Low-grade B-cell lymphoma
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1 Low-grade B-cell lymphoma Patho-Basic 11. September 2018 Stephan Dirnhofer Pathology
2 Outline Definition LPL, MBL/CLL/SLL, MCL FL Subtypes & variants Diagnosis including Grading Transformation Summary
3 Be aware - in Lymphoma aggressive vs indolent high grade versus low grade large cell versus small cell does not mean the same!
4 Definition No grading in lymphoma Exception: Follicular Lymphoma (FL) «low grade lymphoma» does not exist synonymous with «cytic» or «small cell», but cave: MCL, etc Clinical approach: «indolent» vs «aggressive» Pathological approach: «small lymphoid B-cell neoplams» «High-grade B-cell lymphoma»: specific category in WHO2017 NOS DH/TH
5 Lymphoplasmacytic lymphoma (LPL)/WM MYD88 L265P in >95% LPL MGUS, IgM in 50-80% 2012 PCM, MGUS, IgA & IgG negative Very rare in other SBCL (<5%) DLBCL: 10-30%, adverse prognosis Predictive biomarker Ibrutinib sensitive
6 SLL/CLL: diffuse/pseudofollicular
7 SLL/CLL: Phenotype CD20 CD23 CD3 CD5
8 Monoclonal B cell lymphocytosis (MBL) Definition Monoclonal PB lymphocyte populations up to 5x10 9 /L either with the phenotype of CLL, atypical CLL (CD5+, bright CD20, some include CD23-) or non-cll (CD5-) in the absence of lymphomatous features. MBL population has to be present for at least 3 months MBL, CLL type Distinguish low count (<0.5) from high count MBL MBL, non CLL type Related to (splenic) marginal zone lymphoma Xochelli, Blood, 2014 Bruscaggin, BJH, 2014 WHO, 2017
9 MBL, CLL-type and CLL Same phenotype Similar genotype Distinguish low count (<0.5) from high count MBL low count MBL : limited, if any, risk of progression high count MBL: routine (yearly) follow up Eliminate CLL Dx if < 5x10 9 /L & cytopenia without extramedullary disease Giné, Haematologica, 2010 Bullan, JCO 2014
10 Mantle cell lymphoma (MCL): diffuse/nodular
11 MCL: Phenotype/Genotype CD3 CD20 CD5 Cyclin-D1
12 Mantle cell lymphoma (MCL) In situ mantle cell neoplasia (ISMCN) Formerly: In situ MCL, MCLis Rare (frequency <1%) Low rate of progression Avoid calling these lymphoma Require clinical assessment Not systematically diagnosed Leukemic non-nodal MCL (15%) PB, BM & spleen Adam et al. Mod Pathol 2012 No adenopathy SOX11 -, IgH mutated Clinically indolent (may transform to aggressive disease) MCL, classical-type Lymph nodes & extranodal sites SOX11 +, IgH unmutated
13 Follicular lymphoma: Definition A lymphoma of germinal center B-cells (centrocytes & centroblasts) with at least a partially follicular pattern
14 FL - major features Most common lymphoma worldwide (30%) Median age yrs; male = female Generalized lymphadenopathy, Splenomegaly, BM Indolent clinical course, but: transformation & progression Follicular with diffuse areas Centroblast & centrocytes; FDC, reactive T-cells Grade 1 & 2 (low grade), 3A&B (high grade) Phenotype: CD19, CD20; CD10, BCL6, HGAL, LMO2; BCL2 Genotype: IgH rearranged, t(14;18) and IgH/BCL2
15 Phenotype of FL B-cell markers: CD19, CD20, PAX5, CD79A GC-markers: BCL6, CD10, Stathmin, HGAL, GCET1, LMO2 Appl Immunhistochem Mol Morphol 2015
16 Genotype of FL Clonal IgH rearrangement Somatic hypermutation in variable regions (ongoing) Intraclonal variation t14;18 (IgH/BCL2): 90% (ambiguous protein expression) BCL6 rearranged: 15% MYC rearranged: rare (2-4%) Recurrent mutations: KMT2D, CREBBP, EZH2, BCL2 Leich et al. Leukemia 2016 Miao et al. Human Pathol 2017
17
18 FL variants & related lymphomas In situ follicular neoplasia (ISFN) Duodenal-type FL Diffuse-appearing FL with del1p36 Extranodal FL Pediatric-type FL
19 In situ follicular neoplasia (ISFN) Formerly: in-situ Follicular lymphoma, FLis Indolent clonal population High frequency (2-3% of patients ) Low rate of progression Avoid calling these lymphoma Require clinical assessment Not systematically diagnosed Am J Surg Pathol 2016 Xerri, Dirnhofer et al. Virchow, 2016
20 Duodenal-type FL Variant of FL Different from generic GI-tract FL Low grade (G1) BCL2 positive (t14;18 positive) Excellent prognosis Avoid overtreatment Watch-and-wait strategy? Schmatz et al., JCO 2011
21 Pediatric-type FL Pediatric FL a provisional entity in 2008 monograph Promoted to definite entity Name change & refined criteria Can occur in (young) adults Large expansile follicles, Grade 3, high Ki-67 BCL2 negative (t14;18 negative) Head & neck Excellent prognosis (only excision) DD: FL, Grade 3, conventional type Quintanilla-Martinez et al. Virchow,
22 Different subtypes of t(14;18) negative FL FL with conventional morphology 50-70% express BCL2, often CD10 negative No clinical impact Diffuse variant of FL with deletion 1p36 Grade 1 2 Large nodal mass in inguinal region, localized Deletion 1p36 Good prognosis Primary extranodal FL Cutaneous Pediatric-type FL Promoted to definite entity LBCL with IRF4-rearrangement Provisional entity Leich et al. Blood 2009 Leich et al. Leukemia 2016 Katzenberger et al. Blood 2009 Höller et al. Human Pathol 2012
23 Grading of FL Jaffe E., Hematopatholoy 2017 WHO 2017 An excisional biopsy is recommended for primary diagnosis.
24 Grading of FL FL I FL II FL IIIa FL IIIb DLBCL
25 Survival of patients with FL according to histological grade Weisenburger et al. 2006; from: Jaffe et al, Hematopathology 2017
26 Transformation Occurs in many types of small B-cell lymphomas Most common in FL (2-3% per yr) Broad morphologic spectrum Mechanisms of transformation (in FL) Divergent evolution from common progenitor cell (CPC) Linear evolution High-level CNA Recurrent mutations in TP53, MYC, CDKN2A, B2M Okosun et al, Nat Gen 2014 Schmidt et al, Leukemia 2014 Brunner et al, Leukemia 2014 Wagner-Johnston et al, Blood 2015 Casulo et al, Blood 2015 Agbay et al, Am J Surg Pathol 2016 Bouska et al, Leukemia 2017 Kridel et al, PLOS Medicine 2017 Kridel et al, Blood 2017 from: Pasqualucci et al, Cell 2014
27 tfl: Histotypes DLBCL, incl. DLBCL CD30+ HGBCL, NOS (former BCL,u) HGBCL with double-hit (BCL2/MYC) Lymphoblastic Lymphoma (TdT+; CD34+) chl Histiocytic Sarcoma DD: true composite lymphoma 2016
28 Thank you!
29 The Pathobiology of FL - Summary Most common B-cell lymphoma Clinicopathological variants in updated WHO-classification Advanced stage, indolent course Grade 1 & 2; 3A & 3B Grading is mandatory (and prognostic), cave CNB Recurrent genetic alteration t14;18 (BCL/IgH) in 85% No clinical difference of t14;18-negative cases Transformation common (2-3%/yr) tfl: DLBCL, HGBCL-DH/TH, HGBCL-NOS, PBL, chl, HS
30 Am J Surg Pathol 2005
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