[7] Extranodal marginal zone lymphomas (EMZLs) are a form of MZL[9] in which malignant marginal zone B-cells initially infiltrate MALT tissues of the stomach (50-70% of all EMZL) or, less frequently, the esophagus, small intestine, large intestine, rectum, conjunctiva of the eye, nasal passages, pharynx, lung bronchi, vulva, vagina, skin, breast, thymus gland, meninges (i.e. membranes) that envelop the brain and spinal cord, or other organs.

Patients commonly present at an early stage of the disease[23] with various symptoms such as nausea, vomiting, indigestion, upper abdominal pain, and gastric bleeding as indicated by coughing up blood, bloody bowel movements, and/or iron deficiency anemia.

[17] 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[26]) plus any one of several different antibiotic combinations (e.g. Clarithromycin + Amoxicillin or levofloxacin + nitazoxanide + doxycyclin).

[16] 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.

[27] 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.

[27] 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.

[27] 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.

[10] 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.

[31] 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[31] and is suggested to be the preferred treatment for patients with Helicobactor pylori-positive primary rectal EMZL.

Endoscopy, endosonography and chest CT scans reveal a solitary esophageal mass of varying size[32] or, more commonly, a linear central indentation or ridge in the esophagus.

[7] Primary pulmonary EMZL usually afflicts patients 50–60 years old; in almost 50% of cases the disease is diagnosed in symptom-free individuals who present with an abnormal chest X-ray or CT scan conducted for unrelated reasons.

[18] 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.

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.

[50] 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.

For patients with disseminated disease, treatment options include watchful waiting and chemotherapy (typically employing a CHOP or CHOP-like regimen) with or without radiation therapy and/or excision.

They occur most commonly in middle aged females who have a history of chronic cystitis, i.e. inflammation of the bladder due to urinary tract infection or other causes.

[20] Presenting symptoms of primary bladder lymphoma include weight loss, fatigue, hematuria, dysuria, nocturia, urinary frequency, and pain in the abdomen and/or suprapubic area.

Localized disease should be confirmed using, e.g. Positron emission tomography–computed tomography (i.e. PET/CT), Magnetic resonance imaging (i.e. MRI) of the pelvis area, and Bone marrow examination.

Patients who underwent surgical resection with or without chemotherapy or rituximab treatment regimens and were observed over a median period of 31 months had mostly positive outcomes: 92% survived, 8% died of causes unrelated or only indirectly related to their cancer, and 11% had relapses.

The lymphoma typically occurs 15–25 years (median times) after the viral infection and involves the skin (35% of cases), salivary glands (25%), orbital adnexa (15%) or, uncommonly, the stomach or other tissues.

It is associated with type II cryoglobulinemia, i.e. the circulation of an immune complex consisting of polyclonal IgG, monoclonal IgM, and hepatitis C viral RNA.

More recently, drugs (e.g. simeprevir, daclatasvir, sofosbuvir, and dasabuvir) that directly inhibit the virus's reproduction have cured the infection and achieved lymphoma responses in up to 100 and 73%, respectively, of patients with one year overall and progression-free survival rates of 98 and 75%, respectively.

Since chemotherapy regimens are highly toxic in patients with liver disease, they should be avoided, where possible, in treating EMZL associated with hepatitis C virus infection.

[64][68][66] The genomic abnormalities thought to contribute to this malignant transformation include: Overall, mutations in the NOTCH, NF-κB, and KLF2 signaling pathways appear particularly important in the pathogenesis of SMZL.

Before the development of directly acting anti-viral agents, several studies reported that IFN-α treatment of these patients produced improvements not only in the viral infection but also remissions (~65% of cases) in their lymphomas.

[74] Almost all patients with NMZL present (median age 50–64 years;[72] male to female ration 1.5 to 1[74]) with non-bulky enlargement of their lymph nodes in the neck, groin, abdomen, and thoracic regions;[72] some cases may also exhibit this involvement in their Waldeyer's tonsillar ring.

[74] 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.

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.