Peripheral T-cell lymphomas
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1 XXXVI REUNIÓN ANUAL Peripheral T-cell lymphomas Dr. Antonio Martinez Hospital Clinic, University ofbarcelona Madrid, February 8th, 2013
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3 T-NHL vs B-NHL: the T-cell paradigm lambda -> Clonality TCR gene rearrangemnt light chain expression Incidence B > T Phenotype Loss of T-cell antigens B specific (CLL, FL, MCL) Presence of neoplastic non T- cell lineage Morphology Large cells (aggressive B-NHL, indolent ALCL) Small cells (indolent B-NHL, aggressive HSTCL) Tumor cells sparse within reactive infiltrate kappa ->
4 T-NHL vs B-NHL: the T-cell paradigm Extranodal disease T > B Location is important in clinical syndrome Prognosis B tends to be better, except for Anaplastic large cell Clinical behaviour Facial/Sinus Syndrome Systemic Illness with organ infiltration Hemophagocytosis Hypergammaglobulinemia Celiac disease Treatment
5 T-cell complexity and plasticity from Nature Review Immunology
6 Cluster analysis Principal Component Analysis AITCL PTCL, NOS ALCL ALK+ T-LBL 7 PCTCL ALCL ALK+, T-LBL and PCTCL, NOS present with a specific identity AITCL and PTCL, NOS show overlapping features A limited number of cytokines reproduce results of previous GEP studies Solidini, EAHP Lisbon 2012
7 Role of cytokine expression in defining T-cell and TCL In TCL, neoplastic T-cells, as their normal counterpart, secrete cytokines which can induce systemic symptoms (fever, rash, haemophagocytic syndrome) Cytokines are responsible for the heterogeneity of the cellular infiltrates. Weisenburger et al. Blood 2011;117(12):
8 T-CELL LYMPHOMA EDPIDEMIOLOGY Fig 1. Distribution of 1,314 cases by consensus diagnosis International T-Cell Lymphoma Project, J Clin Oncol; 26: Copyright American Society of Clinical Oncology
9 T-CELL LYMPHOMA EDPIDEMIOLOGY 1,320 cases, 22 institutions International T-Cell Lymphoma Project, J Clin Oncol; 26: Copyright American Society of Clinical Oncology
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11 LYMPHOMA HL B-NHL T-NHL
12 NORMAL LYMPHOCYTE DEVELOPMENT B-CELL FOLLICLE THYMUS
13 T-MALT
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15 Malignant IEL transformation in Celiac Disease Immunological Reviews 2006 (1),
16 Enteropathy Associated T-cell Lymphoma (EATL) Broad morphological spectrum Adjacent mucosa shows villous atrophy CD3+, CD103+, Cytotoxic markers, TCR often double negative for CD4/CD8, CD56 +/- Often presents with intestinal perforation aggressive clinical course with poor prognosis Evidence of celiac disease clinically, genetically
17 Enteropathy Associated T-cell Lymphoma (EATL) Type 2 24 cases of EATL type 2 Adjacent mucosa shows villous atrophy and Increased IELs Medium sized cells with clear cytoplasm CD56 +, CD8+, CD4- Occur sporadically, without celiac disease (Asian cases) All EBV negative 17 (70%) TCR γδ 6 (25%) TCRαβ 4 TCR silent,3 TCR double 1. Garcia-Herrera, AJSP Chang, AJSP 2011
18 EBV-driven T/NK cell LPD T/NK nasal and nasal type Aggressive NK cell leukemia/lymphoma Systemic LPD of childhood HSTCL T-cell PTLPD PTCL, NOS
19 EBV+ Systemic LPD CD3 CD8 EBER+CD8 EBER
20 REACTIVE LYMPHOID HYPERPLASIA/ PSEUDOLINFOMA? PCSM-TCL PTCL, NOS
21 ALK-positive anaplastic large cell lymphoma following insect bites: evidence for an association in five cases Haematologica March; 95(3):
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24 CD30 EMA TIA 1
25 SEROMA ASSOCIATED ALK Negative ALCL Adapted from Thompson Haematologica 2010 and Jaffe Lisbon 2012
26 WHO 2008 Classification T/NK-cell neoplasms T-cell prolymphocytic leukaemia T-cell large granular lymphocytic leukaemia Aggressive NK cell leukaemia Hepatosplenic T-cell lymphoma Chronic lymphoproliferative disorder of NK cells Sézary syndrome Perpipheral T-cell lymphoma, NOS Angioimmunoblastic T-cell lymphoma Adult T-cell leukemia/lymphoma (HTLV1+) Anaplastic large cell lymphoma ALK+ Anaplastic large cell lymphoma ALK- Extranodal NK/T-cell lymphoma, nasal type Enteropathy-associated T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma EBV positive T-cell lymphoproliferative diseases of childhood LEUKAEMIC / BM INVOLVEMENT NODAL EXTRA-NODAL Mycosis fungoides Primary cutaneous CD30+ T-cell lymphoproliferative disorders Primary cutaneous peripheral T-cell lymphomas, rare subtypes: Primary cutaneous γδ T-cell lymphomas Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma Primary cutaneous CD4+ small/medium T-cell lymphoma CUTANEOUS
27 Adapted from P Gaulard, Lisbon 2012 T-NHL Diagnosis Following Morphology and Primary Presentation BLASTIC MONOMORPHIC MEDIASTINUM CERVICAL LN LEUKEMIC T-LBL Tdt, CD1a, CD10, +/-34 MATURE NODAL PLEOMORPHIC CUTANEOUS NON NODAL NON CUTANEOUS
28 T-NHL Diagnosis NODAL Adapted from P Gaulard, Lisbon 2012 Polymorphic HEV TFH, FDC, EBV, B-cell/plasma cells AITL LARGE CELLS SINUSOIDAL INFILTRATION CD30+ EXCLUSION OF ANYTHING ELSE MATURE PLEOMORPHIC ALK1 + ALCL, ALK+ - ALCL, ALK- PTCL, NOS
29 ANGIOIMMUNOBLASTIC-TCL TFH phenotype CD10, BCL6, PD1,CD57, ICOS, CXCL13+ CD23 Lymph nodes, bone marrow and skin (rash) Systemic disease other sites of involvement, including liver, spleen and lung. Polyclonal hypergammaglobulinemia and Coombs-positive hemolytic anemia; intercurrent infections Median survival is less than 3 years. 50%-97% of cases by in situ hybridization; EBER + B cells
30 EBER PD1 CD10
31 AILT as TFH-related T-cell neoplasm PD1 FOLLICULAR T-CELL LYMPHOMA PERIFOLLICULAR T-CELL LYMPHOMA ANGIOIMMUNOBLASTIC TCL Vinuesa C et al. Nat Rev Immunol 2005
32 T-NHL NODAL Adapted from P Gaulard, Lisbon 2012 NAIVE CD8 AG CD4 CD4 CD8 EFFECTOR MEMORY CD8 ACTIVATED CD4 EFFECTOR MEMORY TFH ALK1 t(6;7) TP53 Syk-Itk Tet2/IDH2 ALCL, ALK+ ALCL, ALK- PTCL, NOS T-FL AITL
33 ALCL, ALK % of pediatric lymphomas Male predominance B-symptoms Nodal and extranodal presentation Mediastinum (30%) Skin (30%) Bone Marrow (10%) Lung, CNS, Soft Tissues Leukemic phase ( small cell variant )
34 Results: cytokine expression in ALCL ALK+ vs. ALK- ALCL ALK+ vs. ALK- Cytokine Fold change (LogRatio) P-values NAP-2/CXCL BMP Siglec E-04 PDGF-BB E-04 IL IGFBP b-ngf E-04 bfgf/fgf2 1, E-04 ENA-78/CXCL E Lamant et al., Blood 2007,109 (5): Agnelli et al., Blood 2012, 120(6): Soldini et al, Lisbon 2012 Agnelli et al., Blood 2012, 120(6):
35 ALCL, ALK+
36 ALCL : Morphological Variants Benarroch et al Blood 1998; 91:
37 ALK Staining Patterns and Cytogenetic Alterations t(2;5) NPM--ALK t(2;3), inv(2) TFG-ALK; ATIC-ALK t(2;19) CLTC--ALK t(x;2) MSN--ALK t(1;2) TPM3--ALK
38 Adapted from P Gaulard, Lisbon 2012 EBER T-NHL Diagnosis NON-NODAL NON-CUTANEOUS + SITE NASAL /EXTRANASAL CD5-/CD56+ TIA1/GRZbp/PF+ SPLEEN, BM, LIVER SINUSOIDAL CD5-CD56+ NK/T NASAL-TYPE NK LEUKEMIA MATURE PLEOMORPHIC - INTESTINAL EATL SITE CD4/CD8 Type 1 or 2 CD56 GRB+ SPLEEN, BM, LIVER SINUSOIDAL CD5-CD56+ HSTL
39 Hepatosplenic T-cell lymphoma Children and young adults Males >> Females Immature cytotoxic T-cell ( ) Systemic disease Liver, Spleen, BM Aggressive course BM SPL
40 Hepatosplenic T-cell lymphoma (WHO 2008) Rare (<1% of all non-hodgkin lymphomas) Male predominance (median 35 years) Chronic immune suppression (20%) Crohn s disease treated with azathioprine and infliximab HSTCL usually lack EBV genomes
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42 Tcr Beta Tcr Delta Tcr TIA Delta Tcr Gamma
43 Bone Marrow cytogenetics
44 T-NHL Diagnosis CUTANEOUS CD30 MATURE + - PLEOMORPHIC PCCD30 T-LPD CYTOTOXIC - ERITHRODERMIC LEUKEMIC - + LOCALIZED LESIONS, SHEETS CD30+ MULTIPLE PAPULONECROTIC SPONTANEOUS REGRESSION CD30 + INTERMINGLED EPIDERMOTROPIC PANNICULITIC BOTH LOGNSTANDING HISTORY PATCH PLAQUES + ALCL LYP CD8 AGG PANNICULITIC αβ PCγδTCL MF - CD4 SMALL/MEDIUM SS Adapted from P Gaulard, Lisbon 2012
45 Primary cutaneous CD30+ T-cell lymphoproliferative disorders 30/3/ /4/2009 Primary cutaneous anaplastic large cell lymphoma Lymphomatoid papulosis
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47 CD 3 CD 30 ALK
48 Provisional entities Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma Primary cutaneous CD4-positive small/medium T-cell lymphoma Diagnosis of mycosis fungoides must be ruled out by: complete clinical examinatation and an accurate clinical history
49 Primary cutaneous CD4-positive small/medium T cell lymphoma A B A B A B C D C D C D E F E F E F G H G H G I J Clin Oncol. 2008; 26:
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51
52 CD20 CD3 CD5 CD7
53 LEISHMANIA
54 Hematopathology Unit Elias Campo Davide Soldini Dolors Costa Antoni Martinez Anna Carrio Josep Lluís Aguilar Marta Aymerich Dolors Colomer Neus Villamor Maria Rozman Lluís Colomo Adriana Garcia Eva Giné Armando López Guillermo Jordi Esteve Gonzalo Gutiérrez Hematology
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