Gastrointestinal MALT Lymphoma

1. Gastrointestinal MALT Lymphoma Scott R. Owens, M.D. srowens@med.umich.edu

2. 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!

3. 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

4. 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

5. 55-65% 20-35% 7-20% Distribution of GI Lymphoma Courtesy of Dr. Alyssa Krasinskas

6. 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

7. 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)

8. 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

9. MALT Morphology Marginal zone Mantle zone Germinal center • 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

10. 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

11. 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)

12. 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

13. 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.

14. Lymphoepithelial lesions Near total destruction of gland Infiltration by few neoplastic lymphocytes “Monocytoid” B-cells

15. “Naked” germinal centers

16. “Naked” germinal center surrounded by lymphoma cells

17. Dutcher body MALT lymphoma with extensive plasmacytic differentiation