Marginal zone lymphoma

Marginal zone lymphoma
Other names	Marginal zone B-cell lymphoma
EMZL infiltrating kidney tissue.
Types	Extranodal marginal zone lymphoma, splenic marginal zone lymphoma, and nodal marginal zone lymphoma.

Marginal zone lymphomas,also known asmarginal zone B-cell lymphomas(MZLs), are a heterogeneous group oflymphomasthat derive from themalignant transformationofmarginal zone B-cells.Marginal zone B cells areinnate lymphoid cellsthat normally function by rapidly mountingIgMantibodyimmune responsestoantigenssuch as those presented by infectious agents and damaged tissues.They arelymphocytesof theB-cellline that originate and mature insecondary lymphoid folliclesand then move to themarginal zonesofmucosa-associated lymphoid tissue(MALT), thespleen,orlymph nodes.Mucosa-associated lymphoid tissue is a diffuse system of small concentrations oflymphoid tissuefound in varioussubmucosal membranesites of thebodysuch as thegastrointestinal tract,mouth,nasal cavity,pharynx,thyroid gland,breast,lung,salivary glands,eye,skinand the humanspleen.

In 2016, the World Health Organization classified MZLs into three different types.Extranodal marginal zone lymphomas(EMZLs) are MZLs that develop in extranodal tissues. Most EMZLs develop in MALT and are often termed extranodal MZL of mucosa-associated lymphoid tissue or, more simply, MALT lymphomas.Splenic marginal zone lymphomas(SMZLs) are MZLs that initially are confined to the spleen, bone marrow, and blood.Nodal marginal zone lymphomas(NMZs) are MZLs initially confined to lymph nodes,bone marrow,and blood.While all of these MZL involve malignant B-cells, they differ not only in the tissues they involve but also in theirpathophysiology,clinical presentations, prognoses, and treatments.

MZLs represent 5–17% of allNon-Hodgkin lymphomaswith the extranodal, splenic, and nodal forms accounting for 50–70%, ~20%, and ~10% of all MZLs.The three MZL subtypes occur more often in older people (age 65–68 years) and are indolent diseases that may, in people without symptoms, be initially treated by awatchful waitingstrategy. However, NMZL carries a somewhat worse long term outcome than the other subtypesand any of the MZL subtypes may progress in a low percentage of cases to a more aggressive lymphoma, particularlydiffuse large B-cell lymphoma.One of the most distinctive feature of MZL is that many cases are associated with the persistent simulation of the immune system by the chronicinflammationthat accompaniesinfectionsorautoimmune diseases.MZL cases associated with certain infectiouspathogenscan be cured by treatment directed at the pathogens causing or associated with these infections.

Extranodal marginal zone lymphoma

Extranodal marginal zone lymphomas (EMZLs) are a form of MZLin which malignant marginal zone B-cells initially infiltrate MALT tissues of the stomach (50-70% of all EMZL) or, less frequently, theesophagus,small intestine,large intestine,rectum,conjunctivaof the eye,nasal passages,pharynx,lungbronchi,vulva,vagina,skin,breast,thymus gland,meninges(i.e.membranes) that envelop thebrainandspinal 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 similarpathophysiological(i.e. disorderedphysiological processesthat cause the disease) andhistopathological(i.e.microscopicfeatures of diseasedtissues). 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

Histology of a normallymphoid follicle,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 ablood cancerparticularly leukemia, or a number of autoimmune diseases such as Sjögren syndrome andlupus 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 theirimmunoglobulin heavy chain locusso that they encodeB-cell receptorsthat 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 ab\normal antigens by taking on features of marginal B-cells and proliferating excessively.In consequence, these B cells progressively acquire in a step-wise fashionchromosome abnormalities,genemutations,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 ofchromosome11 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 theAPI2gene with a part of theMALT1gene to create afusion genethat encodes an Api2-Malt1fusion protein.Thischimeric proteinpromotes the continuous activation of atranscription factor,NF-κB.NF-κB controls the expression of various genes which increase the survival,cytokineproduction, 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 inhibitsprogrammed cell deathto 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 theBCL10gene. 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 theFOXP1gene. FoxP1 protein stimulates production oftranscription factorssuch asPRDM1,IRF4,andXBP1which 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)Inactivationor theTNFAIP3gene 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.TNFAIP3inactivation 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-functionmutations in theMYD88gene 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 theSTAT3andAP1transcription factors.3) Inactivating mutations in theNOTCH1(8% of all cases) andNOTCH2(8% of all cases) genes occur in EMZL. The products of these genes arecell surface receptorproteins which when bound to their activating ligands move to the cell nucleus and contribute to the activation of genes that control the development, proliferation, survival, and migration of B cells.

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 thechimeric genesexpressed by the neoplastic B-cells of the EMZL subtype.

	Subtype	Tissue(s) involved	Infectious agent or autoimmune diseasen	Strength of evidence	Incidence	Chimeric genes expressed (percentage of cases)
	Primary gastric EMZL	stomach	Helicobacter pylori	confirmed	~80%	BIRC3-MALT1(23%),IGH-FOXP1(3%),IGH-BCL-10(2%), andIGH-MALT1(1%)
	Primary gastric EMZL	stomach	Helicobacter heilmannii sensu lato	likely	<1%	similar to the antibiotics used forHelicobacter pylori
	Primary salivary gland EMZL	salivaryandlacrimal glands	Sjögren syndrome	confirmed	~4.3%	IGH-MALT1(6%),BIRC3-MALT1(2%), andIGH-BCL-10(1%)
	Primary thyroid EMZL	thyroid gland	Hashimoto's thyroiditis	confirmed	~0.5%	ICH-FOXP1(50%) andBIRC3-MALLT1(9%)
	Primary ocular adnexa EMZL	ocular adenexa(i.e.orbit,conjunctiva,andeyelids)	Chlamydia psittaci	suggestive	10–50%	IGH-FOXP1(20%),IGH-MALT116%), andBIRC3-MALT1(7%)
	Primary cutaneous EMZL	skin	Borrelia burgdorferi	suggestive	variable	IGH-FOXP1(10%),IGH-MALT1(7%), andBIRC3-MALT1(4%)
	Primary small intestinal EMZL	small intestine	Campylobacter jejuni	low	variable	BIRC3-MALT1(19%) andIGH-BCL10(7%)
	Primary pulmonary EMZL	lung	Achromobacter xylosoxidans	low	<50%	BIRC3-MALT1(45%),IGH-BCL10(8%), andIGH-MALT1(7%)

Histopathology

Thehistopathologic(i.e. microscopic) examination of EMZLlesionstypically reveals a vaguely nodular or diffuse pattern of cells. The malignant cells in these lesions have, in varying proportions, themorphologyof 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.Immunophenotypingor the neoplastic large B cells in these lesions shows that they expressCD20but notCD3surface membraneB cell marker proteins. The cells almost always expressBCL2and may expressMNDA(~70% of cases),CD23(~33% of cases) andCD5(~20% of cases) marker proteins but do not express thecyclin D1marker protein.,the T-cell marker,CD10,orBCL6.

Subtypes, diagnosis, treatment, and prognosis

There are various EMZL subtypes based on the organs they involve. Almost all of these subtypes occur in the mucosa-associated lymphoid tissue of the affected organ and are often termed MALT lymphomas of the affected organ (e.g. gastric MALT lymphoma). However, these lymphomas are also termed primary EMZL of the affected organ (e.g. primary gastric EMZL). While both terms are used here for these subtypes, the primary (organ involved) EMZL is preferred to indicate that the EMZL subtype initially developed in and may remain limited to the indicated tissue. However, approximately 30% of cases disseminate to other sites, predominantly lymph nodes and in rare cases thebone marrow.The malignant B-cells in these subtypes may also circulate in the blood but this is very uncommon. Regardless of the subtype of EMZL or its dissemination to other tissues, the prognosis for these lymphomas is good with 5 year overall survivals generally ranging between 86% and 95%.

Primary gastric

Helicobacter pyloriis 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 diseasewith various symptoms such asnausea,vomiting, indigestion, upper abdominal pain, and gastric bleeding as indicated by coughing up blood,bloody bowel movements,and/oriron deficiency anemia.Rarely, patients present withperforation of the stomachorB symptomssuch as fever andnight sweats.Individuals with chronicHelicobacter pyloriinfection may also havehalitosis.Endoscopicinspection and biopsy of lesionsandendoscopic-based ultrasoundinspection of the upper GI tract show lesions, most often in the stomach'spyloric antrium,that are superficial mucosal erosions, shallow ulcers, nodules, enlargedrugae,and/or thickenings of the stomach wall.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 withHelicobacter pyloriin >80% of cases or withHelicobacter heilmannii sensu latoin <1% of cases.Indications that gastricHelicobactor pyloriis the causes for gastric EMZL include: a positiveurea breath test;a positivestool testthat detects anantigenof the pathogen in the patient's feces; a positiveurease testin a biopsied tissue specimen; a positive serum or whole blood test using specificantibodiesdirected against the pathogen; and growth of the pathogen intissue culturesof a biopsied tissue.Helicobacter heilmannii sensu latodesignates at least 11 differentHelicobactorspecies of which 5 are known to infect the human stomach. It has been more difficult to determine thatHelicobacter heilmannii sensu latois 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 ofHelicobacter heilmannii sensu latotherefore 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.The 'Treatment of localized (i.e.Ann Arbor stageI and II)Helicobactor pylori-positive primary gastric EMZL employs any one of several differentHelicobacter pylorieradication protocols.These protocols include aproton-pump inhibitor(e.g.omeprazoleorlansoprazole) plus any one of several differentantibioticcombinations (e.g.Clarithromycin+Amoxicillinorlevofloxacin+nitazoxanide+doxycyclin).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).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.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 toHelicobactor pylorieradication protocols.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 therapyto the stomach and surrounding (i.e. peri-gastric) lymph nodes has been used to successfully treat:a)localizedHelicobactor pylori-positive primary gastric EZML in which the pathogen has not been eradicated by the cited drug protocols;b)localizedHelicobactor pylori-negative primary gastric EZML cases; andc)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 withwatchful waitingor if symptomatic been treated with theimmunotherapydrug,rituximab(given for 4 weeks) combined withchlorambucilgiven 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 orcyclophosphamidealone.While the treatment ofHelicobactor heilmanni sensu latodepends on far fewer studies, it generally follows the recommendations used for the treatment ofHelicobactor pylori.

Primary small intestinal

Primary small intestinal MZL, also termed primary small intestinal MALT lymphoma, commonly presents withcolickyabdominal pain, diarrhea, and in cases of advanced disease signs and symptoms ofmalabsorption(e.g. weight loss,malnutrition,and anemia), smallbowel obstruction,ascites(i.e. fluid in the abdominal cavity), and/or enlargements of lymph nodes, spleen, and/or liver.While generally a progressive disease, patients with early stage primary small intestinal MZL may have spontaneous and complete remissions.Immunoproliferative small intestinal disease,formerly termed Mediterranean lymphoma or considered a type ofalpha heavy chain disease(IgA/αHCD),is a variant and by far the most common form of small intestinal MZL.This variant isendemicin countries of theMediterranean Basin,particularly those of theMiddle Eastalthough cases of this disease have been found throughout the world usually but not always in immigrants from the Middle East.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 expresshuman leukocyte antigenAI19, B12, or A9 or areblood typeB. It is suggested that these individuals are genetically predisposed to developing the disease.Immunostainingof small bowel lesions in these cases commonly detects the presence ofCampylobacter jejuniand 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:it may merely colonizes the gut of individuals with the disease while other as yet unidentified antibiotic-sensitive bacteria or non-bacterialpathogens,e.g.parasites,underlie the disease's development.

In primary small intestinal EMZL cases,double-balloon enteroscopyandcapsule endoscopyreveal the presence of extensive mucosal erosions and/or, less commonly, polyps, nodules, masses, and/or scarring.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.The lesions consist of lymphocytes, atypicalplasma cellsand, less commonly,centrocyte-like cells infiltrates in the intestinallamina propriawith the lymphocytes and centrocyte-like cells expressing marker proteins (e.g. CD20 and CD79a) that are typical for EMZL.Campylobacter jejuniis detected in these lesions byimmunostaining.Patients with this disease commonly have amonoclonal gammopathyas evidence by the presence of amonoclonal antibodyconsisting of thefragment crystallizable regionof theIgAheavy chainin their blood, jejunum juice, and/or, rarely, urine. The abnormal IgA protein is detected in patients' sera byimmunofixationusing an antibody directed against the heavy chain fragment of IgA.

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 withbroad-spectrum antibioticssuch as tetracycline, metronidazole, or tetracycline + ampicillin.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.CHOPor 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 andautologous stem cell transplantationhave been recommended for refractory and/or relapsed disease.

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 achieveHelicobacter pylorieradication 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.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 withbowel perforationorintussusception.Endoscopic examination most often reveals a singlepolypor 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+prednisoneorcyclophosphamide+vincristine+ prednisone combined with either chlorambucil orrituximab) 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 usingHelicobacter pyloriantibiotic therapy.

Primary rectal

Primary rectal EMZL, more commonly termed MALT lymphoma of the rectum, usually presents at an early stage of disease with anal bleeding and/orblood in the stool.Endoscopic examination reveals a rectal polyp, rectal mass, or, less commonly, a rectal ulcer.Some cases of this lymphoma have been reported to regress spontaneously.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 ofplasma 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 withHelicobactor pyloriGI tract infection.Treatments for the disease have included radiotherapy, surgical resection, endoscopic mucosal resection, various chemotherapies, and antibiotic-based eradication ofHelicobactor pylori.Eradication therapy forHelicobactor 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.However, radiotherapy for localized disease has given 5-year disease-free and overall survival rates of 76% and 96%, respectively, in 16 of 19 reviewed casesand is suggested to be the preferred treatment for patients withHelicobactor pylori-positive primary rectal EMZL.

Primary esophagus

Primary EMZL of the esophagus, also termed MALT lymphoma of theesophagus,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,endosonographyand chestCT scansreveal a solitary esophageal mass of varying sizeor, 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 concurrentHelicobacter pyloriinfection. 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.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 treatHelicobactor pylori-associated EMZL of the esophagus had not been reporteduntil a recent case with the disease was treated withvonoprazan+ 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.

Primary ocular adnexa

Primary ocularadnexaEZML (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, particularlyClamydophelia psittaci,a communicableintracellularbacteriumthat infects feral birds, farm animals, and humans. In humans, it causes respiratorypsittacosisand eye infections, particularly chronicconjunctivitis.Clammydophelia psittacihas 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.GastricHelicobactor pyloriinfection orHepatitis C virusinfection 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 withHerpes simplex virus 1,Herpes simplex 2,adenovirus 8,adenovirus 19,Chlamydia trachomatis,orChlamydophila abortusinfection. The relationship(s) of these infections to the development and/or progression of primary ocular adnexa EZML is unclear.

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 asexophthalmos(i.e. a bulging of the eye) (27% of cases), apalpableeye 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.Patients with conjunctiva disease may be asymptomatic.A variable percentage of patients with primary ocular adnexa MZL may concurrently be affected byHashimoto's thyroiditis,Sjögren syndrome,orIgG4-related disease.Some studies have also found that the disease is associated withHelicobactor pyloriinfection 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 containcentrocyte-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 theMALT1gene, 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.

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 aCHOPregimen 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 withchlorambucilin 33 patients has achieved complete responses in 26 patients after 24 months of follow-up;4)immunotherapy withrituximabhas achieved variable results over the short-term and requires further study over longer follow-up periodswith somewhat better results occurring in patients with conjunctival disease;and5)antibiotic therapy withdoxycyclinehas achieved 2 year and 5 year failure-free survival rates of 67% and 55%, respectively, and a 5-year progression-free rate of 61%.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%).

Primary skin

Primary cutaneous EMZL or primary cutaneous MALT lymphoma (also termedskin-associated lymphoid tissue lymphoma) typically presents as single or multiple smallpapulesorplaquesusually located on the arms and/or trunk. Histologically, these lesions consist of reactive germinal centers containing a mixture of small B cells that have aplasma cell-like ormonocyte-likemorphologyinterlaced with numerousT celllymphocytes.The B-cells in these lesions express the B-cell markers commonly seen in EMZL.TheDNAofBorrelia burgdorferi,the causative agent ofLyme disease,has been detected in the lesions of 10%–42% of patientsin 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.Treatment of primary cutaneous EMZL has been conservative, given the diseases indolent behavior. InBorrelia burdorferi-positive disease, antibiotic therapy (courses of acephalosporinortetracyclineare regarded as first-line antibiotic choices) should be consideredalthough this measure is less applicable in areas, such as the United States, where the bacterium has not been associated with the disease.Treatment ofBorrelia 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 ofinterferon-alphaorrituximabinto the lesions, and localizedexternal 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;chlorambucilchemotherapy with or without intravenous rituximab has significantly improved event-free survival times; andCHOPchemotherapy is recommended for patients withB symptoms(e.g. fever, night sweats, weight loss, etc.), elevated levels of serumlactic acid dehydrogenase,or disease that has progressed to a more aggressive stage.

Primary lung

Primary pulmonary EMZL (orprimary 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 evidencedAchromobacter xylosoxidansDNAin their lung lesions.Achromobacter xylosoxidansis abetaproteobacteriathat is routinely isolated from the lungs ofcystic fibrosispatients; it has a lowvirulencebut is extremely resistant to antibiotics.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 orCT scanconducted for unrelated reasons.Patients with symptoms usually present with chest pain, shortness of breath, and/or a history of recurrent respiratory infections.Chest X-rays and CT scans typically show bilateralalveolaropacities that are <5 cm. More severe lung damage (e.g.atelectasis,pleural effusion,ormediastinal lymphadenopathy) occur in <10% of cases. Patients with more advanced disease may present withbone marrowinvolvement (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, systemicB symptomssuch as fever,night sweats,and/or weight loss. Amonoclonal gammopathy(i.e. excessive amounts of amonoclonalgamma globulinin theblood) 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 thebroncheal airwaysand are diagnosed by needle biopsy, bronchial biopsy, trans-bronchial biopsy, and/orbronchoalveolar 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 lavagefluid 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 andtrisomyof chromosomes 3 and/or 18.

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%include surgery, radiotherapy, chemotherapy,immunotherapy,andwatchful waiting.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 withfludarabine,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.

Primary salivary gland

Primary salivary gland EMZL (also termed MALT lymphoma of thesalivary glands) or, in cases primarily involving thelacrimal glands,primary lacrimal gland EMZL (also termed MALT lymphoma of the lacrimal gland) is a complication ofSjögren syndrome,anautoimmune diseasecharacterized by chronic inflammation of the salivary and/or lacrimal glands.This autoimmune disease is thought to be caused by a combination ofgeneticandenvironmentalfactors includinginfectious agents.This lymphoma affects ~3% of patients with Sjögren syndromeand involves one or more of the affected salivary or, less commonly, lacrimal glands.The median time between diagnosis of the autoimmune disease and EMZL varies between 7.5and 11 years.Affected individuals typically are 55–60 years old and present with localized hardening and/or enlargement of theparotid glandor, less commonly, other salivary or lacrimal gland. Some 20% of cases present with or progress to involve local lymph nodes or the spleen to causelymphadenopathyorsplenomegalywhile ~10% of cases present with or progress to a high-grade lymphoma, primarily diffuse large B-cell lymphoma.Histologically, the involved glands show lymphocyte-based lesions that are typical of EMZL with the infiltrating lymphocytes in some cases having morphological features resemblingplasma cells.In individuals with more advanced disease, these lesions develop in the mucosal linings of theeye socket,nasal cavity,pharynx,airways of the lowerrespiratory tract,stomach, and/or thyroid gland.

Treatment of primary salivary/lacrimal gland EMZL has not been standardized. A minority of patients have been treated bywatchful waitingbut most patients have been subjected to surgery, radiotherapy, chemotherapy (i.e.chlorambucil), immunotherapy (i.e.rituximab,or a combination (e.g. chlorambucil + rituximab orfludarabine+ rituximab orbendamustine+ 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.

Lymphoepithelial sialadenitis

Lymphoepithelial sialadenitis,also termed chronic sialadenitis, is a benign infiltration of salivary glands by B-cells with morphological features of marginal zone B-cells, centrocytes, and monocytes. Histologically, this disorder is associated withatrophyof thecolumnar epitheliumin salivary gland ducts as well as the proliferation of epithelial cells andlymphoepithelial lesionsin these glands. While usually a component of Sjorgen syndrome, these histological finding can also occur in patients without evidence of this syndrome. Very rarely, lymphoepitheleial sialadenitis progressed to salivary gland EMZL.

Primary thyroid

Primary thyroid EMZL, also termed MALT lymphoma of thethyroid gland,is extremely rare. It occurs almost exclusively in thyroid glands affected byHashimoto'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.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 developedhoarseness,high-pitchedbreath sounds,and/or difficulty in swallowing and/or breathing.Histologically, the lesions in this lymphoma generally consist of reactivelymphoid folliclesandlymphoepithelial lesionswhich 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 indiffuse 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.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.

Treatment of primary thyroid EMZL is generally conservative since up to 90% of patients are diagnosed with early stage disease.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%and an estimated 5 year disease-free survival of 95%.Surgery plus radiotherapy does not appear to give better results that radiotherapy alone.Patients with extensive disease or disease that has progressed to a higher grade lymphoma (principally diffuse B-cell lymphoma) have been treated withchemotherapy(usuallyCHOP) and/orimmunotherapy(i.e.rituximab). However, the 5 year survival rates in chemotherapy-treated patients with disseminated primary thyroid EMZLor disease that has progressed to a more malignant lymphomaare only 35% and 44%, respectively.

EMZL and other autoimmune diseases

Patients with anautoimmune diseaseother than Hashimoto's thyroiditis also have an increased risk of developing an EMZL in one or more tissue sites. For example, patients withsystemic lupus erythematosushave a 7.5-fold increased risk of developing an EMZL compared to the general population and at diagnosis of this development have a median age of 50 years and been diagnosed with systemic lupus erthyematosis for 6.7 to 17.8 years.Patients withrheumatoid arthritis,immune thrombocytopenic purpura,andautoimmune hemolytic anemiaare 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.Treatment of patients with an autoimmune disease complicated by EMZL has usually involved the standard measures used to treat both the autoimmune disease and EMZL.

Primary central nervous system

Primary EMZL of thecentral nervous systemis 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 thedura mater,i.e. thick membrane surrounding the brain and spinal cord, (56 cases), the brain or spinalparenchyma(6 cases), the brain'scavernous sinusn(4 cases), the brainschoroid plexus(3 cases), inside brain [[Ventricular system[ventricle]] (1 case), thecerebellopontine angle(2 cases), and theoptic 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 wereheadache(30 cases);seizures(22 cases); and visual changes (19 cases). Less commonly, patients presented withparesthesias(i.e. abnormal skin sensations), motor deficits, andataxias,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 thecerebrospinal fluidin 5 of the 19 cases tested for this.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.

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, includingintrathecal 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.

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.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 ofplasma cellsormonocytes,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,mastectomyis not recommended and wide excision is not usually necessary to treat localized disease. For patients with disseminated disease, treatment options includewatchful waitingand chemotherapy (typically employing aCHOPor 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,andoxaliplatin.

Primary urinary tract

Primaryurinary tractEMZLs of theurinary bladderand 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 chroniccystitis,i.e. inflammation of the bladder due tourinary tract infectionor other causes.

Primary bladder

Presenting symptoms of primary bladder lymphoma include weight loss, fatigue,hematuria,dysuria,nocturia,urinary frequency, and pain in the abdomen and/orsuprapubicarea.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.The histopathology of these lesions is typical of EMZL; they contain small lymphocytes some or many of which have plasma cell features with the malignant cells in these lesions typically expressing CD20 and PAX-5 but not CD5 or CD10 marker proteins.The cells may also contain the t(11;18)(q21:q 21) translocation typical of EZML.Treatment of primary bladder EMZL depends on the extent of disease. Localized disease should be confirmed using, e.g.Positron emission tomography–computed tomography(i.e. PET/CT),Magnetic resonance imaging(i.e. MRI) of thepelvisarea, andBone marrow examination.Confirmed localized disease has been treated by surgery and radiotherapy with radiotherapy being the clearly preferred and most appropriate modality given this lymphoma's high sensitivity to radiation. However, surgical resection withresection of bladder tumor(i.e. TURBT) may be the best treatment where fertility is of concern. Disseminated and recurrent primary bladder EMZL have been treated with systemic chemotherapy (usually aCHOPor CHOP +rituximabregimen.Prognoses for treated localized and disseminated disease are goodwith long-term (e.g. up to 40 years) remissions reported for most patients with localized disease and (up to 10 years) for patients with disseminated disease.

Kidney

Kidney EMZL (i.e. kidney MALT lymphoma, renal EMZL, or renal MALT lymphoma) occurs primarily in individuals >50 years old but has been reported in individuals as young as 9 years. In slightly more than half of the reported cases, this lymphoma was localized to the kidney or detected in the kidney plus lymph nodes around the kidney, elsewhere in theretroperitonium,or along theabdominal aorta.These cases could therefore be regarded as primary kidney EMZLs. The remaining cases had widespread disease some of which appear related to primary salivary gland EMZL, primary orbital EMZL,Helicobactor pylori-associatedgastritis,systemic lupus erythematosus, or possibly anEpstein–Barr virus-associated lymphoproliferative disease,i.e. a lymphocyte-proliferating disease related to and thought to be caused by infection with this virus.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 serumcreatinine). The best treatment for kidney EMZL is unclear. Reported cases have been subjected tonephrectomyand/or chemotherapy.

Primary gallbladder

PrimarygallbladderEMZL (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.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;these include pain in the upper right-side of the abdomen, nausea, vomiting, and in about two-thirds of cases,gallstoness.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.The lesions in these gallbladders show infiltrates in the gland'ssubmucosathat consist of small lymphocytes interspersed withlymphoepithelial lesions.The lymphocytes have marker protein profiles (e.g. CD20 and Bcl-2 positive; CD5, cyclin D1and CD10negative) 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.

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.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 ( principallyhepatitis B viral hepatitisorhepatitis C viral hepatitis,less commonly,primary biliary cirrhosisorhepatocellular carcinoma,and, rarely, other liver diseasessuch ashepatitis 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 ofliver enzymes,and/or evidence of one or more liver masses as detected bymagnetic resonance imaging,computed tomography scans,orpositron emission tomography.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.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 containedlymphoepithelial lesions.Immunohistochemistrytesting 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 orrituximabtreatment 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.

EMZL associated with hepatitis C

EMZL occurs more frequently (~2.5-fold increased risk) in individuals who havehepatitis C virus-inducedhepatitis.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 withtype II cryoglobulinemia,i.e. the circulation of an immune complex consisting ofpolyclonalIgG,monoclonalIgM,and hepatitis C viralRNA.This immune complex causessigns and symptoms of vasculitisin 10% of cases. Other signs and symptoms of the disorder include those associated withchronic hepatitisand the specific subtype of EMZL.Rarely EMZL associated with hepatitis C virus infection presents as single or multiple soft, mobile sub-cutaneous nodules.This presentation occurs mainly in female (83% of cases) and elderly patients.Patients with this disorder may have detectable levels of circulating hepatitis C virus.The histology of the lesions in EMZL associated with hepatitis C virus infection is typical of EMZLalthough 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.Treatment of this disease had relied on eradicating the virus usingpeginterferon-alfas,interferon-alpha-like drugsto 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,anddasabuvir) 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 includerituximabor rituximab + a peginterferon-alfa. Sincechemotherapyregimens 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

See also:Splenic marginal zone lymphoma

Splenic marginal zone lymphoma(SMZL) is a low grade lymphoma in which malignant B-cells accumulate in the spleen, bone marrow, and, less commonly, the circulation. While generally an indolent disease, about 5-10% of cases transform into a far more aggressive malignancy,diffuse large B-cell lymphoma.In a variable percentage of cases, SMZL has been observed to occur with an increased incidence in individuals who are chronically infected withHepatitis C virusor have any one of various chronic autoimmune diseases or abnormalities.

Signs and symptoms

At presentation, patients (median age 65 years; range 30–90 years) generally exhibit enlargement of their spleens (75% of cases).They typically do not have enlargements of theirlymph nodesexcept for thelymph nodes around the hilum of their spleens.Most patients have no systemic symptoms such as fever,night sweats,weight loss, or fatigue.Blood tests reveal reductions in the levels of red blood cells,platelets,and/or white blood cells in 25% of cases;an abnormal circulatingIgMmyeloma proteinin <33% of cases; and in ~20% of cases evidence ofautoimmunityabnormalities such as circulatingautoantibodies(i.e.antibodiesdirected against the patients' own antigens), autoimmune hemolytic anemia, immune thrombocytopenic purpura,cold agglutinins,and/or anticoagulant antibodies.Individuals with SMZL also commonly exhibit increased levels of circulating bloodlymphocyteswhich in some cases can be identified as malignant B-cells; these malignant cells may have hair-like projections similar to the malignant B-cells found in the circulation of patients withhairy cell leukemia.Patients with SMZL may also present with signs and symptoms of acquired von Willebrand disease, angioedema due to C1-esterase inhibitor deficiency,or hepatitis C virus infection (e.g.clinical hepatitis,circulating hepatitis C virus). The association of hepatitis C virus infection with SMZL varies with location and may be as high as 10% in some areas.Finally, careful examination of patient bone marrows almost always finds pockets or more extensive accumulations of malignant B-cells.

Pathophysiology

The malignant cells involved in SMZL are tentatively identified as antigen-experienced B-cells. The disease appears to be initiated in at least some cases by chronic antigen stimulation of the precursor B-cells that thereby become antigen-experienced. Evidence for this derivation comes from studies showing that the antigen-experienced B-cells inn SMZL express structurally restrictedimmunoglobulinsandB-cell receptors(seeclonal selection) that likely bind specific but generally unidentified antigens.Furthermore, patients with SMZL are often found to have autoimmune abnormalities such as circulatingautoantibodies(i.e.antibodiesdirected against patients' own antigens),autoimmune hemolytic anemia,immune thrombocytopenic purpura,cold agglutinin disease,circulating anticoagulant antibodies, acquiredvon Willebrand disease,andangeoedemadue to C1-esterase inhibitor deficiency.It is thought that the B-cell receptor binding of unidentified antigens including those involved in the cited autoimmune abnormalities stimulate the B-cells' proliferation, long-term survival, and thereby the step-wise acquisition of genomic abnormalities which ultimately cause the antigen-experienced B-cells to become malignant.The genomic abnormalities thought to contribute to this malignant transformation include:

• Chromosome abnormalities such as: 1) deletions in the long (i.e. "q" ) arm of chromosome 7 (annotated as del7q) in 30-40% of cases (this deletion is rare in other lymphomas and therefore used as a marker for SMZL);2) deletion of a region on the short (i.e. "p" ) arm of chromosome 17 in 3-17% of cases to result in a loose of one of the twop53genes that encode atumor suppressorthat acts to regulate cellular survival; and 3) gains in the q arm of chromosome 3 in 10-20% of cases.
• Mutationsin genes such as: 1KLF2(21% of cases),atranscription factorthat indirectly regulates theNF-κBsignaling pathway of cellular survival, proliferation, and the production of cell-stimulatingcytokines;2)NOTCH2(20% of cases),a membrane protein that regulates the development of marginal zone B-cells from their precursor cells and hastumor suppressoractivity to thereby promote cellular survival;3)TP53(14% of cases), a transcription factor that indirectly regulates cell proliferation andprogrammed cell deathto thereby promote cellular survival;4)IGLL5(14% of cases) with unclear functions;5)TNFAIP3(13% of cases), which acts indirectly to inhibit NF-κB activation and programmed cell death;and 6) in <10% of cases at least 16 other genes.

Overall, mutations in the NOTCH, NF-κB, and KLF2 signaling pathways appear particularly important in the pathogenesis of SMZL.

Diagnosis

The clearest evidence for the diagnosis of SMZL is obtained by examination of patients' spleens obtained bysplenectomy.These spleens characteristically show lymphoid infiltrates in thewhite pulpand, to a lesser and more variable extent, thered pulp.These infiltrates consist of small lymphocytes, marginal zone B-cells,centroblast-like B-cells,monocyte-like B-cells, andplasma cells.Epithelioid-likehistiocytesmay be found in the red pulp. Splenic hilar lymph nodes may show nodular infiltrates of small lymphocytes. Careful and thorough examination of patients' bone marrow commonly shows aggregates of lymphoid cells between the organstrabeculaeand within itssinuses.Neoplastic B-cells may also circulate in patient's blood. The neoplastic cells in all of these tissues, similar the neoplastic cells in extranodal and nodal MZL, expressCD20,CD27,andBCL2but notCD10,CD23,CD5,CD43,CD38,BCL6,cyclin D1,orannexin A1marker proteins. These cells may also express the del7q deletion (i.e. deletions in the q arm of chromosome 7) in 30-40% of casesand in lower percentages of cases the mutated genes listed in the Pathophysiology section. While the diagnosis of SMZL was initially based on the examination of splenic tissue, currently the diagnosis is made in most cases on clinical findings plus examinations of patients' bone marrow and/or blood that detect neoplastic B-cells that express some of the proteins and/or genomic abnormalities cited above;however, cases difficult to diagnose based on bone marrow and blood findings require examination of the spleen to obtain a definitive diagnosis of SMZL.

Treatment

Given its rarity, there have been no systematic and controlled studies on the treatment of SMZL. Current recommendations for this include the following.Watchful waiting,which is the withholding of specific treatments while performing follow-up examinations every 3 to 6 months to detect disease progression. This course is recommended for the ~33% of SMZL patients who present with asymptomatic, non-progressive, or slowly progressive disease. These patients may not require therapeutic interventions for long periods. Historically, the initial therapy for patients with rapidly progressing disease wassplenectomy.Some 90% of these patients show reductions in their symptoms and improvements in their low red blood cell, platelet, and white blood cell counts; they had median progression-free, 5 year overall, and 10 year overall survival rates of 8.2 years, 84%, and 67%, respectively. However, these patients show no alteration in the neoplastic B-cells levels in their blood, were subject to serious complications from their splenectomy (e.g.thrombosis,infections), and did not show alter overall survival rates better than those obtained with other treatment strategies. Accordingly, splenectomy for SMZL has been limited to cases of significantly symptomaticenlarged spleensin patients with mild-to-moderate bone marrow involvement and no bulky lymph node enlargements.

Current treatment recommendations for patients with symptomatic or rapidly progressive SMZL rely on drugs.Rituximab,a commercial preparation of amonoclonal antibodydirected at the CD20 protein on B-cells, is significantly active in SMZL, with short-term treatments (e.g. ~4 weeks) achieving overall response rates of 90-100%, complete remission rates of >50%, and a 7-year progression-free survival rate of 69%. Long-term maintenance therapy with rituximab appears to improve these results and patients who relapse after rituximab therapy commonly respond to a second course of the drug. Prior to rituximab availability, single drugchemotherapy(e.g.chlorambucil,cyclophosphamide,fludarabine,pentostatin,2CDA,orbendamustine) and multiple drug regimens (i.e. the CVP regimen ofcyclophosphamide,vincristine,andprednisone,or theCHOPregimen of CVP plusdoxorubicin) were used to treat the disease. However, current studies indicate that these chemotherapeutic agents are not superior to single agent rituximab therapy in terms of response rate as well as the quality and duration of these responses.A phase II clinical trial has found that the treatment of SMZL with a combination of rituximab plus bemdamustine achieves overall response and complete response rates of 91% and 73%, respectively, with percentage responses enduring for >3 years, progression-free survival rate, and overall survival rate of 93%, 90%, and 96%, respectively. The results of this trial, while requiring confirmation, strongly suggest that this two-drug regimen be used in place of rituximab alone, the cited chemotherapy regimens, or rituximab plus the cited chemotherapy regimens for patients with symptomatic/progressive SMZL.

Experts recommend that SMZL patients who also have hepatitis C virus infection should be treated with drugs that act to eliminate the virus as their first line approach. Before the development of directly acting anti-viral agents, several studies reported thatIFN-αtreatmentof these patients produced improvements not only in the viral infection but also remissions (~65% of cases) in their lymphomas.Several newer, directly acting anti-viral agents, e.g.grazoprevir,daclatasvir,sofosbuvir,anddasabuvir,are more effective in treating hepatitis C viral infectionand in s small number of patients have been or are expected to be more effective in producing lymphoma remissions in patients with SMZL plus hepatitis C virus infection.

Prognosis

SMZL generally follows an indolent course with 10 year survival rates of 42-95%.About one-third of these deaths are unrelated to SMZL and ~5-10 of these deaths are due to the transformation of their SMZL disease to diffuse large C-cell lymphoma.

Nodal marginal zone lymphoma

Nodal marginal zone lymphoma (NMZL), previously termed monocytoid B-cell lymphoma, nodal monocytoid B-cell lymphoma, and nodal marginal zone lymphoma with or without monocytoid B-cells, is an infiltration of tissues with malignant lymphoid cells that have themorphologicalandphenotypicalfeatures of all marginal zone lymphomas.NMZL differs from the other subtypes of marginal zone lymphomas by its primary involvement oflymph nodesrather than other tissues and organs.NMZL is the least common subtype of the three marginal zone lymphomas.

Signs and symptoms

Almost all patients with NMZL present (median age 50–64 years;male to female ration 1.5 to 1) with non-bulky enlargement of their lymph nodes in the neck, groin, abdomen, and thoracic regions;some cases may also exhibit this involvement in theirWaldeyer's tonsillar ring.Patients at presentation are generally fully functional but in 10-20% of cases complain ofB symptomssuch as fever,night sweats,weight loss, and/or fatigue.Laboratory studies show malignant B[cells infiltrating thebone marrowin ~33% of patients and an abnormalIgMmyeloma proteinin ~20% of cases. Rarely, patients may present with circulating malignant marginal zone B cells and/or reductions in one or more types of circulating normalblood cells.Biopsy of involved tissues various patterns (e.g. diffuse throughout lymph node, centered between the follicles of lymph nodes, and/or a nodules spread throughout the lymph node) lymphocyte infiltration.These patterns are similar to those seen in EMZL MALT lymphomas.The cells in these infiltrations ore, in varying proportions, small lymphocytes, marginal zone-like B-cells,centrocyte-like cells,monocyte-like cells,plasma cell-like cells, and in >20% of cases largeblastic B-cells.The malignant B-cells in these infiltrations are, like those in other marginal zone lymphomas, Marginal zone B-cells that typically expressCD20,CD19,CD79,andBcl2but notCD10,CD5,CD23,orcyclin D1.

Pathophysiology

Some 6-19% of NMZL cases have been reported to be associated withautoimmune diseasessuch asrheumatoid arthritis,Sjögren syndrome,autoimmune hemolytic anemia,and chronicthyroiditis.However, there is little evidence that these diseases contribute to the development of NMZL.Furthermore, the association of NMZL withhepatitis C virusinfections found in earlier studies has not been confirmed in more recent studies.It therefore appears that the postulated role of chronic immune stimulation in promoting extranodal and splenic marginal zone lymphomas has not been clearly demonstrated in and may not apply to NMZL: the underlying initiating cause for developing this disease is currently unclear. Nonetheless, instigating B-cells in NMZL acquire genomic abnormalities that are thought to contribute to their malignant transformation.These genomic abnormalities include the following.

• Chromosomal abnormalities such as: 1)trisomyof chromosome 3 (24% of cases) which causes the overexpression ofFOXP1,NFKBIZ,andBCL6whose protein products promote cellular proliferation and survival;2) trisomy of chromosome 18 (~50% of cases) causing the overexpression ofNFATC1whose protein product may act to promote cell proliferation and survival;3) uncommonly, trisomy of chromosomes 7 and 12 and deletion of the long arm of chromosome 6 which have as yet unknown functional effects;and 4)chromosomal translocationbetween the short (i.e. "p" ) arm of chromosome 2 at position 24 and the long (i.e. "q" ) arm of chromosome 14 at position 32, a translocation of as yet unknown functional consequence but not found in the other marginal zone lymphoma forms and therefore useful as a diagnostic marker for NMZL.
• Mutations in genes such as: 1)NOTCH2(25% of cases)a membrane protein that regulates the development of marginal zone B-cells from their precursor cells and also is atumor suppressorwhich acts to regulate cellar survival;2)TNFAIP3(5-15% of cases) whose product is adeubiquitinating enzymethat functions to suppress theNF-κBtranscription factorand thereby the NF-κB signaling pathway which controls cellular activation, proliferation, and survival;3)BIRC3,which encodes the cIAP2 protein that functions to regulate cell death caused byapoptosis;3)MYD88(0-10% of cases) whose protein product indirectly regulates activation of theNF-κBcell signaling pathway;4)KLF2whose product protein is a transcription factor which indirectly regulates theNF-κBcell signaling pathway;5)PTPRDwhose product protein is areceptor tyrosine phosphatasethat hastumor suppressoractivity and indirectly regulates several signaling programs that regulate cell proliferation and responses tocytokines;and 5) in ~40% of cases one or more of various other genes such asMLL2,SIN3A,ARID1A,EP300,CREBBP,andTBL1XR1) that havechromatin remodelingactivity to thereby regulate the expression of a wide range of other genes.

Diagnosis

The diagnosis of NMZL depends upon identifying neoplastic B-cells in lymph nodes and in some cases the bone marrow but not, at least in early stage disease, in extra-nodal organs. These neoplastic cells should express the marker proteins common to marginal zone lymphomas (refer to previous section) and, in most cases, one or more of the genomic abnormalities indicated in the Pathophysiology section.

Treatment

Recommended treatments for NMZL depend on the diseases state. Asymptomatic NMZL may usewatchful waitingwith routine follow-up examinations every, e.g. 3–6 months, to check for disease progression. However, localized disease, even in asymptomatic patients, has been successively treated with surgery followed by local radiotherapy. Disease that moves past a localized stage to become disseminated, rapidly progressive disease, and symptomatic disease have been treated with a single chemotherapy drug (e.g.cladribine,fludarabine,chlorambucil,orbendamustine); a singleimmunotherapydrug (e.g. rituximab); a multiple drug chemotherapy regimen (e.g.CHOP), or a combination multiple chemotherapy drug plus immunotherapy drug regimen (i.e. CHOP + rituximab). It is not clear that any one or more of these regimens achieves is superior to the others.

Prognosis

NMZL is considered an incurable but relatively indolent disease that takes a slowly progressive, relapsing course. Its prognosis appears to be slightly worse than that seen in extranodal and splenic marginal zone lymphomaswith ~15% of people progressing to a more aggressive lymphoma, diffuse large B cell lymphoma, at median time of ~4.5 years after the diagnosis of NMZL.In different studies, people with the disease have 5 year survival rates of 62-90%.

Children

In children NMZL has been classified by theWorld Health Organization(2016) as a separate variant of NMZL based on its presentation,histologyof the involved lymph nodes, and clinical course.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 orpathogen-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 thegerminal centersof affected lymph nodes by lymphoid cells usually expressing CD20 andCD43,often (~50% of cases) expressing Bcl2, and usually not expressing CD10 orBCL6.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.The course of pediatric NMZL is extremely indolent with the disease having a low relapse rate and typically an excellent outcome.Observation periods of up to 12–18 years have found that patients have overall survival rates of 100% and relapse rates of ~4%.Treatment of pediatric NMZL has used awatchful waitingstrategy,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.

Recent research

B-cell receptor.

Various new drugs such asB-cell receptor(see adjacent figure) signaling blockers andibritumomab tiuxetan(Zevlin) are being tested in clinical trials for MZL.These trials are important in determining dosages and safety of the drugs in study. As of January 19, 2017, theFDAapproved the first ever targeted drug for MZL,ibrutinib.This drug works by inhibitingBruton's tyrosine kinase(BKT), which is able to send signals to the nucleus for survival. In other words, it slows the growth ofB-cells.Vaccineshave been developed that greatly reduce the number ofHelicobacter pyloriin the stomach of animals previously colonized with these bacteria. One or more of these vaccines may be a promising candidates to controlHelicobacter pyloriinfection in humans as well as farm and domesticated animals.