Pathology of the indolent B-cell lymphomas Elias Campo
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1 Pathology of the indolent B-cell lymphomas Elias Campo Hospital Clinic, University of Barcelona
2 Small B-cell lymphomas Antigen selection NAIVE -B LYMPHOCYTE MEMORY B-CELL MCL FL LPL MZL CLL Small cell size Low proliferation Homing growth patterns Immunomodulation by microenvironment Indolent clinical behavior
3 Heterogeneity of Small B-cell Lymphomas CLL FL FL MCL MCL MCL CLL Median: 10 years FL Median: 9 years p 1 0,75 0,5 MCL Median: 3-5 years 0,
4 Lymphoid Cell Circulation and Lymphoid Tissue Compartment Key elements in Small B-cell lymphomas CLL LPL MCL FL MZL
5 Transformation in Small B-Cell Lymphomas Microenvironment B cell Primary Genetic Events Small B-cell neoplasms Transforming Genetic Events DLBC Genetic alterations
6 Chronic lymphocytic leukaemia CD43 CD5 CD19 Presence of 5 x 10 9 /L monoclonal lymphocytes with the CLL phenotype CD23 CD20 w IgS w CD22 w CD79b w SLL is the same disease but restricted to tissues without evidence of leukemic involvement
7 Disease progression in CLL DLBCL Richter syndrome MBL Clonal B-cell selection and expansion CLL Progressed Refractory CLL MBL? DLBCL: diffuse large B-cell lymphoma; MBL: monoclonal B-cell lymphocytosis
8 Patients surviving (%) Patients surviving (%) Chronic lymphocytic leukaemia Clinical impact of molecular and genetic subtypes Mutated IGHV 1 del(17p) and del(11q) 2 Mutated IGHV Unmutated IGHV 17p deletion 12q trisomy 11q deletion Normal 100 p< q deletion as sole abnormality Months Months 1. Zenz T, et al. Nat Rev Cancer 2010; 10: Döhner H, et al. N Engl J Med 2000; 343:
9 Chemorefractoriness (%) del(17p)/tp53 mutations significantly reduce time to chemotherapy-refractory disease TP53 mutation del(17p) Median 6.3 months p< Median 21.4 months p= Median 72.7 months 60 Median 66.3 months TP53 mutations 20 del17p13 0 No TP53 mutations No del17p Time (months) Time (months) Consecutive series of 308 patients with previously untreated CLL Rossi D, et al. Clin Cancer Res 2009; 15:
10 Follicular Lymphoma Usually follicles of similar size/shape but some variation may occur Cytologically monotonous with cleaved nuclei and no tingible body macrophages Polarization of normal follicles absent CD20 CD3 CD10 Bcl-2
11 WHO classification: Grading in FL Grade Centroblasts/high power field Characteristics A >15 Centroblasts with intermingled centrocytes 3B >15 Pure sheets of blasts Grade 1 Grade 2 Grade 3a Grade 3b WHO: World Health Organization
12 Diffuse component in FL
13 Follicular Lymphoma: A single disease? FL subtypes Follicular lymphoma, pediatric type Primary duodenal follicular lymphoma Primary cutaneous follicular centre lymphoma Diffuse variant of follicular lymphoma Follicular lymphoma negative for the t(14;18) Xerri L et al Virchows Arch. 2016;468: Quintanilla-Martinez L et al V irchows Arch. 2016;468:141-57
14 Different subtypes of t(14;18) negative FL FL with conventional morphology 1 30% BCL2 protein positive Lower GC expression signature (CD10 negative) Higher proliferation No clinical impact Diffuse variant of FL 2 Large nodal tumors in inguinal region Localized disease CD10, BCL2, BCL6, CD23 positive Del 1p36 1 Leich et al. Blood 2009;114: Katzeberger T et al Blood 2009;113:
15 Extra Nodal MZL: Morphology
16 Extra Nodal MZL: Etiological Factors Chronic Inflammatory Response Stomach H pylori Ocular Chlamydia Psittaci Salivary Gland Sjogren s Thyroid Hashimoto s Skin Borrelia Other? HCV? Genetic and enviromental background Polymorphisms Thymic MZL Asians
17 Nodal Marginal Zone Lymphoma NMZL resembles extranodal or splenic MZL but is only localized in lymph nodes Adults median age 60, M=F Need to rule out extranodal site Hepatitis C virus? Tri 3, 18, 7 Mutations in KLF2, NOTCH2, PTPRD 50-60% have 5 year survival
18 Lymphoplasmacytic Lymphoma MYD88 L265P 95% WM/LPL 29% DLBCL-ABC 6% MZL 3% CLL CXCR % WM/LPL Associated with MYD88 More active disease Less lymphadenopathy More resistant disease to new drugs BTK Patients treated with Ibrutininb Mutations before clinical progression Useful information in the differential diagnosis of LPL Need to be interpreted in the global context of the disease Tiacci et al NEJM 2011; Ngo Nature 2011; Puente Nature 2011; Xi L et al Blood 2012; Schmidt et al Br J Haematol 2015; Cao et al Leukemia, , ; Xu L et al Blood 2017
19 Mantle Cell Lymphoma Cyclin D1 Probability Years Complete Response 25% (6-50%) 14 der(14) 11 der(11) Duration of CR 1.5 yrs ( yrs) IGH/CCND1 Median Survival 3-4 years
20 Mantle cell lymphoma CCND1-negative variant CCND2 trans 55% Classic MCL Cyclin D1 CCND1 neg MCL Cyclin D1 Sox11 Mozos et al Haematologica 2009 Salaverria et al Blood 2013
21 Mantle cell lymphoma Indolent Variants Clinical concept with different pathological conditions In situ MC neoplasia, Mantle zone pattern, low proliferation index (SOX11+ or SO11-) In situ MC neoplasia Mantle Zone MCL Low proliferation Leukemic non-nodal subtype of MCL Non-nodal leukemic (splenomegaly) disease SOX11-negative Hypermutated IGHV Simple karyotypes May transform into blastoid MCL (TP53 mut) Ki67 Swerdlow S et al Blood ;127(: Richard et al J Clin Pathol 2006; Jares P et al J Clin Invest 2013
22 Molecular Pathogenesis and Clinical Subtypes of MCL Sox11- Non-nodal, leukemic and splenic MCL TLR2 Blastoid MCL Pre B-Cell In situ MCL lesion Genetically stable t(11;14) Naïve B-cell Hyperrmutated IG TP53 Inactivation SOX11- Cyclin D1 Neg Sox11+ Unmutated/Minimally Mutated IG Classic MCL Blastoid MCL Fernandez V et al Cancer Res 2010 Jares P et al J Clin Invest 2013 Genomic Instability, Proliferation, and cell survival ATM, NOTCH1/2 WHSC1, MLL2, MEF2B
23 Small B-cell Lymphomas A heterogeneous group of lymphoid neoplasms with different clinico-pathological characteristics Increasing recognition of early or in situ lesions (Multi-step pathogenesis in NHL) Specific variants in each disease with particular clinical and pathologic characteristics
Chronic Lymphocytic Leukemia Mantle Cell Lymphoma Elias Campo
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