents with colicky abdominal pain, diarrhea, and in cases of advanced disease signs and symptoms of malabsorption (e.g. weight loss, malnutrition, and anemia), small bowel obstruction, ascites (i.e. fluid in the abdominal cavity), and/or enlargements of lymph nodes, spleen, and/or liver.^[26] While generally a progressive disease, patients with early stage primary small intestinal MZL may have spontaneous and complete remissions.^[7] Immunoproliferative small intestinal disease, formerly termed Mediterranean lymphoma or considered a type of alpha heavy chain disease (IgA/αHCD),^[27] is a variant and by far the most common form of small intestinal MZL.^[26] This variant is endemic in countries of the Mediterranean Basin, particularly those of the Middle East although cases of this disease have been found throughout the world usually but not always in immigrants from the Middle East.^[26] In its endemic areas, immunoproliferative small intestinal disease constitutes ~30% of all GI tact lymphomas, mainly afflicts individuals 20–30 years old who are of low socioeconomic status, and is associated with infection by the food-borne bacterium, Campylobacter jejuni. Campylobacter jejuni-associated disease is more prevalent in individuals who express human leukocyte antigen AI19, B12, or A9 or are blood type B. It is suggested that these individuals are genetically predisposed to developing the disease.^[18] Immunostaining of small bowel lesions in these cases commonly detects the presence of Campylobacter jejuni and is predictive that the disease will respond to antibiotics. However, it is not clear that this bacterium is the actual cause of immunoproliferative small intestinal disease:^[26] it may merely colonizes the gut of individuals with the disease while other as yet unidentified antibiotic-sensitive bacteria or non-bacterial pathogens, e.g. parasites, underlie the disease's development.^[26]

In primary small intestinal EMZL cases, double-balloon enteroscopy and capsule endoscopy reveal the presence of extensive mucosal erosions and/or, less commonly, polyps, nodules, masses, and/or scarring.^[22] These lesions localizes to the duodenum, jejunum, or ilium in about 63, 17, and 8% of cases, respectively, or involve more than one small intestinal site in ~17% of cases.^[26] The lesions consist of lymphocytes, atypical plasma cells and, less commonly, centrocyte-like cells infiltrates in the intestinal lamina propria^[18] with the lymphocytes and centrocyte-like cells expressing marker proteins (e.g. CD20 and CD79a) that are typical for EMZL.^[26] Campylobacter jejuni is detected in these lesions by immunostaining. Patients with this disease commonly have a monoclonal gammopathy as evidence by the presence of a monoclonal antibody consisting of the fragment crystallizable region of the IgA heavy chain in their blood, jejunum juice, and/or, rarely, urine. The abnormal IgA protein is detected in patients' sera by immunofixation using an antibody directed against the heavy chain fragment of IgA.^[26]

The Treatment of primary small intestinal EMZL has focused on nutritional support and control of symptoms including surgery and/or radiotherapy to treat bowel obstructions and highly localized disease. However, studies indicate that individuals with the disease, particularly those with the immunoproliferative small intestine disease form, have overall response rates of ~90% following treatment with broad-spectrum antibiotics such as tetracycline, metronidazole, or tetracycline + ampicillin.^[3] These responses are durable in most cases. Accordingly, antibiotic therapy is recommended to treat early stage disease. Patients refractory to antibiotic therapy have been treated with chemotherapy (i.e. CHOP or a CHOP-like regimes) followed by long-term maintenance with tetracycline. This treatment regimen has achieved 5 year overall survival rates of 70%. Since surgery and radiotherapy are not curative for the disease, high dose chemotherapy regimens and autologous stem cell transplantation have been recommended for refractory and/or relapsed disease.^[2]

Colorectal EMZLs

EMZLs involving the colon or rectum are extremely rare. In a 2019 review of 73 cases, persons diagnosed with one of these EMZL subtypes had a median age of 62 years (range 26–72), were predominately female (66%), and had their primary tumors located in the rectum (74% of cases), right colon (13.6%), transverse colon (4.1%), or sigmoid colon (8.2%). Thirty percent of these individuals had multiple tumors, ~40% of which were in sites in the gastrointestinal tract outside of the colon and rectum. These individuals were initially treated and achieved complete remissions with local surgical resection in 18 of 19 cases, more extensive surgical resection in 18 of 19 cases, chemotherapy in 12 of 13 cases, radiation therapy (in 4 of 5 cases, or antibiotic therapy to achieve Helicobacter pylori eradication in 12 of 15 cases. Two individuals received no treatment with one of these having a spontaneous remission. The 8 cases not achieving a complete remission required second-line treatment; 3 cases were remission failures.^[28] The following sections further describe these two EMZL subtypes.

Primary esophagus

Primary EMZL of the esophagus, also termed MALT lymphoma of the esophagus, is extremely rare with most cases of it being reported from Japan. It presents with symptoms of difficult swallowing and/or sensations of a foreign body in the esophageal area. Endoscopy, endosonography and chest CT scans reveal a solitary esophageal mass of varying size^[31] or, more commonly, a linear central indentation or ridge in the esophagus.^[32] 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.^[31] Treatment of EMZL of the esophagus has consisted of endoscopic resection, surgical resection, radiotherapy, endoscopic resection plus radiotherapy, or chemotherapy. Most patients show a complete response to these interventions. However, the long-term efficacy of these responses is not known since treatment follow-up times have been short (6–35 months). Systematic antibiotic-based eradication therapy to treat Helicobactor pylori-associated EMZL of the esophagus had not been reported^[31] until a recent case with the disease was treated with vonoprazan + amoxicillin + clarithromycin for 1 week. The patient showed evidence of eradicating the bacterium based on a urea breath test but nonetheless subsequently evidenced progression the lymphoma.^[33]

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.^[34] 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.^[14] Gastric Helicobactor pylori infection or Hepatitis C virus infection have been reported to be associated with primary ocular adnexa EZZML in ~33% and 2-36%, respectively, of cases; in rare cases, the disease has also been associated with Herpes simplex virus 1, Herpes simplex 2, adenovirus 8, adenovirus 19, Chlamydia trachomatis, or Chlamydophila abortus infection. The relationship(s) of these infections to the development and/or progression of primary ocular adnexa EZML is unclear.^[34]

Patients present with conjunctival (25% of cases) or intra-orbital (75% of cases) lesions which typically involve one eye but in 10-15% of cases, particularly in conjunctival cases, involve both eyes. Conjunctiva lesions usually present as a salmon red patch that covers the outer layer of the eyeball; intra-orbital lesions commonly present as exophthalmos (i.e. a bulging of the eye) (27% of cases), a palpable eye mass (19%), ptosis (i.e. eyelid drooping) (6%) and/or, less commonly, diplopia (i.e. double vision), impaired orbital mobility, excessive tearing, and/or orbital nodules.^[34] Patients with conjunctiva disease may be asymptomatic.^[35] 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.^[36] 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.^[34]

Treatment of the disease requires further study. In patients with localized disease: 1) radiotherapy has achieved complete responses in 52-93% of cases and 5 year systemic-free (but not local-free) relapse rates of >90%; 2) chemotherapy with a CHOP regimen in 15 patients has achieved remissions without relapse in 9, local relapse in 5, and systemic relapse in 2 patients after 55 months of follow-up; 3) chemotherapy with chlorambucil in 33 patients has achieved complete responses in 26 patients after 24 months of follow-up; 4) immunotherapy with rituximab has achieved variable results over the short-term and requires further study over longer follow-up periods^[36] with somewhat better results occurring in patients with conjunctival disease;^[34] and 5) antibiotic therapy with doxycycline has achieved 2 year and 5 year failure-free survival rates of 67% and 55%, respectively, and a 5-year progression-free rate of 61%.^[36] The generally recognized treatment of choice for patients with systemic involvement uses various chemotherapy regimens often combined with rituximab. Complete responses have been observed in most patients treated with chlorambucil, CHOP regimens, or rituximab but recurrence rates have been high (e.g. ~33%).^[34]

Primary skin

Primary cutaneous EMZL or primary cutaneous MALT lymphoma (also termed skin-associated lymphoid tissue lymphoma) typically presents as single or multiple small papules or plaques usually located on the arms and/or trunk. Histologically, these lesions consist of reactive germinal centers containing a mixture of small B cells that have a plasma cell-like or monocyte-like morphology interlaced with numerous T cell lymphocytes.^[37] The B-cells in these lesions express the B-cell markers commonly seen in EMZL.^[38] The DNA of Borrelia burgdorferi, the causative agent of Lyme disease, has been detected in the lesions of 10%–42% of patients^[39] in Germany, Italy, Japan, and Turkey but not of patients from Spain, Finland, the Netherlands, or the United States.^[40] 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.^[40] Treatment of primary cutaneous EMZL has been conservative, given the diseases indolent behavior. In Borrelia burdorferi-positive disease, antibiotic therapy (courses of a cephalosporin or tetracycline are regarded as first-line antibiotic choices) should be considered^[7] although this measure is less applicable in areas, such as the United States, where the bacterium has not been associated with the disease.^[38] Treatment of Borrelia burdorferi-negative disease or disease for which antibiotic therapy is not an option or has failed depend on the extent of the lesions. Single lesion treatments include surgical resection, direct injection of interferon-alpha or rituximab into the lesions, and localized external beam radiotherapy. Disease-free rates found 5 and 10 years after these treatments are 57% and 43%, respectively. In disseminated disease, watchful waiting, intravenous rituximab, and chemotherapy have been used. Intravenous rituximab achieves remission rates of 85% in patients that have not received chemotherapy; chlorambucil chemotherapy with or without intravenous rituximab has significantly improved event-free survival times; and CHOP chemotherapy is recommended for patients with B symptoms (e.g. fever, night sweats, weight loss, etc.), elevated levels of serum lactic acid dehydrogenase, or disease that has progressed to a more aggressive stage.^[7]

Primary lung

Primary pulmonary EMZL (or primary pulmonary MALT lymphoma) is a rare disorder but nonetheless represents up to 80% of all lymphomas originating in the lung. The cause for developing this lymphoma is unclear. Some 16% of individuals with the disease present with features of an autoimmune disorder with one study reporting that 57 of 124 patients with the disorder evidenced Achromobacter xylosoxidans DNA in their lung lesions.^[41] 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.^[7] Primary pulmonary EMZL usually afflicts patients 50–60 years old; in almost 50% of cases the disease is diagnosed in symptom-free individuals who present with an abnormal chest X-ray or CT scan conducted for unrelated reasons.^[41] Patients with symptoms usually present with chest pain, shortness of breath, and/or a history of recurrent respiratory infections.^[14] Chest X-rays and CT scans typically show bilateral alveolar opacities that are <5 cm. More severe lung damage (e.g. atelectasis, pleural effusion, or mediastinal lymphadenopathy) occur in <10% of cases. Patients with more advanced disease may present with bone marrow involvement (13-30% of cases), involvement or other sites outside the lung such as the stomach, eyes, ears, nose, and/or throat (25-35% of cases), or in rare cases of particularly aggressive disease, systemic B symptoms such as fever, night sweats, and/or weight loss. A monoclonal gammopathy (i.e. excessive amounts of a monoclonal gamma globulin in the blood) is found in 20-60% of cases, occurring particularly in individuals with tissue lesions that contain lymphocytes that have a plasma cell-like appearance. The lesions in primary pulmonary lymphoma are in the mucosa of the broncheal airways and are diagnosed by needle biopsy, bronchial biopsy, trans-bronchial biopsy, and/or bronchoalveolar lavage. Findings consistent with the diagnosis include biopsy specimens revealing mucosa infiltrates of small B-cells bearing the typical B cell markers found in EMZL; occasional specimens consist of B lymphocytes with a plasma cell appearance. Bronchoalveolar lavage fluid may contain >10% of cells which bear these markers. B-cells in the pulmonary lesions have the t(11;18)(q21;q21) translocation and therefore express the API2-MALT1 chimeric protein in ~40% of cases. Other, less frequently occurring genomic abnormalities in these cells include t(1;14)(p22;q32), t(14;18)(q32;q21), and t(3;14)(p14.1;q32) translocations and trisomy of chromosomes 3 and/or 18.^[41]

Treatment of primary pulmonary EMZL varies. Antibiotic therapy has not been studied and cannot be recommended. Recommended treatments which have afforded overall 5 year survival rates of 89-100%^[42] include surgery, radiotherapy, chemotherapy, immunotherapy, and watchful waiting.^[41] Surgical resection or radiotherapy may be considered for localized disease. In more extensive disease, rituximab immunotherapy has achieved a 70% response rate but with a high rate of recurrence (~36%). Treatment with fludarabine, CHOP, chlorambucil, or chlorambucil + rituximab have been used to treat extensive disease with each treatment giving approximately similar overall median survival times of >10 years.^[41]

Primary salivary gland

Primary salivary gland EMZL (also termed MALT lymphoma of the salivary glands) or, in cases primarily involving the lacrimal glands, primary lacrimal gland EMZL (also termed MALT lymphoma of the lacrimal gland) is a complication of Sjögren syndrome, an autoimmune disease characterized by chronic inflammation of the salivary and/or lacrimal glands.^[17] This autoimmune disease is thought to be caused by a combination of genetic and environmental factors including infectious agents. This lymphoma affects ~3% of patients with Sjögren syndrome^[8] and involves one or more of the affected salivary or, less commonly, lacrimal glands.^[17] The median time between diagnosis of the autoimmune disease and EMZL varies between 7.5^[17] and 11 years.^[19] Affected individuals typically are 55–60 years old and present with localized hardening and/or enlargement of the parotid gland or, less commonly, other salivary or lacrimal gland. Some 20% of cases present with or progress to involve local lymph nodes or the spleen to cause lymphadenopathy or splenomegaly while ~10% of cases present with or progress to a high-grade lymphoma, primarily diffuse large B-cell lymphoma.^[17] Histologically, the involved glands show lymphocyte-based lesions that are typical of EMZL with the infiltrating lymphocytes in some cases having morphological features resembling plasma cells. In individuals with more advanced disease, these lesions develop in the mucosal linings of the eye socket, nasal cavity, pharynx, airways of the lower respiratory tract, stomach, and/or thyroid gland.^[8]

Treatment of primary salivary/lacrimal gland EMZL has not been standardized. A minority of patients have been treated by watchful waiting but most patients have been subjected to surgery, radiotherapy, chemotherapy (i.e. chlorambucil), immunotherapy (i.e. rituximab, or a combination (e.g. chlorambucil + rituximab or fludarabine + rituximab or bendamustine + rituximab) immunotherapy plus chemotherapy regimen. In general, overall survival rates after 5, 10, and 15 years of treatment have been 95%, 85%, and 78% respectively. While the response to these therapeutic regimens has been very good, ~33% of treated patients have experience a recurrence of their lymphoma in the salivary/lacrimal glands, lymph nodes, or other sites.^[19]

Primary thyroid

Primary thyroid EMZL, also termed MALT lymphoma of the thyroid gland, is extremely rare. It occurs almost exclusively in thyroid glands affected by Hashimoto's thyroiditis, an autoimmune disease characterized by the accumulation of lymphocytes, including B-cells, in the thyroid gland and the subsequent destruction of thyroid tissue by these cells.^[43] Patients with this syndorme 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.^[17] Histologically, the lesions in this lymphoma generally consist of reactive lymphoid follicles and lymphoepithelial lesions which are populated by intermediate-sized B-cells, centrocytes, plasma cells, and, in ~1/3 of cases, sheets of large lymphocytic cells similar to those seen in diffuse large B-cell lymphomas. The malignant cells in these lesions express B-cell markers that are typical for EMZL, e.g. CD20 and BCL-6 but not CD10 proteins.^[44] 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.^[17]

Treatment of primary thyroid EMZL is generally conservative since up to 90% of patients are diagnosed with early stage disease.^[17] Although the optimal treatment for this disease is uncertain, the majority of patients with localized disease are treated with surgery, radiotherapy, or a combination of both modalities and attain overall response rates of up to 100%^[19] and an estimated 5 year disease-free survival of 95%.^[17] Surgery plus radiotherapy does not appear to give better results that radiotherapy alone.^[44] Patients with extensive disease or disease that has progressed to a higher grade lymphoma (principally diffuse B-cell lymphoma) have been treated with chemotherapy (usually CHOP^[44][45]) and/or immunotherapy (i.e. rituximab^[44]). However, the 5 year survival rates in chemotherapy-treated patients with disseminated primary thyroid EMZL^[46] or disease that has progressed to a more malignant lymphoma^[17] are only 35% and 44%, respectively.

Primary central nervous system

Primary EMZL of the central nervous system is an extremely rare disorder. Compared to other central nervous system lymphomas which are highly aggressive, primary EMZL of the central nervous system is a non-aggressive, low-grade lymphoma. In a review of 70 published cases, the disease involved the proliferation of malignant marginal zone B-cells within the dura mater, i.e. thick membrane surrounding the brain and spinal cord, (56 cases), the brain or spinal parenchyma (6 cases), the brain's cavernous sinusn (4 cases), the brains choroid plexus (3 cases), inside brain [[Ventricular system[ventricle]] (1 case), the cerebellopontine angle (2 cases), and the optic nerve (2 cases). Patients (77% female; median age 55 years, ranging from 18 to 78 years) presented with various neurological signs and symptoms depending on the site of involvement. The most common presenting symptoms were headache (30 cases); seizures (22 cases); and visual changes (19 cases). Less commonly, patients presented with paresthesias (i.e. abnormal skin sensations), motor deficits, and ataxias, memory failures, and dizziness. At the time of diagnosis, there was no evidence of EMZL outside of the central nervous system. Malignant cells were detected in the cerebrospinal fluid in 5 of the 19 cases tested for this.^[49] 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.^[49][50] Fifty percent of cases tested for trisomy of chromosome 3 were positive.^[49]

Treatment of localized disease consisted of surgery, radiotherapy, or a combination of both modalities whereas treatment of extensive central nervous system disease consisted of chemotherapy, including intrathecal chemotherapy, with or without surgery and/or radiotherapy. Regardless of treatment regimen, primary central nervous system EZML has a good prognosis with complete response (CR) occurring in 77% of patients and 22% of patients alive with evidence of disease after 1–86 months of follow-up times. The values of systemic and intrathecal chemotherapy in treating the disease are unclear and require further study.^[49]

Primary breast

Primary EMZL of the breast (also termed primary MALT lymphoma of the breast) is an exceedingly rare disease. It usually presents as a palpable breast mass in an otherwise symptom-free patient.^[51] 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.^[52] 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.^[51]

Primary urinary tract

Primary urinary tract EMZLs of the urinary bladder and kidney are extremely rare but the most common forms of lymphoma that are found in these organs. They occur most commonly in middle aged females who have a history of chronic cystitis, i.e. inflammation of the bladder due to urinary tract infection or other causes.^[19]

Primary gallbladder

Primary gallbladder EMZL (i.e. extranodal marginal zone lymphoma of the gallbladder,^[57] primary MALT lymphoma of the gall bladder^[58]) is an extremely rare disease with only 17 cases being reported in the literature as of 2017.^[58] Presenting features in individuals (aged 31–84 years, median age 74, >60% females) with the disease are similar to those seen in other lymphomas and non-lymphomatous cancers of the gallbladder;^[57] these include pain in the upper right-side of the abdomen, nausea, vomiting, and in about two-thirds of cases, gallstoness.^[58] Given these similarities as well as similarities in the laboratory, medical ultrasound, and X-ray findings of primary gallbladder EMZL compared to other gallbladder cancers which account for >99% of bladder cancers, the diagnosis of primary gallbladder EMZL has not yet been made pre-operatively. Rather, its diagnosis has rested exclusively on examination of surgically removed gallbladders.^[58] The lesions in these gallbladders show infiltrates in the gland's submucosa that consist of small lymphocytes interspersed with lymphoepithelial lesions. The lymphocytes have marker protein profiles (e.g. CD20 and Bcl-2 positive; CD5, cyclin D1^[58] and CD10^[57] negative) that are typical for EMXL. Cholecystectomy, i.e. surgical removal of the gallbladder, has produced remissions in all patients with only one recurrence over observation periods of 2 to 96 months.^[58]

Primary hepatic

Primary hepatic EMZL (i.e. primary hepatic extranodal marginal zone B-cell lymphoma, primary hepatic mucosa-associated lymphoid tissue lymphoma, primary hepatic mucosa-associated lymphoma) is an extremely rare malignancy representing <3% of all primary lymphomas of the liver.^[59] Only 47 cases of primary hepatic EMZL were reported in the English literature as evaluated by a 2019 review.^[60] 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^[60] such as hepatitis A viral hepatitis. Patients (median age 63 years, range 30–85 years) presented with no symptoms (~64% of cases) or symptoms (which may have been related to their other liver diseases) such as abdominal pain, generalized weakness, cough, elevations in their blood levels of liver enzymes, and/or evidence of one or more liver masses as detected by magnetic resonance imaging, computed tomography scans, or positron emission tomography.^[60] These presentations are virtually identical to those seen in other forms of liver cancer. Accordingly, the diagnosis of primary hepatic EMZL has been extremely hard to make without obtaining tissue by surgical methods.^[59] Histological examination of involved liver tissues commonly showed diffuse infiltrations of small- to medium-sized atypical lymphocytes. These infiltrations, which may involve the liver's bile ducts, often contained lymphoepithelial lesions. Immunohistochemistry testing of these tissues revealed lymphocytes that expressed CD20 and BCL-2 but not CD10 or cyclin D1. While optimal therapeutic strategies for this disease have not been established, primary hepatic EMZL appears to be an indolent cancer. Patients who underwent surgical resection with or without chemotherapy or rituximab treatment regimens and were observed over a median period of 31 months had mostly positive outcomes: 92% survived, 8% died of causes unrelated or only indirectly related to their cancer, and 11% had relapses.^[60]

EMZL associated with hepatitis C

EMZL occurs more frequently (~2.5-fold increased risk) in individuals who have hepatitis C virus-induced hepatitis. The lymphoma typically occurs 15–25 years (median times) after the viral infection and involves the skin (35% of cases), salivary glands (25%), orbital adnexa (15%) or, uncommonly, the stomach or other tissues. It is associated with type II cryoglobulinemia, i.e. the circulation of an immune complex consisting of polyclonal IgG, monoclonal IgM, and hepatitis C viral RNA. This immune complex causes signs and symptoms of vasculitis in 10% of cases. Other signs and symptoms of the disorder include those associated with chronic hepatitis and the specific subtype of EMZL.^[61] Rarely EMZL associated with hepatitis C virus infection presents as single or multiple soft, mobile sub-cutaneous nodules.^[27] This presentation occurs mainly in female (83% of cases) and elderly patients.^[61] Patients with this disorder may have detectable levels of circulating hepatitis C virus.^[39] The histology of the lesions in EMZL associated with hepatitis C virus infection is typical of EMZL^[39] although the genomic abnormalities in the disorders malignant cells has not been well-defined beyond their expression of the t(14;18) chromosome translocation in a significant number of cases.^[62] 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.^[61]

Children

In children NMZL has been classified by the World Health Organization (2016) as a separate variant of NMZL based on its presentation, histology of the involved lymph nodes, and clinical course.^[73] Of the more than 60 published cases, 95% of Pediatric NMZL cases occurred in adolescent boys with >90% of cases presenting as an asymptomatic, localized (Stage I/II) disease involving enlargement of the lymph nodes of the head and neck regions. These cases showed no associations with autoimmune or pathogen-induced inflammatory diseases. All of these findings contrast with those seen in extranodal marginal zone lymphomas occurring in children. Histologically, the involved lymph nodes show infiltrations in the germinal centers of affected lymph nodes by lymphoid cells usually expressing CD20 and CD43, often (~50% of cases) expressing Bcl2, and usually not expressing CD10 or BCL6. The marginal zone B-cells in these infiltrations have relatively few genomic abnormalities compared to NMZL in adults. Trisomy of chromosome 18 has been reported in 21% of cases and, in rare cases, trisomy of chromosome 3. No recurrent gene mutations have been reported to occur in these cells.^[77] The course of pediatric NMZL is extremely indolent with the disease having a low relapse rate and typically an excellent outcome.^[73] Observation periods of up to 12–18 years have found that patients have overall survival rates of 100% and relapse rates of ~4%.^[77] Treatment of pediatric NMZL has used a watchful waiting strategy, rituximab, chemotherapy, and/or local radiation therapy. The watchful waiting strategy has done as well as the other therapies and is therefore the recommended initial treatment for the disease.^[77]