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. 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) plus any one of several different antibiotic combinations (e.g. clarithromycin + amoxicillin or levofloxacin + 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 to helicobactor pylori eradication 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 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. 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. 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. 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 of alpha heavy chain disease (iga/αhcd), is a variant and by far the most common form of small intestinal mzl. 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. 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. 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: 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. 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. 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, atypical plasma cells and, less commonly, centrocyte-like cells infiltrates in the intestinal lamina propria with the lymphocytes and centrocyte-like cells expressing marker proteins (e.g. cd20 and cd79a) that are typical for emzl. 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. 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. 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. colorectal emzls enzls involving the colon or rectum are extremely rare. in a 2019 review of 73 cases, persons diagnosed with one of these enzl 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. the following sections further describe these two emzl subtypes. primary colonic primary colonic emzl, also termed primary colonic malt lymphoma, usually presents at an early stage of disease with evidence of lower gi tract bleeding (e.g. tarry bowel movements and/or iron deficiency anemia), less commonly with lower abdominal pain, and rarely with bowel perforation or intussusception. endoscopic examination most often reveals a single polyp or rarely multiple polyps, a mucosal ulcer, or a mucosal nodule. diagnosis is passed on biopsy of the lesions showing a histology typical of emzl, e.g. diffuse infiltrates composed of small to medium-sized lymphocytes that may show morphological features of monocytes and/or plasma cells. the lymphocytes in these lesions express b cell markers (e.g. cd19 and cd79a) typical of emzl lesions. the best treatment regimen for this lymphoma is debated. surgical resection, endoscopic resection, radiation, and chemotherapy have been employed. surgery followed by chemotherapy (mitoxantrone + chlorambucil + prednisone or cyclophosphamide + vincristine + prednisone combined with either chlorambucil or rituximab) have been regarded as first-line treatment for the disease. more recently, rituximab alone as a single agent has also been found successful in treating primary colonic malt lymphoma. finally, rare cases of primary colonic emzl have been completely resolved using helicobacter pylori antibiotic therapy. 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/or blood 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 of plasma cells). the malignant cells in these lesions may contain the t(11;18) translocation and therefore express the api2-malt1 chimeric protein (11% of cases). some 22-45% of casests are associated with helicobactor pylori gi tract infection. treatments for the disease have included radiotherapy, surgical resection, endoscopic mucosal resection, various chemotherapies, and antibiotic-based eradication of helicobactor pylori. eradication therapy for helicobactor pylori-positive cases using currently recommended standard antibiotic regimens has given complete responses in 12 of 19 cases and therefore is regarded as proper treatment for such cases. surgical resection for localized disease has achieved long-term survivals in individual cases. 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 cases and is suggested to be the preferred treatment for patients with helicobactor pylori-positive primary rectal emzl. 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 or, more commonly, a linear central indentation or ridge in the esophagus. in a 2017 review, 6 of 18 patients with emzl of the esophagus had evidence of concurrent helicobacter pylori infection. the histopathology of the lesions in emzl of the esophagus is typical of emzl in showing the presence of centrocyte-like cells, monocyte-like cells, and small lymphocytes that express cd20 but not cd10. 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 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. primary ocular adnexa primary ocular adnexa ezml (also termed primary emzl of the ocular adnexa, primary ocular adnexa malt lymphoma, or primary malt lymphoma of the ocular adnexa) occurs primarily in older patients (median age 65 years). individuals may be predisposed to the disease by having a long history of exposure to livestock, mainly cattle and pigs or working with meat from these animals; autoimmune diseases, particularly autoimmune thyroid disease; and infections, particularly clamydophelia psittaci, a communicable intracellular bacterium that infects feral birds, farm animals, and humans. in humans, it causes respiratory psittacosis and eye infections, particularly chronic conjunctivitis. clammydophelia psittaci has been detected in the lesions of 47-80% of patients with primary ocular adnexa emzl with the highest rates of this detection occurring in italy, austria, germany, and korea. much lower detection rates are reported in the united kingdom and southern china while there has been little or no evidence of this organism in cases from the united states and japan. gastric helicobactor pylori infection or hepatitis c virus infection have been reported to