Difficult Differentials in B-Cell Lymphomas Small B-Cell Lymphoma - PowerPoint PPT Presentation

5/24/2018 Difficult Differentials in B-Cell Lymphomas Small B-Cell Lymphoma with Increased Large Cells vs. Transformation to DLBCL Patrick Treseler, MD, PhD University of California San Francisco Small B-Cell Lymphoma with Increased Large Cells vs. DLBCL The Problem:  Small B-cell lymphomas (esp. MZL) can have variable numbers of admixed large cells  How many large cells does it take to indicate transformation to diffuse large B-cell lymphoma? 1

5/24/2018 Transformation of Extranodal MZL (MALT lymphoma) to DLBCL Definition according to 2017 WHO… “MALT lymphoma, by definition, is a lymphoma composed predominantly by small cells. Transformed centroblast-like or immunoblast- like cells may be present in variable numbers, but when solid or sheet-like proliferations of transformed cells are present , the tumor should be diagnosed as diffuse large B-cell lymphoma (DLBCL) and the presence of accompanying MALT lymphoma noted.” JR Cook et al. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (Swerdlow et al., eds). Lyon, France: International Agency for Research on Cancer, 2017, pp. 259-62. 2

5/24/2018 CD21 CD21 3

5/24/2018 Small B-Cell Lymphoma with Transformation of Follicular Increased Large Cells vs. DLBCL Lymphoma to DLBCL The Solution (for MALT lymphoma Definition according to 2017 WHO… at least): “The presence of diffuse areas composed  Solid clusters (dozens to hundreds?) entirely or predominantly of large centroblasts or diffuse sheets of large cells (that would fulfil the criteria for grade 3 FL) in FL of any grade is equivalent to DLBCL, and a  Make sure you are not looking at a separate diagnosis of DLBCL should be made.” B-cell follicle (use a CD21 stain)! • Meets criteria for grade 3 FL • Architecture entirely diffuse (CD21)  If large cells are increased but fall short of clear-cut DLBCL, be ES Jaffe et al. Follicular lymphoma. In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues descriptive & share your concern (Swerdlow et al., eds). Lyon, France: International Agency for Research on Cancer, 2017, pp. 266-73. Grading of Follicular Lymphoma Follicular Lymphoma Grading per 2017 WHO Cos Berard’s actual “eyeball” method (per Nancy Harris) Grade* Definition  Grade 1: Grade 1-2 (low grade) 0-15 centroblasts/HPF Practically all centrocytes; centroblasts present, 1 0-5 centroblasts/HPF but a little hard to find. 2 6-15 centroblasts/HPF  Grade 2: Grade 3 (high grade) >15 centroblasts/HPF Centroblasts easy to find, but mainly single 3A Centrocytes present scattered cells, and clearly in the minority 3B Solid sheets of centroblasts  Grade 3: ES Jaffe et al. Follicular lymphoma. In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (Swerdlow et al., eds). Lyon, France: International Agency for Research on Cancer, 2017, pp. 266-73. Lots of centroblasts, often forming clusters *WHO grading method derived from method of Mann and Berard (Mann RB, Berard CW. Criteria for the cytologic or sheets subclassification of follicular lymphomas: a proposed alternative method. Hematol Oncol. 1983 Apr-Jun;1(2):187-92.) 4

5/24/2018 FL, low grade (gr. 1-2) FL, grade 3A 5

5/24/2018 CD21 FL, grade 3B CD21 6

5/24/2018 Small B-Cell Lymphomas Progression of CLL/SLL and its transformation to DLBCL Basic Immunophenotypes Definition according to 2017 WHO… t(11;14) “Histologically aggressive CD20 CD5 CD43 CD23 BCL1 BCL6 CD10 CLLs are recognized by Cyclin D1 proliferation centers that are CLL/SLL + + + + - - - broader than a 20x field or becoming confluent . Cases Gine et al. Haematologica 95:1526; 2010 Mantle cell + + + - + - - may also belong in this category when the Ki-67 index is >40% or there are >2.4 mitoses in the Follicular + - - -/+ - + +/- proliferation centers .” Full transformation to DLBCL is less precisely defined in the WHO, but Marginal + - -/+ - - - - would likely be best handled in a manner similar to that for extranodal marginal zone lymphoma. Campo et al. Chronic lymphocytic leukemia/small lymphocytic lymphoma. In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (Swerdlow et al., eds). Lyon, France: International Agency for Research on Cancer, 2017, pp. 216-21. Proportion of cases positive: + >90%, +/- 50-90%, -/+ 10-50%, - <10% Transformation of Mantle Cell Lymphoma to DLBCL Doesn’t happen! But there are variants of mantle cell lymphoma that can be quite rich in large cells, and mimic DLBCL, specifically the pleomorphic variant. In the pleomorphic variant of MCL, the “cells are pleomorphic, but many are large,” and may have prominent nucleoli as well. Best gauge of prognosis in MCL is proliferative activity: - Worst prognosis: Ki-67 >30%, mitoses >50/mm 2 - Best prognosis: Ki-67 <10%, mitoses <25/mm 2 Swerdlow et al. Mantle cell lymphoma. In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (Swerdlow et al., eds). Lyon, France: International Agency for Research on Cancer, 2017, pp. 285-90. 7

5/24/2018 CD20 CD5 Mantle cell lymphoma, BCL1 pleomorphic variant 8

5/24/2018 Plasmacytoid Small B-Cell Lymphoma vs. Plasmacytoma The Problem: Plasmacytoid Small  Plasmacytoid small B-cell lymphomas B-Cell Lymphoma vs. (e.g., MZL) can have variable numbers of mature plasma cells Plasmacytoma  If the proportion of plasma cells approaches 100%, is it still a lymphoma, or is it a plasmacytoma? 9

5/24/2018 CD20 Kappa 10

5/24/2018 CD20 Kappa Lambda Extramedullary plasmacytoma as Plasmacytoid Small B-Cell form of marginal zone lymphoma? Lymphoma vs. Plasmacytoma Hussong et al. (AJCP 111: 111; 1999) The Solution:  Studied patients with extramedullary  Regard extraosseous tumors of mature plasmacytomas of GI tract, salivary gland, plasma cells as MZL/MALT lymphoma with dura, and lymph nodes extensive/extreme plasmacytic differentiation particularly if they:  All had lymphoepithelial lesions, if epithelium present in tissues  Present in sites commonly involved by MALT lymphoma  All did well with resection ± radiation  Have destructive lymphoepithelial lesions  Argued that extramedullary plasmacytoma may be extreme form of MZL, distinct from  But diagnose descriptively, encourage clinical plasmacytoma of bone and myeloma evaluation to exclude myeloma 11

5/24/2018 Plasmacytoid Small B-Cell Lymphoma vs. Plasmacytoma And finally, keep in mind:  Plasmacytoid variants have been described for Plasmacytoma vs. essentially all small B-cell lymphomas Plasmablastic Lymphoma  Look for expression of specific markers in the residual small B-cells to rule those in :  CD5/CD23/LEF1  CLL/SLL  CD5/BCL1/SOX11  mantle cell lymphoma  CD10/BCL6  follicular lymphoma Plasmacytoma vs. Plasmablastic Lymphoma The Problem:  Plasmacytomas (e.g., in myeloma patients) have variable numbers of plasmablasts (large neoplastic plasma cells with distinct to prominent nucleoli)  How many plasmablasts does it take to call it plasmablastic lymphoma (DLBCL with plasma cell phenotype)? 12

5/24/2018 Plasmacytoma vs. Plasmablastic Lymphoma (PBL) The Solution: >50% (That was easy!)  Colomo et al. (AJSP 28:736) defined plasmablastic lymphoma as subtype of DLBCL with:  Predominantly (>50%) large lymphoid cells (plasmablasts and/or immunoblasts)  Plasma cell phenotype (CD20 neg/weakly pos., Oct-2 pos.)  Subtypes of PBL (per Colomo et al.)  PBL of oral mucosa type: All cells large  PBL with plasmacytic differentiation: Most cells large immunoblasts or plasmablasts, but differentiation to small plasma cells present too  Extramedullary plasmablastic tumor: Identical to PBL with plasmacytic diff, but history of prior or concurrent well differentiated plasma cell neoplasm (usually myeloma) PBL, oral mucosa type PBL, oral mucosa type 13

5/24/2018 CD20 PBL, with plasmacytic diff. CD3 CD138 14

5/24/2018 Follicular lymphoma Plasmacytoma CLL/SLL Burkitt lymphoma Plasmablastic Mantle cell MZL Lymphoblastic leukemia/lymphoma DLBCL lymphoma DLBCL? DLBCL Germinal Center CD34 Surface Ig CD19 CD20 CD10 CD10 CD5 CD138 CD79a Pax-5 Oct-2 Ig heavy chain genes rearranged Ig light chain genes rearranged Ig genes hypermutated Pax-5 CD20 15

5/24/2018 Burkitt Lymphoma vs. Diffuse Large B-Cell Lymphoma Oct-2 Burkitt Lymphoma vs. DLBCL Old WHO (2008): Burkitt lymphoma The Problem: B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma  There are some B-cell lymphomas that (DLBCL/BL), a “gray zone” lymphoma (roughly generally resemble BL, but either: corresponding to high-grade Burkitt-like lymphoma of  Have increased numbers of large 2001 WHO) cells more typical of DLBCL; or New WHO (2017):  Lack the CD10+ BCL6+ BCL2- Burkitt lymphoma phenotype of classical BL DLBCL/BL “gray zone” cases all moved to new categories:  What do we call these lymphomas? - HGBL with rearrangements MYC and BCL2 +/- BCL6 BL? DLBCL? A BL/DLBCL gray zone? - HGBL, NOS Something else? 16