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LNH Cosa occorre sapere Classificazione REAL con tipo di aggressività clinica per ogni forma Cellula dorigine B T Livello maturativo della cellula dorigine.

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Presentazione sul tema: "LNH Cosa occorre sapere Classificazione REAL con tipo di aggressività clinica per ogni forma Cellula dorigine B T Livello maturativo della cellula dorigine."— Transcript della presentazione:

1 LNH Cosa occorre sapere Classificazione REAL con tipo di aggressività clinica per ogni forma Cellula dorigine B T Livello maturativo della cellula dorigine (se noto) EziopatogenesiFattori eziologici Fattori predisponenti Modello EBV e linfoma di B Burkitt, linfoma MALT Patogenesi citogenetico- molecolare Stadiazione Quadri di presentazione e concetti di terapia Principali danni genetici Ann Arbor Relazione coi principali istotipi

2 Quadro di presentazione generale Linfoadenopatie in 2/3 dei casi 1.Adenopatia persistente (> 1 cm per >4 settimane) 2.Non dolente 3.Andamento del volume delle adenopatie fluttuante nelle forme indolenti Da differenziare 1.Adenopatie infettive 2.(Batteri, Mononucleosi CMV, HIV,Toxoplasmosi, Istoplasmosi) 3.Sarcoidosi (mediastino) 4.Adenopatie metastatiche Sintomi correlati a linfoadenopatie Mediastino Addome Extranodali 1.Tosse persistente 2.Senso di fastidio retrosternale 3.Sindrome medistinica 4.Senso di gonfiore, dolore, 5.Splenomegalia 6.Linfedema 7.SNC, midollo spinale 8.Gastrico 9.Orbita 10.ossa 11.Testicolo 12.cute Sintomi sistemici20% circa dei casiSoprattautto negli alti gradi e negli stadi avanzati

3 Schematic representation of the lymph node structure CELL ORIGIN AND HISTOLOGICAL TYPES OF NHL

4 Section of a normal hyperplastic lymph node

5 Follicular lymphoma: neoplastic follicles of uniform shape efface the LN architecture Both centrocytes and centroblasts are present (right) Follicular lymphoma Cell of origin: centrobasts/centrocytes in the follicole centre which have encountered the Ag Immunophenotype: sIgM>IgG+ sIgD+; cyIg+/-; CD19+; CD5-; CD10+/-; CD43-

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7 The t(14;18) which is the hallmark of FL leads to the overexpression of BCL2 within the neoplastic follicle (left). Reactive germinal centres are BCL2 negative (right)

8 The lymph node architecture is replaced by centrocyte-like cells Residual germinal centre cells (arrow) Cyclin D1 overxpression by Neoplastic cells and not by GC cells Mantle cell lymphoma: Cell of origin: B-lymph in the follicle mantle which did not encounter the Ag Immunophenotype: CD19+; CD5+; sIgM>D+CD10-/+; CD23-; CD43+

9 Marginal zone Lymphoma Small lymphocytic lymphoma Cell origin of B-lymphoid neoplasia B-precursor cell Naive B-cell (no Ag) Germinal centre Diffuse large B cell lymphoma Mantle cell Lymphoma Multiple myeloma Plasma cell Lymphoplasmacytic lymphoma Pre-plasma cell Lymphoblastic NHL Pre-germinal centre (no IGVH mutation) Burkitts lymphoma Memory B-cell Bone marrow blood LYMPH NODE (post)-germinal centre (IGVH mutation) Mantle zone Marginal zone Follicular lymphoma

10 Angiocentric NHL Intestinal NHL Angiocentric NHL Intestinal NHL Cell origin of T-lymphoid neoplasia T-ALL BM T-precursor cell THYMUS Peripheral blood ALCL PTCL ALCL PTCL Mycosis fungoides Sezarys syndrome Mycosis fungoides Sezarys syndrome skin T-cell CLL/PLL CD4+ lymphocytes CD8+ lymphocytes LGL expansion Mucosae Bowel Germinal centre Hepato-splenic γδ NHL Hepato-splenic γδ NHL Lymph node Spleen liver AITL Follicular helper T-cells

11 Trends in incidence of hematopoietic neoplasms by broad subtype category, 9 SEER registries, to * All incidence rates are age adjusted to the 2000 United States population and presented for 12 fixed 2-year time periods ( to ). Lymphoid neoplasms excepting Hodgkin lymphoma and plasma-cell neoplasms. Predominantly myeloid leukemia. Predominantly multiple myeloma. NHL Non lymphoid Hemopoietic tumors Myeloma Hodgkins lymphoma

12 Copyright ©2006 American Society of Hematology. Copyright restrictions may apply. Morton, L. M. et al. Blood 2006;107: Incidence of lymphoid neoplasms by subtype and race, 12 SEER registries,

13 Causative factors Virus EBVBurkitts + others HTLV1Adult T-cell leukemia/lymphoma HCVIndolent B-cell lymphoma HHV-6Angioimmunoblastic lymphadenopathy (variety of T-cell NHL / Hodgkins disease (rare) HHV-8Body cavity Lymphoma (rare B- NHL) Bacteria Helicobacter pyloriMucosa associated lymphoid tissue (MALT) lymphoma (variety of marginal zone B-cell lymphoma) Chlamydia psittaciOrbit lymphoma

14 Immunodeficiency (AIDS, organ transplant recipients) Ionizing radiation Pesticides (?) Organic solvents (?)

15 Types of non Hodgkins lymphoma Clinically Indolent / clinically aggressive (slow growth= low grade lymphoma (rapid growth and invasiveness = high grade lymphoma) B-cell / T-cell (immunophenotype) Histopathologic types Pattern of growth recalling primarily involved lymph node structure. (i.e. mantle zone, germinal centre, marginal zone) Morphology and immunophenotype of the neoplastic cells; pattern of growth in the lymph node

16 Most frequent types of non Hodgkins lymphoma Follicular lymphoma Marginal zone B-cell lymphoma Small lymphocytic lymphoma/CLL Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia) Clinically Indolent - B-cell type extranodal (gastric) Splenic nodal - T-cell type Peripheral T-cell lymphoma (some) Mycosis fungoides LGL expansion (T or NK)

17 Most frequent types of non Hodgkins lymphoma Diffuse large B-cell lymphoma Mantle cell lymphoma Anaplastic large cell lymphoma Burkitts lymphoma Lymphoblastic lymphoma Clinically aggressive - T-cell type Anaplastic large cell lymphoma (ALK+) Peripheral T-cell lymphoma (some) Sezarys syndrome T- Prolymphocytic leukemia Lymphoblastic lymphoma Angioimmunoblastic lymphoma - B-cell type

18 Presentation picture and diagnosis Sistemic symptoms B symptoms in Ann Arbor staging system: unexplained fever > 38°C; weight loss >10% body weight over 6 months, night sweats = pruritus other sistemic: pruritus Tumor-related symptoms Superficial adenopathy > 1cm for more than 4 weeks (wax and wane in low-grade lymphomas) Thorax (cough, discomfort, superior vena cava syndrome) Abdomen (chronic pain, early satiety, left quadrant discomfort, jaundice, intestinal symptoms) Lymphedema Extra-nodal (depending on tissue involved)

19 Diagnosis Biopsy of any lymph node enlargement > 1 cm for > 4 weeks without an obvious explanation Imaging techniques according to symptoms No blood test is specific for NHL

20 Essentials for Diagnosis and Staging Histopathology: histologic type allows for the identification of distinct clinical behaviour: low grade lymphoma vs high grade or indolent vs aggressive lymphoma Each entity deserve different treatment Visit with documentation of systemic (B) symptoms CT scan (thorax and abdomen) CNS study in special subtype (i.e. Burkitts lymphoma) or in symptomatic patients Bone biopsy (BM involvement) + Complete blood count (possible leukemic involvement) Liver +renal function, uric acid, LDH, calcium beta-2-microglobulin, electrophoresis

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22 Entità clinicopatologicaPresentazioneEvoluzione istologica e clinica Linfomi indolenti a) Linfoma linfocitico b) linfoma marginale c) linfoma centrofollicolare Frequentissimo coinvolgimento ematico (LLC) Variante extranodale (MALT) Linfomi gastrici, bronchiali, gh. salivari Variante linfonodale Variante splenica (linfoma marginale splenici con o senza linfocicti villosi circolanti) Malattia frequentemente disseminata Linfoma ad alto grado (s Richter) Linfoma malt con componente ad alto grado (grandi cellule) Linfoma marginale ad alto grado Linfoma alto grado a grandi cellule (p53, p16) (avviene nel 5-10% dei casi per anno) Linfomi aggressivi a) linfoma del mantello b) linfoma B diffuso a grandi cellule c) linfoma a grandi cellule con sclerosi del mediastino d) linfomi T periferici e) linfoma anaplastico CD30+ Frequente iniziale coinvolgimento BM e PB Malattia spesso disseminata (sedi linofonodali ed extranodali), con splenomegalia e leucemizzazione Crescita rapida ed invasiva (compressione vasi sanguigni, nervi, bronchi, ossa) Localmente invasivo (mediastino) Svariate entità di malattia primitivo interessamento cutaneo malattia disseminata Trasformazione in linfoma mantellare blastoide Tenere presente possibile estensione tardiva al SNC Se buona risposta alla terapia (CTx + RT) remissioni durature Buona risposta alla terapia

23 Survival Patterns are Different for Indolent and Aggressive NHL Probability of survival (%) Years Indolent NHL (e.g. Follicular lymphoma) Aggressive NHL (e.g. Diffuse large B-cell lymphoma) The Non-Hodgkins Lymphoma Classification Project. Blood 1997;89:3909–3918

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25 Therapy Depends on Age and performance status Histogic features low-grade vs high grade, specific types (B vs T, Burkitts) Tumor dissemination (Staging) Is compete remission a reasonable goal?

26 Flow chart for treatment of follicular lymphoma (indolent lymphoma) Follicular lymphoma (Stage 1) Watchful waiting Consider age Involved field radiotherapy Localized (Stage 2) Chemotherapy CVP, chlorambucil Anti CD20 monoclonal antibody (?) Disseminated Stage II bulky Stage 3,4 Consider age <60 >60 CHOP+/- anti CD20 high dose therapy in selected cases with autologous BMT CVP or CHOP +/- anti CD20 Radiactive anti CD20 in relapsed or resistant Radiactive anti CD20 in relapsed or resistant

27 Flow chart for treatment of large cell lymphoma (aggressive lymphoma) Large cell lymphoma (Stage 1) CHOP -/+ RT CVP if unfit Consider age Localized (Stage 2) Chemotherapy +/- RT Anti CD20 monoclonal antibody Disseminated Stage II bulky Stage 3,4 Consider age <60 >60 Aggressive regimens + anti CD20 +/- autologous BMT CHOP + anti CD20 Radiactive anti CD20 (?) in relapsed or resistant Radiactive anti CD20 (?) in relapsed or resistant

28 Outcome of advanced DLCL with various chemotherpy regimens

29 Event- Free Survival P < Years R-CHOP CHOP Survival P = GELA Trial: Survival Years R-CHOP CHOP Median follow-up of 2 years

30 Effetti tossici della chemio + radioterapia Nausea e vomito Mucosite Tossicità ematologica Tossicità neurologica Tossicità polmonare Tossicità cardiologica Tossicità endocrina


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