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. 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. patients with conjunctiva disease may be asymptomatic. a variable percentage of patients with primary ocular adnexa mzl may concurrently be affected by hashimoto's thyroiditis, sjögren syndrome, or igg4-related disease. some studies have also found that the disease is associated with helicobactor pylori infection of the stomach (45% of cases) or emzl in other tissues (25% of cases). the lesions in primary ocular adnexa emzl are typical of emzl: they contain centrocyte-like b-cells, monocyte-like b-cells, and/or small lymphocytes many of which express cd20, cd791, paz5, and bcl2 but not cd10 or cyclin d1 proteins. the t(1:14)(p22:q320 chromosome translocation, which leads to the over expression of the malt1 gene, trisomy 3, trisomy 18, and deletions at position 23 on the long arm of chromosome 6 are also often found in primary ocular adnexa emzl. 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 with somewhat better results occurring in patients with conjunctival disease; 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%. 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 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. the b-cells in these lesions express the b-cell markers commonly seen in emzl. the dna of borrelia burgdorferi, the causative agent of lyme disease, has been detected in the lesions of 10%–42% of patients in germany, italy, japan, and turkey but not of patients from spain, finland, the netherlands, or the united states. while the disease almost always has a highly indolent course, it is subject to repeated relapses that are usually limited to the skin. rarely, primary cutaneous emzl disseminates to other tissues and becomes a systemic disease. 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 although this measure is less applicable in areas, such as the united states, where the bacterium has not been associated with the disease. 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. 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. 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. 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. 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 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. 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, and watchful 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 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. 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. 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 and 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 7.5 and 11 years. 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. 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. 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. 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 with atrophy of the columnar epithelium in salivary gland ducts as well as the proliferation of epithelial cells and lymphoepithelial lesions in 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 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. 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. 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. 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 with chemotherapy (usually chop) and/or immunotherapy (i.e. rituximab). however, the 5 year survival rates in chemotherapy-treated patients with disseminated primary thyroid emzl or disease that has progressed to a more malignant lymphoma