GASTROINTESTINAL MALT LYMPHOMAScott R. Owens, M.D.srowens@med.umich.edu

Unique to GIOr at least things that make it interesting….

• Our “gross” is often the endoscopist’s description• We are often (usually) dealing with very small pieces of tissue

• The GI tract is rife with inflammatory conditions that can result in lymphoproliferative disorders… and confound our diagnosis of them

• The GI tract is also rife with normal populations of lymphoid tissue that can give rise to lymphoproliferative disorders…and confound our diagnosis of them!

Why lymphoma?• Primary GI lymphoproliferative disorders are fairly

uncommon• About 1-4% of GI tumors

• But…the GI tract is the most common extranodal site of lymphoma• 4-20% of non-Hodgkin lymphoma• B-cell lymphoma most common

• And…the development of lymphoma can complicate other disorders

GI Lymphoma Facts• Distribution

• Stomach• Primary site in 55-65%• 1-7% of all gastric malignancies

• Small intestine• Primary site in 20-35%• About 25% of small intestinal malignancies

• Large intestine• Primary site in 7-20%• About 0.5% of colonic malignancies

• Other sites• Liver• Appendix

Distribution of GI Lymphoma

55-65%

20-35%

7-20%

Courtesy of Dr. Alyssa Krasinskas

What is MALT?• Definition:

• Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT)

• Heterogeneous, predominantly small B-lymphocytes• Includes centrocyte-like cells, monocytoid cells, scattered larger cells

(immunoblast- and/or centroblast-like)• Some cases have plasma cell differentiation

• The lymphoepithelial lesion (LEL) is a hallmark

MALT Mania• Epidemiology

• About 7-8% of all B-cell lymphomas• GI tract is most common site

• About 50% of primary gastric lymphomas• 85% of GI MALTs are in the stomach

• Median age 61 years• Females > males (1.2:1)

• Associated with chronic inflammatory conditions• Autoimmune, infectious• Often seen with Helicobacter pylori in the stomach• A lymphoma of acquired MALT (as opposed to pre-

existing MALT like Peyer’s patches)

More MALT

• Clinical features• Majority present with low-stage disease• Bone marrow often uninvolved in GI cases• M-proteins are rare, despite relatively frequent

plasmacytic differentiation• In immunoproliferative small intestinal disease (IPSID), a

subtype of MALT, a paraprotein is usually found

• Etiology• Activated T-cells (e.g., by H. pylori antigens) are

thought to be essential to B-cell proliferation

MALT Morphology• Morphology

• Reactive B-cell follicles with surrounding, expanded “marginal zones” of neoplastic cells (analogous to Peyer’s patches)

• Neoplastic cells infiltrate mucosa widely, creating LELs• Defined as at least three neoplastic cells, causing epithelial

damage• While usually easily found, LELs are not (on their own)

diagnostic of MALT lymphoma/EMZL• Small/medium-sized lymphocytes with irregular nuclei

(resembling centrocytes) and relatively abundant cytoplasm• More cytoplasm gives a “monocytoid” appearance

Germinal center

Mantle zone

Marginal zone

More MALT Morphology• Morphology (cont.)

• Cells may also be smaller, with less abundant cytoplasm

• Plasma cell differentiation present (in varying degree) in about 1/3 of cases• Often most pronounced in the “superficial” (i.e.,

luminal) part of the mucosa• Can be focal/scattered, or predominant (raising the

differential diagnosis of extramedullary plasmacytoma and/or lymphoplasmacytic lymphoma (LPL)• While plasmacytic differentiation is fairly common,

paraproteins are not

MALT Madness

• Morphology (cont.)• May colonize follicles, mimicking FL, or be diffuse

• Large/transformed (centroblast- or immunoblast-like) cells can vary in number• If infiltrate is diffuse and predominantly large cells, the

appropriate diagnosis is DLBCL• Report low-grade MALT lymphoma component, if present

• IPSID• Similar, but usually with more pronounced plasma cell

component (and a paraprotein, often)

MALT Markers

• Immunophenotype• IgM (less often IgG or IgA) positive with light-chain restriction (on flow cytometry)• Immunohistochemical evidence of light chain

restriction mostly associated with plasmacytic differentiation

• IPSID has α-heavy chain expression

• Positive: CD20, CD79a, CD43+/-, CD21, CD35• CD43 + in about 1/3-1/2 of cases

• Negative: CD5, CD10, CD23• Bottom line: no specific MALT/EMZL marker

Molecular MALT• Genetics

• t(11;18)(q21;q21)• API2/MALT1 gene fusion• ~25% of gastric MALT lymphomas

• t(1;14)(p22;q32)• BCL10 deregulated by coming under control of Ig gene• Some intestinal MALT lymphomas

• t(14;18)(q32;q21)• MALT1/Ig fusion• <5% of gastric MALT lymphomas

• Trisomy 3, 12, 18 (often associated with t(1;14)• p53 mutation; methylation of p15 and p16 promoters• Mutations of fas

• Owens SR, Smith LB. Molecular aspects of H. pylori-related MALT lymphoma. Patholog Res Int. 2011 Jan 24;2011:193149.

Lymphoepithelial lesions

Near total destruction of gland

Infiltration by few neoplastic lymphocytes

“Monocytoid” B-cells

“Naked” germinal centers

“Naked” germinal center surrounded by lymphoma cells

MALT lymphoma with extensive plasmacytic differentiation

Dutcher body