Small B-cell (Histologically Low Grade) Lymphoma
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1 Frequency of Lymphoid Neoplasms Small B-cell (Histologically Low Grade) Lymphoma Stephen Hamilton-Dutoit Institute of Pathology Aarhus University Hospital B-cell neoplasms 88% Diffuse large B-cell lymphoma 31% Follicular lymphoma 22% MALT lymphoma 8% CLL/SLL 7% Mantle cell lymphoma 6% Mediastinal large B-cell lymphoma 2% Nodal marginal zone lymphoma 2% Burkitt/Burkitt-like lymphoma 3% Lymphoplasmacytic lymphoma 1% Splenic marginal zone lymphoma <1% T-cell neoplasms 12% Peripheral T-cell NOS 4% Anaplastic large cell lymphoma 2% Precursor T-LBL 2% Nasal NK/T-cell lymphoma 1% Angioimmunoblastic T-cell lymphoma 1% Enteropathy-type T-cell lymphoma <1% Adult T-cell lymphoma/leukemia <1% Armitage et al, 1997 WHO Classification of B-cell Neoplasms 2008 WHO Classification of B-cell Neoplasms 2008 Precursor B-lymphoblastic leukemia/lymphoma (precursor B-ALL) 8 genetic subtypes Mature B-cell neoplasms B-cell CLL/SLL B-cell prolymphocytic leukemia Splenic marginal zone B-cell lymphoma +/- villous lymphocytes/slvl Hairy cell leukemia Lymphoplasmacytic lymphoma Heavy chain disease Plasma cell myeloma Solitary plasmacytoma of bone Extraosseous plasmacytoma Extranodal marginal zone B-cell lymphoma (MALT type) Nodal marginal zone B-cell lymphoma +/- monocytoid B cells Follicular lymphoma Primary cutaneous follicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma, NOS T-cell / histiocyte-rich; primary CNS ; primary leg skin; EBV+ elderly Diffuse large B-cell lymphoma with chronic inflammation Lymphomatoid granulomatosis Primary mediastinal large B-cell lymphoma Intravascular large B-cell lymphoma ALK+ large B-cell lymphoma Plasmablastic lymphoma Large B-cell lymphoma associated with HHV8+ Castleman disease Primary effusion lymphoma Burkitt lymphoma B cell lymphoma, unclassifiable, Burkitt-like B cell lymphoma, unclassifiable, Hodgkin lymphoma-like Mature B-cell neoplasms - 1 B-cell CLL/SLL B-cell prolymphocytic leukemia Splenic marginal zone B-cell lymphoma +/- villous lymphocytes/slvl Hairy cell leukemia Lymphoplasmacytic lymphoma Heavy chain disease Plasma cell myeloma Solitary plasmacytoma of bone Extraosseous plasmacytoma Extranodal marginal zone B-cell lymphoma (MALT type) Nodal marginal zone B-cell lymphoma Follicular lymphoma Primary cutaneous follicular lymphoma Mantle cell lymphoma WHO: Histologically Low Grade B-Cell Lymphomas B-CLL / SLL minority are clinically aggressive Prolymphocytic clinically aggressive Mantle cell lymphoma clinically aggressive Survival Small B-Cell Lymphomas: Overall Survival Small Lymphocytic (CLL) Marginal Zone Log Rank Test: p<0.001 Mantle Cell Years Armitage et al,
2 Typical Immunophenotype of Small B-Cell Lymphomas Histologically Low Grade B-Cell Lymphomas: Differential Diagnosis CD20 CD79A CD10 CD23 CD5 CD43 bcl-2 CyclinD1 TdT CLL FL MCL LPL / MZL / SMZ / MALT / HCL BLB - / / - + / WHO Classification of B-cell Neoplasms 2008 Mature B-cell neoplasms - 1 B-cell CLL/SLL B-cell prolymphocytic leukemia Splenic marginal zone B-cell lymphoma +/- villous lymphocytes/slvl Hairy cell leukemia Lymphoplasmacytic lymphoma Heavy chain disease Plasma cell myeloma Solitary plasmacytoma of bone Extraosseous plasmacytoma Extranodal marginal zone B-cell lymphoma (MALT type) Nodal marginal zone B-cell lymphoma Follicular lymphoma Primary cutaneous follicular lymphoma Mantle cell lymphoma WHO Classification of B-cell Neoplasms 2008 Mature B-cell neoplasms - 1 B-cell CLL/SLL B-cell prolymphocytic leukemia Splenic marginal zone B-cell lymphoma +/- villous lymphocytes/slvl Hairy cell leukemia Lymphoplasmacytic lymphoma Heavy chain disease Plasma cell myeloma Solitary plasmacytoma of bone Extraosseous plasmacytoma Extranodal marginal zone B-cell lymphoma (MALT type) Nodal marginal zone B-cell lymphoma Follicular lymphoma Primary cutaneous follicular lymphoma Mantle cell lymphoma B-cell Small Lymphocytic Lymphoma (CLL) B-Cell CLL/SLL: Pseudofollicular Pattern Morphology small lymphocytes proliferation centres Immunology surface IgMD weak CD19, 20, 79a + CD5 + CD23 + CD10, CycD1 - Genetics trisomy 12 or 13q in 25% clonal IgH IgL > 60 % have somatic mutations Clinical usually leukaemic adults indolent CD23 CD5 2
3 Small Lymphocytic Lymphoma (CLL) Small Mature B-Cell NHL Small lymphocytic lymphoma Tissue variant of CLL Lymphoplasmacytoid lymphoma Older patients, male predominance Paraprotein with associated symptoms Overlap with Waldenstrom s CD5 in lymphoma SLL (CLL): Richter s Transformation 80% T cell lymphomas >95% SLL (CLL-like) NHL (strong) >90% mantle cell lymphoma (weak) Minority of DLBCL Other B-cell NHLs negative SLL CD5 WHO Classification of B-cell Neoplasms 2008 Differential diagnosis: IHC SLL vs B-LB TdT neg CD5 pos CD23 pos SLL vs MCL CD23 pos cyclin-d1 neg Ki-67 low SLL vs FL CD5 pos CD23 pos BCL-6 neg (proliferation centres) Mature B-cell neoplasms - 1 B-cell CLL/SLL B-cell prolymphocytic leukemia Splenic marginal zone B-cell lymphoma +/- villous lymphocytes/slvl Hairy cell leukemia Lymphoplasmacytic lymphoma Heavy chain disease Plasma cell myeloma Solitary plasmacytoma of bone Extraosseous plasmacytoma Extranodal marginal zone B-cell lymphoma (MALT type) Nodal marginal zone B-cell lymphoma Follicular lymphoma Primary cutaneous follicular lymphoma Mantle cell lymphoma 3
4 Follicular Lymphoma Follicular Lymphoma: definition Lymphoma of follicle centre B-cells (centrocytes/cleaved FCC and centroblasts/noncleaved FCC) which has at least a partially follicular growth pattern Follicular Lymphoma Morphology germinal centre cells CBs & CCs follicular Immunology surface Ig + CD19, 20, 22, 79a + BCL-2 + CD10 +/- Bcl-6 + CD5 - Genetics t(14;18) BCL-2 rearranged Clinical Adults; indolent CD20 CD3 CD10 Follicular hyperplasia vs Follicular Lymphoma Welldefined mantle Indistinct mantle t(14;18) BCL-2 Follicular hyperplasia vs Follicular Lymphoma Follicular Hyperplasia Heterogenous cytologi Homogeneous cytologi Zonation (polarity) Tingible body macrophages 4
5 Follicular Hyperplasia Small centrocytes (small cleaved) Large centroblasts (large non-cleaved) Follicular dendritic cells Tingible body macrophages Case årig kvinde Vægttab 10 kg indenfor 1 år Gennem 1 måned hastig voksende lymfeknude på hals 3 cm stor tumor basis linguae - biopteret Case 17-1 Case 17 -diagnoseforslag Case 17: CD20 Diagnoser: Mantlecelle lymfom 7 blastoid -1 DLBCL & high grade B 3 Ekstraossøst plasmacytom - 3 Diff. diagnose MCL, (evt. blastoid) PTL BL MCL DLBCL Maltom FL B-CLL / SLL HL Carcinoma Grey zone lymphoma 5
6 Case 17: CD5 Basic stains: CD5 Modulates T & B cell signalling Pan-T cell marker 95% thymocytes 100% post-thymic T-cells expression with maturity Minor population normal B-cells: ca. 10%+ peripheral B-cells in autoimmunity Lymphomas: 90% T-cell neoplasias B-cell NHL B-CLL B-cells dim reactive T-cells strong* B-CLL / SLL (90%) Mantle cell NHL (90%) 10%+ DLBCL CD5 dim CD5 in lymphoma Case 17: CD5 80% T cell lymphomas >95% SLL (CLL-like) NHL (strong) Minority of DLBCL Other B-cell NHLs negative >90% mantle cell lymphoma (weak) SLL CD5 CD5 dim Case 17: Ki-67 Basic stains: Cyclin D1 cyclin family control cell cycle normal proliferating cells, e.g. basal epidermal cells positive variable clone sensitivity Bcl-1 gene product at 11q13 upregulated in cells with t(11;14) >90% MCLs positive (nuclear) 15% myelomas positive (nuclear) Cyclin-D1 Mantle cell NHL: cyclin-d1 6
7 Case 17: Cyclin-D1 Case 17: supplementary CD23 neg Cyclin-D1 pos SOX11 pos Abnormal: 1Y 1G 1O Paraffin FISH: split at 11q13 (BCL-1; CCND1) Compatible with t(11;14) split Case 17: Diagnosis Mantle cell lymphoma Mantle Cell Lymphoma 1 Morphology small-medium lymphocytes irregular angled nuclei blastoid variant nodular or mantle-zone or diffuse Clinical adults (elderly males) LN, liver, spleen, Waldeyer s ring frequent spread to blood and bone marrow may be extra-nodal - lymphomatoid polyposis aggressive median survival 3-4 yrs CD5 Mantle Cell Lymphoma 2 Mantle Cell Lymphoma cyclin D1 Immunology surface Ig + CD5 + CD19, 20, 22, 79a + cyclin D1 + CD10 (blastoid) - CD23 - Genetics t(11;14) BCL-1 rearranged CD5 CD10 7
8 Mantle Cell Lymphoma Mantle Cell Lymphoma: Blastoid Variant Mantle Cell Lymphoma: Blastoid Variant Mantle Cell Lymphoma: Lymphomatous Polyposis Ki-67 Multiple polyps of varying size; can involve entire GI tract (stomach, small and large bowel) Mantle cell lymphoma: Lymphomatous polyposis MCL vs B-LB Favours MCL: coexpression of CD5 and B-cell Ag TdT - CyclinD1 pos SOX11 pos 8
9 WHO Classification of B-cell Neoplasms 2008 Mature B-cell neoplasms B-cell CLL/SLL B-cell prolymphocytic leukemia Splenic marginal zone B-cell lymphoma +/- villous lymphocytes/slvl Hairy cell leukemia Lymphoplasmacytic lymphoma Heavy chain disease Plasma cell myeloma Solitary plasmacytoma of bone Extraosseous plasmacytoma Extranodal marginal zone B-cell lymphoma (MALT type) Nodal marginal zone B-cell lymphoma Follicular lymphoma Primary cutaneous follicular lymphoma Mantle cell lymphoma Marginal Zone NHL MALT Extranodal sites: gastric, skin, ocular, lung, brest, thyroid May have history of Autoimmunity Helicobacter pylori Indolent local treatment Antibiotics Transformation Nodal marginal zone Primary splenic (villous lymphocytes) MALT Lymphoma: Primary Sites 20% - 50% of extranodal NHL GI only: 42% Stomach: 33% Helicobacter pylori Intestine: 9% Head/neck: 11% Skin: 10% Orbit: 10% Chlamydia psitacci Lung: 10% Thyroid: 4% Breast: 3% Multiple MALT: 11% (78% GI) Marginal Zone Lymphoma (MALToma) Morphology small centrocyte-like monocytoid B cells plasma cells Immunology surface Ig + CD19, 20, 22, 79a + CD5, 10, 23 - Genetics t(11;18) trisomy 3 Clinical extranodal & nodal indolent autoimmune disease gastritis: H.pylori trisomy 3 Helicobacter pylori Marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type: definition Normal MALT: Peyer s Patch extranodal lymphoma heterogeneous small B cells including in varying proportions marginal zone (centrocyte-like) cells monocytoid cells small lymphocytes scattered immunoblast- and centroblast-like cells plasma cell differentiation in 40% of the cases infiltrate in the marginal zone of reactive B-cell follicles and extends into the interfollicular region. 9
10 Gastric MALT Lymphoma Gastric MALT lymphoma: MZ B cells Gastic MALT lymphoma Gastric MALT Lymphoma: Lymphoepithelial lesions Basic immunoarchitecture CD79a positive lymphoma cells surround reactive follicles Gastric MALT Lymphoma: Lymphoepithelial lesions Gastric MALT Lymphoma: Lymphoepithelial lesions 10
11 Gastic MALT lymphoma Gastric MALT lymphoma: MZ B cells neoplastic B cells form lymphoepithelial lesions a marginal zone distribution is often seen when MALT lymphoma spreads to lymph nodes MALT lymphoma: Follicular colonization MALT lymphoma: Follicular colonization Marginal zone/malt type lymphoma: Grading MALTOMA use only for histologically low-grade lesion (mostly small cells) scattered large cells - still good prognosis - (no need to grade as for FL) Areas of diffuse large B-cell lymphoma - diagnose separately (similar to FL with DLBCL) Marginal zone B-cell lymphoma of MALT type Diffuse large B-cell lymphoma (estimate proportion of each) Not: high-grade MALT lymphoma Marginal zone/malt lymphoma: Immunophenotype Immunoglobulin + (M>G>A; D-); cig 40% B-cell antigens + (CD20, CD79a, CD19, CD22) CD 23 +/-, CD43 +/- CD5-, CD10-, Cyclin D1- HE CD21 Bcl-6 Bcl-2 11
12 Marginal zone/malt lymphoma: Genetics Cytogenetics Trisomy 3: 60% t(11;18)(q21;q21): 40% do not respond to H. pylori eradicaton t(1;14): rare Gastric MALT Lymphoma:Treatment H. Pylori infection in % Eradication of HP: regression in 50-90% of positive cases t(11;18) do not respond Differential diagnosis gastritis vs MALTOM Decide diagnosis before treating with HP therapy MALT lymphoma: Differential diagnosis Reactive lymphoid infiltrate e.g. follicular gastritis, thyroiditis, lymphoepithelial sialadenitis, follicular conjunctivitis Extrafollicular proliferation of marginal zone B cells Epithelial infiltration in stomach Look for Ig light chain restriction (surface, cytoplasmic) Consider PCR clonality studies Other small B-cell lymphomas Lymphoplasmacytic Distinguish on clinical features FL, MCL, CLL: immunophenotype usually diagnostic MALT vs Reactive Favours MALT: diffuse sheets CD20 + B-cells lymphoepithelial lesions cytological atypia Dutcher bodies CD43 + B-cells MALT vs B-Cell Lymphoma Marginal Zone B-cell Lymphoma: Lymph node Involvement MALT vs MCL CD5 - CyclinD1 - MALT vs FL CD10 - CD5 - Bcl-6-12
13 Splenic Marginal Zone Lymphoma vs Other B-Cell Lymphoma marginal zone component outer zone with blasts no mantle zone CD10 - CD5 - CD43 - CyclinD1 13
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