Angioimmunoblastic T-cell lymphoma (AITL) and other Follicular Helper cell (TFH)-related PTCL
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1 Impossibile visualizzare l'immagine. La memoria del computer potrebbe essere insufficiente per aprire l'immagine oppure l'immagine potrebbe essere danneggiata. Angioimmunoblastic T-cell lymphoma (AITL) and other Follicular Helper cell (TFH)-related PTCL Bologna April 27-29, 2015 Philippe Gaulard Département de Pathologie & Inserm U955 Hôpital Henri Mondor, Créteil, France Impossibile visualizzare l'immagine. La memoria del computer potrebbe essere insufficiente per aprire l'immagine oppure l'immagine potrebbe essere danneggiata. Riavviare il computer e aprire di nuovo il file. Se viene visualizzata di nuovo la x rossa, potrebbe essere necessario eliminare l'immagine e inserirla di nuovo. Impossibile visualizzare l'immagine. La memoria del computer potrebbe essere insufficiente per aprire l'immagine oppure l'immagine potrebbe essere danneggiata. Riavviare il computer e aprire di nuovo il file. Se viene visualizzata di nuovo la x rossa, potrebbe essere necessario eliminare l'immagine e inserirla di nuovo.
2 From angioimmunoblastic lymphadenopathy to angioimmunoblastic T-cell lymphoma! WHO classification(s) KIEL updated REAL 2015 :? revisit its defining criteria and its border 2012 : «specific» mutational landscape (TET2, IDH2, DNMT3, RHOA, : cell of origin of AITL = T FH cell : Angioimmunoblastic T-cell lymphoma - clonal cytogenetic abnormalities - clonal T-cell receptor (TCR) gene rearrangements 1979: atypical T cells -! «immunoblastic T-cell lymphoma» 1974: Description of «angioimmunoblastic lymphadenopathy with dysproteinemia»
3 Angioimmunoblastic T-cell lymphoma (AITL) : empiric therapies are not working! 5 periods studied «No survival differences over1me ( )..»
4 TFH
5 The main Th cell subsets STAT4 TBX T FH 21 T- bet T H 1 cell - > IFN- γ Intracellular bacteria STAT6 GATA3 T H 2 cell - > IL4, IL5, IL13 Helminths Naive CD4+ IL6 TGF- β STAT3 RORγ T H 17 cell - > IL17, IL21 Extracellular bacteria, fungi STAT3 Ascl2 BCL6 T FH cell - > IL21 B- cell help STAT5 FOXP3 T reg cell - >TGF- β, IL10 Regulatory funcbon
6 T FH cells: a unique T- cell subset ICOS Transcrip1on factors BCL6 MAF others Soluble factors IL21 CXCL13 Cell surface receptors CXCR5 ICOS PD1 CD40L " A specific function: interaction with B cells to provide help and allow antibody responses " A unique transcriptional profile " Express Bcl-6 and secrete IL-21 " CXCL13+, CXCR5 high, ICOS high, PD1 high, low levels of T-bet, Gata-3, Rorγt and FoxP3 " Plasticity : Heterogeneous T FH cell subsets Tangye SG et al, Nature Rev Immunol 2013
7 Criteria to postulate a T FH derivation in a given tumor Sensi1vity Specificity ICOS c-maf PD1 BCL6 CXCL13 CD10 " No single marker is 100% sensibve, or 100% specific " ICOS and PD1 are sensi1ve but less specific and CXCL13 and CD10 more specific but less sensi1ve " CD10 stains only a proporbon of tumor cells "!! Some are expressed by other subtypes of PTCL (incl ALCL- ICOS, PD1/CD10 MF/ SS) " A combina1on of several markers (at least 2 or 3?) to be recommanded (incl CD10)? Grogg et al 2005; Dupuis et al 2006; Grogg et al 2006; Dorfman et al 2006; Krenacs et al 2006; Roncador et al 2007; Ortonne et al 2007; Xerri et al 2008; Yu et al 2009; Rodriguez- Justo et al 2009; MarafioF et al 2009; Dorfman et al. 2011; Bisig B Histopathol 2011; AgosFnelli C et al. Histopathol 2011, AOygalle Histopathology 2014; Ame- Thomas et al. Blood 2015
8 T FH cells and human diseases Immune deficiencies (Primary, HIV) Autoimmune diseases (SLE, Sjogren s Sme, RA,..) Lymphoid neoplasms B- cell neoplasms /Hodgkin lymphoma Lymphomas derived from T FH cells
9 The cellular origin of AITL from follicular helper T cells (T FH ) CD5/CXCL13 ICOS PD1 de Leval et al. Blood, 2007 Bcl-6 CD10
10 AITL: the prototype of T FH -derived lymphoma 1. Described as a dysimmune non neoplasbc condibon 2. DisBncBve clinical features, with immunologic abnormalibes 3. Peculiar pathological aspects TFH Angioimmunoblastic T-cell lymphoma AITL PTCL-F Subset of CD4+ cutaneous T-cell lymphomas PTCL, NOS with TFH phenotype («TFH-like»)
11 The paradigm of AITL Pathological aspects of AITL CD4+ αβt cells (T FH ), often CD10+ B-blasts (often EBV+) CD10 FDC expansion CD20 EBER CD23
12 AITL: clinical & biological features Median age yrs Advanced stage (III/IV) % B symptoms % Polyadenopathy % Skin rash % Bulky mass 5 26 % Hyperγglobulinemia % Posi1ve Coombs test % Monoclonal gammopathy % Manifesta1ons of immune dysregula1on are typical of AITL, but not universal and therefore not mandatory for the diagnosis Reviewed in de Leval L et al, Br J Haematol 2010; Attygalle AD et al. Histopathology 2014; International T-cell Lymphoma Project, J Clin Oncol 2008; Parrens M et al. ASH proceedings 2012
13 Importance of the microenvironment in AITL Microenvironment (B- cells, FDC, macrophages, vessels, eosinophils, mast cells ) ( ) Neoplas1c T FH cells Variable morphology: wide spectrum+++ Clinical presenta1on/outcome? ( ) CriBcal in sustaining tumor cells (no cell lines) ( ) May vary over Bme in a single case and from case to case
14 Microenvironment in AITL may have a prognostic impact " M2 macrophages, Th17/mast cells, VEGF expression or vascular density, plasma EBV DNA (B Cells) related with prognosis (Niino et al. Pathol Intern 2010; Tripodo. Am J Pathol 2012; Zhao et al. Lab Invest 2004; Ganjoo et al. Leuk Lymphoma 2014; Au et al. Blood 2014) " Molecular prognosticator in AITL Iqbal et al. Blood 2010 Iqbal et al. Blood 2014
15 Plasma cells, Plasmocytosis Ig Y Y Y Y Y Y (EBV+) LPD/ DLBCL + Th17 IL21 - Th1 IL10 TGF-β Treg - Immune deregulation, altered immune surveillance PC B CD40-CD40L ICOSL-ICOS T FH PTCL, NOS TFH-like IL5 IL6 MC CXCL13 LT-β LT-β VEGF Angio poietin TARC Eo FDC HEV MAC Gaulard P, de Leval L, Semin Cancer Biology 2014
16 Spectrum of B- cell prolifera1ons is broad in AITL 1. From scacered to increased B blasts to DLBCL like 2. HRS- like cells may be seen; should not be misdiagnosed as chl or composite! 3. EBV posibve (more oeen) or EBV negabve 4. Plasma cell proliferabon (monotypic or not) 5. Up to one third of AITL show clonal B- cell populabon : clonality analysis may be misleading! 6. Mechanisms: - favoured by T FH help and decreased immune surveillance - Hypermutated Ig genes with destrucbve mutabons CD20/EBER LMP1 Brauninger J Exp Med 2001; Lome-Maldonado Leukemia 2002; Willenbrock BJH 2007; Attygalle AJSP 2007; Nicolae AJSP 2013; Attygalle Histopathology 2014
17 MH Delfau-Larue et al. Haematologica 2012
18 Oncogenic pathways?? 1. No recurrent translocabon 2. Gains and losses 3. No «true» mouse model (SANROQUE, cmaf) TFH??? Angioimmunoblastic T-cell lymphoma AITL? PTCL-F Subset of CD4+ cutaneous T-cell lymphomas PTCL, NOS with TFH phenotype («TFH-like»)
19 Recurrent RHOA muta1ons discovered by NGS Inac1ve GAP GDP RHOA RHOA GEF Loss of func1on Dominant nega1ve G17V RHOA GTP Ac1ve acbn cytoskeleton, cell polarizabon transcripbon by SRF Up to 70% AITLs and a subset of PTCL, NOS with T FH like features Absent in myeloid, confined to tumor cells RHOA G17V in most cases, associa1on with TET2 muta1ons Inducibly expressed G17V RHOA does not affect the growth or cell cycle progression in Jurkat cells Could also act as a TSG in ATLL (Sakata- Yanagimoto, 2014 EHA meefng), gastric carcinoma (Wang, Nat Genet 2014, Kakiuchi, Nat Genet 2014)) and Burkic lymphoma (Rhode, GCC, 2014) Palomero et al, Sakata-Yanagimoto et al, Yoo H-Y et al Nat Genetics 2014; L de Leval & P Gaulard, unpublished [RHOA mut: AITL (65%, n=76); PTCL, TFH-like (46%, n=13)]
20 TET2, DNMT3A & IDH2 are involved in DNA methylation In AITL, the 3 muta1ons are commonly associated Adapted from Shih et al. Nat Rev Can.2012
21 A peculiar model of lymphomagenesis. 2 nd hit AML Sakata-Yanagimoto et al. Nat Genetics 2014 TET2 HSC Proliferative advantage M M M M CTCF FLT3 SRSF2 RAS JAK2 ASXL1 CMM L MF ICOS//IDH2 Lemonnier, Dupuy et al. unpublished DNMT3A L L Quivoron, Couronné et al. Cancer Cell 2011 Sakata-Yanagimoto et al. Nat Genetics 2014 LyT T FH? RHOA IDH2 Others.. AITL PTCL, NOS T FH
22 PTCL,NOS or AITL «tumour-cell rich? A patient with a past history of AITL CD23
23 Revisit the diagnostic criteria of AITL? AITL" PTCL,NOS, TFH-like" Loss of the microenvironment ( inflammatory component, vascularity, FDC) Enrichment in large neoplastic cells
24 Nodular growth pattern small/medium sized T cells CD4+, CD10+ Expression of T FH markers (BCL6, CXCL13, PD1, ICOS), CD57+ Follicular PTCL t(5;9) translocation (SYK-ITK fusion) in 20-30% of cases TET2 mutations Relationship to AITL? # 23: t(5;9) positive CD3 de Leval L et al. AJSP 2001; Streubel B et al. Leukemia 2006; Bacon C et al. Br J Haematol 2008; Qubaja M et al. Human Pathol 2008; Huang L et al. AJSP 2009
25 Courtesy: Louise Galmiche-Rolland
26 Nodal T FH -related PTCL Future evolutions of the WHO classification AITL PTCL, Follicular classical Variants - epitheliod - pacerns 1/2/3 - tumor- cell rich PTCL, NOS T FH Phenotype " Despite a different morphology, share a similar TFH profile, likely similar genebc alterabons and GEP " RecommandaBon: extensively invesbgate any case of «PTCL, NOS» for FDC, CD10, T FH markers, EBV.. " In the next future, may influence the clinical management & therapy
27 Nodal T FH -related PTCL : implications for therapy? - Microenvironment: anti-angiogenic (thalidomide, anti-vegf/bevacizumab), macrophages?, B-blasts (Rituximab), - Immunomodulatory compounds: IFNγ, cyclosporine, lenalinomide,.. - Neoplastic T FH antigens (campath, TFH antigens, cytokines (IL21, IL6), chemokines (CXCL13) - Specific pathways (PDGFRA, SYK, IDH2 inhibitors, demethylating agents ) PD1 CTLA-4 BCL-6 TFH cell CD200 ICOS Pathologically and biologically-oriented clinical trials..
28 The lymphoma classification will continue to evolve! 2014 WHO CAC Meeting, Chicago
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