MALT lymphoma C 88.4

The rare marginal zone lymphomas (MZL) belong to the mature cell, indolent (slow-moving) non-Hodgkin lymphomas. The cell of origin of marginal zone lymphoma is considered to be the mature B cell, which is considered to be closely related to the plasma cell, which may result in certain similarities to multiple myeloma/MGUS.

Number of new cases (incidence) of all non-Hodgkin lymphomas per year in Germany is estimated to be 10 to 15 per 100,000 persons.

Extranodal marginal zone lymphomas of the MALT type account for 7% to 8% of newly diagnosed non-Hodgkin lymphomas. They can occur in almost any organ (Raderer M et al 2016). Relative to the total population of all marginal zone lymphomas, extranodal marginal zone lymphoma (extranodal MALT lymphoma) affects approximately 50-70% of all marginal zone lymphomas, followed by splenic (approximately 20%) and nodal marginal zone lymphoma (approximately 10%).

MALT lymphomas affect the following regions:

• Stomach (36-67%)
• Intestine (3-5%)
• Lung - BALT=Bronchus-associated lymphatic tissue (5-11%)
• Eye appendages (6-22%)
• Skin - SALT=Skin-associated lymphatic tissue (2-9%)
• Thyroid gland (1-3%)
• mamma (2-3%)

The risk of developing MALT lymphoma is increased mainly by autoimmune diseases and by chronic infections (Zucca E et al. 2016). The coincidence with autoimmune diseases is about 40% (Sjögren's syndrome 70%; autoimmune thyroiditis 13%, rheumatoid arthritis 3% (Wohrer S et al (2007). In patients with autoimmune diseases, the female gender predominates. There are no differences with regard to prognosis and course. Risk factors to develop MALT lymphoma are:

Family history of malignant lymphocytic disease

history of peptic ulcer disease

Autoimmune disease

• Lymphoepithelial sialadenitis(Sjögren's syndrome)
• Chronic autoimmune thyroiditis (Hashimoto's)
• Rheumatoid arthritis

Chronic infections:

• Hepatitis C
• Helicobacter pylori for MALT lymphoma of the stomach
• Campylobacter jejuni for MALT lymphoma of the small intestine (IPSID)
• Chlamydophila psittaci for MALT lymphomas of the ocular appendages.

Additionally discussed are:

• Borrelia burgdorferi for cutaneous MALT lymphoma (SALT).
• Achromobacter xylosoxidans for MALT lymphoma of the lung
• Hepatitis C for MALT lymphoma of different localizations

The median age at diagnosis is 65 years. W:m= 1.5: 1; in the overall cohort of MALT lymphomas, MALT lymphomas of the parotid gland and mamma are significantly more common in women.

Many patients are completely asymptomatic. Lymphoma is often discovered by chance during a routine endoscopy or imaging procedure. Symptoms vary depending on the location and are mostly nonspecific, so that the time from the first symptoms to diagnosis can be correspondingly long. For MALT lymphomas of the ocular appendages, it is a median of seven months (Raderer M et al. 2016). Laboratory parameters are usually nonspecific. Occasionally, elevations of LDH and beta-2-microglobulin are detectable. Monoclonal immunoglobulins are frequently found (about 40% of patients). Multilocular manifestation is found in about 25% of gastric and in almost 45% of extragastric MALT lymphomas.

Anamnesis: especially questioning about autoimmune diseases and their symptoms (e.g. Sjögren's syndrome).

physical examination including lymph node status, eyes, head and neck region, liver and spleen size

Laboratory peripheral blood: blood count, differential blood count, reticulocytes,

Immunophenotyping only in leukemic course (very rare, then suspicion of splenic marginal zone lymphoma).

LDH, β2microglobulin, total protein, electrophoresis, immunoglobulins quantitative and immunofixation, free light chains, GOT, GPT, AP, γ-GT, bilirubin, creatinine, uric acid, blood glucose, Quick, PTT, HIV, HCV and HBV serology, Helicobacter serology. Urinalysis, immunoglobulin light chains if necessary for monoclonal gammopathy in the blood. Bone marrow aspiration is not routinely recommended.

Sonography: abdominal organ status and abdominal and peripheral lymph node status.

Computed tomography with contrast: thorax, abdomen and pelvis,

CT head and neck only in case of supradiaphragmatic involvement

MRT facial skull in case of localization in the head region

Endoscopy: gastroduodenoscopy with multiple step biopsies from cardia, stomach, duodenum and from macroscopically conspicuous mucous membrane

Colonoscopy with step biopsies and biopsy from the terminal ileum

Diagnosis requires sufficient biopsy material and may necessitate extensive rebiopsies, especially for endoscopically obtained specimens. The infiltrate typically consists of small, centrocytoid cells that are immunohistochemically positive for CD79 and CD20 and negative for CD23, CD10, and cyclin D1 . Rarely, CD5 is expressed. So-called lymphoepithelial lesions may be formed. Depending on the localization (with predominance for extragastric localizations), plasma cells may appear. Isolated blasts. When blasts are present in a lawn-like fashion and occupy more than 20% of the infiltrate there is rare transformation (in 2% to 3% of cases) to diffuse large B-cell lymphoma (DLBCL).

Genetics: MALT lymphomas are not characterized by a 'genetic hallmark'. The translocation t(11;18)(q21;q21) is found in MALT lymphoma but not in splenic and nodal MZL (Isaacson PG et al 2004).

The most common cytogenetic aberrations in MALT lymphoma are.

• t(11;18)(q21;q21) with formation of an API-2/MALT1 fusion protein.
• t(1;14)(p22;q32) with involvement of IgH and BCL10
• t(14;18)(q32;q21) with involvement of IgH and MALT1
• t(3;14)(p14.1;q32) with involvement of FOXP1 and IgH.

The translocation t(11;18)(q21;q21) is found in gastric (up to 26%), pulmonary (31% to 53%), and intestinal (12% to 56%) MALT lymphomas. Routine cytogenetic testing is not currently recommended due to lack of therapeutic consequence.

The diagnosis is made on the basis of the criteria of the current WHO classification 2016 on sufficient biopsy material. In any case, a sufficient diameter of the biopsy needle is absolutely required for punch biopsies. The routine performance of molecular biological examinations (especially clonality analyses) is not recommended in the ESMO and EGILS guidelines, since persistent monoclonality has also been described in HP gastritis and after achieving complete remission of lymphoma (Ruskone-Fourmestraux A et al. (2011). The presence of a translocation t(11;18)(q21;q21) may be diagnostically helpful.

In principle, there are three therapeutic options for MALT lymphoma. These include "watch-and-wait", local therapy (surgery, radiation) and systemic therapy. Due to the indolent course of the disease, an initial "watch-and-wait" strategy is a viable approach in asymptomatic patients at any stage.

While the majority of recommendations are based on retrospective analyses and clinical experience, results from a few randomized trials of systemic therapy are now available. For example, in MALT lymphoma of the stomach after Helicobacter eradication, chlorambucil was compared with watch-and-wait, and a three-arm randomized trial compared chlorambucil versus rituximab (R) plus chlorambucil versus R monotherapy.

Radiotherapy: Radiotherapy is potentially curative in stages I and II and remains the therapy of choice for many sites. The size of the radiation field depends on the particular localization and stage. Currently, doses of up to 24 Gy in involved site technique are recommended, although excellent results with minimal side effects for symptom control in advanced stages have also been achieved with the application of only 2 x 2 Gy (Pinnix CC et al. 2017). However, recurrences are found outside the radiation field in up to 45% regardless of dose. Limiting factors are the radiation sensitivity of the affected organ and adjacent structures.

Surgery: The role of surgery is mainly of diagnostic character (e.g. in small intestine, lung, salivary glands, orbita) due to the often multifocal nature of the disease according to current guidelines.

In contrast to other indolent lymphomas (e.g. follicular lymphoma), there are currently no clearly defined guidelines for the optimal start of therapy. The individual choice of the therapy regime has to take into account in particular the expected spectrum of toxicity and possible comorbidities.

While systemic therapy was used exclusively in disseminated stages in the past, it is now also increasingly used in localized stages (Kiesewetter B et al.(2015). Conventional systemic therapy options for MALT lymphoma include chemotherapy, the anti-CD20 antibody Rituximab, or a combination of these two modalities, but also radioimmunotherapy or antibiotic administration. Other newer therapeutic approaches and agents, individually and sometimes in combination include bortezomib, lenalidomide +/- rituximab, the BTK inhibitor ibrutinib (Noy A et al. 2017), and PI3K inhibitors and the macrolide antibiotic clarithromycin (Ferreri AJM et al. 2018). In general, aggressive anthracycline-containing regimens are not recommended in first-line therapy due to toxicity.

Typically, marginal zone lymphoma develops insidiously over a period of years, so that the diagnosis is made by chance in some patients. Sometimes, however, symptoms develop over a longer period of time, which are related to the proliferation of the lymphoma cells. The "normal" organ functions are disturbed. The predominant symptoms depend on the organ systems affected. In the most common localization involving the stomach, these patients report abdominal pain or digestive complaints. In nodal marginal zone lymphomas, there is usually non-painful swelling of the lymph nodes. Characteristic of splenic marginal zone lymphomas is an enlarged spleen, which not infrequently causes pain. In addition, patients with splenic marginal zone lymphoma more often suffer from B symptoms (fever (above 38.5 °C), weight loss of > 10% of body weight within 6 months, night sweats with the need to change clothes).

Prognosis: The 5-year survival rates in the totality of patients with MALT lymphoma range from 70% to 100%. Relevant prognostic parameters in the context of a defined prognostic score (MALT-IPI) are age > 70 years, stage III/IV and an elevated LDH level. The presence of none, one, and two or more of these parameters delineated three risk groups (low, intermediate, and high) that differed significantly with respect to progression-free and overall survival. Analogous to other lymphoma types, POD24 (Progression Of Disease at 24 months) was also defined as a negative prognostic parameter in MALT lymphoma. In gastric MALT lymphoma, the achievement of a complete remission after initial therapy is associated with a prolonged PFS.

1. Ferreri AJM et al (2018) Clarithromycin as a 'repurposing drug' against MALT lymphoma. Br J Haematol 182:913-915.
2. Isaacson PG et al (2004) MALT lymphoma: from morphology to molecules. Nat Rev Cancer. 4:644-653.
3. Kiesewetter B et al.(2015) Chemoimmunotherapy for mucosa-associated lymphoid tissue-type lymphoma: A Review of the Literature. Oncologist 20:915-925.
4. Noy A et al (2017) Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood 129:2224-2232.
5. Pinnix CC et al (2017) Ultra-low-dose radiotherapy for definitive management of ocular adnexal B-cell lymphoma. Head Neck 39:1095-1100.
6. Raderer M et al (2016) Clinicopathologic characteristics and treatment of marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). CA Cancer J Clin66:153-171.
7. Ruskone-Fourmestraux A et al (2011) EGILS consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT. Gut 60:747-758.
8. Swerdlow SH et al. (2017): WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC.
9. Wohrer S et al. (2007) MALT lymphoma in patients with autoimmune diseases: a comparative analysis of characteristics and clinical course. Leukemia 21:1812-1818.
10. Zucca E et al. (2016) The spectrum of MALT lymphoma at different sites: biological and therapeutic relevance. Blood 127:2082-2092.