MANTLE CELL Lymphoma (WITH EMPHASIS ON THE gi TRACT) Scott R. Owens, M.D. srowens@med.umich.edu

Unique to GI Or 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 Small intestine Large intestine 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

Mantle Cell Lymphoma Definition Monomorphous small/medium-sized lymphocytes Resemble centrocytes (small follicle center cells) Often with angular (not cleaved) nuclear contours Centroblasts and paraimmunoblasts (prolymphocytes) are absent

Measuring Mantle Epidemiology Sites of involvement Accounts for 3-10% of all non-Hodgkin lymphoma Occurs in middle-aged and older individuals Median age ~60 years Males > females (about 2:1) Sites of involvement Most commonly affects lymph nodes Extranodal sites Commonly disseminates to spleen and bone marrow GI tract is most common extranodal site (involved in up to 30% of MCL patients) Many (but not all!) cases of lymphomatous polyposis are MCL Waldeyer’s ring

Mantle Manifestations Clinical manifestations Most present at advanced stage (stage III or IV) >50% have massive splenomegaly, marrow positivity

Mantle Morphology Morphology Pattern can be diffuse, nodular, “mantle zone” Mantle zone pattern has central follicle with neoplastic cells around it Cells with irregular nuclei, often angulated Resemble centrocytes, but usually not cleaved Inconspicuous nucleoli Small, hyalinized vessels are common Large, epithelioid histiocytes may be scattered throughout (“pink histiocytes”) May mimic “starry sky” pattern at low power Non-neoplastic plasma cells may also be admixed

More Mantle Morphology MCL does not transform to large cell lymphoma Some cases (especially relapsed) can have aggressive features Larger cells, fine chromatin Blastoid MCL Cells resemble lymphoblasts Very high mitotic rate (usually >20/10 hpf) Pleomorphic MCL Cells with large, oval or irregular (possibly cleaved-appearing) nuclei Prominent nucleoli Beware diagnosing these as DLBCL!

Mantle Markers Immunophenotype Positive: Negative: Surface IgM and/or IgD CD19, CD20 CD5, CD43 (usually), FMC-7 bcl-2 Cyclin-D1 47 homing receptor on GI cases Negative: CD10, CD23 (usually), bcl-6 Occasionally CD5 (should still be cyclin-D1 positive)

Molecular Mantle Genetics Ig genes t(11;14)(q13;q32) Others: IgH rearranged Variable regions usually unmutated Indicates pre-germinal center B-cells t(11;14)(q13;q32) Seen by classical cytogenetics in 70-95% Involves the IgH and cyclin-D1 genes (PRAD1, bcl-1) Seen in virtually 100% by FISH Results in over-expression of cyclin-D1 mRNA Others: p53, p16, p18 may be mutated Especially in blastoid variant 13q14 deletion Total or partial trisomy of chromosome 12 Latter two also seen in CLL/SLL

CD20 CD3

CD5 Cyclin-D1