LNH Cosa occorre sapere Eziopatogenesi Fattori eziologici Classificazione REAL con tipo di aggressività clinica per ogni forma Cellula d’origine B T Livello maturativo della cellula d’origine (se noto) Eziopatogenesi Fattori 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

Quadro di presentazione generale Linfoadenopatie in 2/3 dei casi Adenopatia persistente (> 1 cm per >4 settimane) Non dolente Andamento del volume delle adenopatie fluttuante nelle forme indolenti Da differenziare Adenopatie infettive (Batteri, Mononucleosi CMV, HIV,Toxoplasmosi, Istoplasmosi) Sarcoidosi (mediastino) Adenopatie metastatiche Sintomi correlati a linfoadenopatie Mediastino Addome Extranodali Tosse persistente Senso di fastidio retrosternale Sindrome medistinica Senso di gonfiore, dolore, Splenomegalia Linfedema SNC, midollo spinale Gastrico Orbita ossa Testicolo cute Sintomi sistemici 20% circa dei casi Soprattautto negli alti gradi e negli stadi avanzati

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

Section of a normal hyperplastic lymph node

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- Follicular lymphoma: neoplastic follicles of uniform shape efface the LN architecture Both centrocytes and centroblasts are present (right)

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)

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+ Cyclin D1 overxpression by Neoplastic cells and not by GC cells The lymph node architecture is replaced by centrocyte-like cells Residual germinal centre cells (arrow)

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

Cell origin of T-lymphoid neoplasia Mycosis fungoides Sezary’s syndrome T-cell CLL/PLL skin Angiocentric NHL Intestinal NHL Mucosae Bowel CD4+ lymphocytes T-ALL THYMUS Hepato-splenic γδ NHL Spleen liver Peripheral blood BM T-precursor cell Lymph node ALCL PTCL CD8+ lymphocytes LGL expansion Germinal centre AITL Follicular helper T-cells

NHL Non lymphoid Hemopoietic tumors Myeloma Hodgkin’s lymphoma Trends in incidence of hematopoietic neoplasms by broad subtype category, 9 SEER registries, 1978-1979 to 2000-2001. *All incidence rates are age adjusted to the 2000 United States population and presented for 12 fixed 2-year time periods (1978-1979 to 2000-2001). Lymphoid neoplasms excepting Hodgkin lymphoma and plasma-cell neoplasms. Predominantly myeloid leukemia. Predominantly multiple myeloma. Non lymphoid Hemopoietic tumors Myeloma Hodgkin’s lymphoma

Morton, L. M. et al. Blood 2006;107:265-276 Incidence of lymphoid neoplasms by subtype and race, 12 SEER registries, 1992-2001 Morton, L. M. et al. Blood 2006;107:265-276 Copyright ©2006 American Society of Hematology. Copyright restrictions may apply.

Causative factors Virus Bacteria EBV Burkitt’s + others HTLV1 Adult T-cell leukemia/lymphoma HCV Indolent B-cell lymphoma HHV-6 Angioimmunoblastic lymphadenopathy (variety of T-cell NHL / Hodgkin’s disease (rare) HHV-8 Body cavity Lymphoma (rare B-NHL) Bacteria Helicobacter pylori Mucosa associated lymphoid tissue (MALT) lymphoma (variety of marginal zone B-cell lymphoma) Chlamydia psittaci Orbit lymphoma

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

Types of non Hodgkin’s 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

Most frequent types of non Hodgkin’s lymphoma Clinically Indolent - B-cell type Follicular lymphoma Marginal zone B-cell lymphoma Small lymphocytic lymphoma/CLL Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia) extranodal (gastric) Splenic nodal - T-cell type Peripheral T-cell lymphoma (some) Mycosis fungoides LGL expansion (T or NK)

Most frequent types of non Hodgkin’s lymphoma Clinically aggressive - T-cell type - B-cell type Anaplastic large cell lymphoma (ALK+) Peripheral T-cell lymphoma (some) Sezary’s syndrome T- Prolymphocytic leukemia Lymphoblastic lymphoma Angioimmunoblastic lymphoma Diffuse large B-cell lymphoma Mantle cell lymphoma Anaplastic large cell lymphoma Burkitt’s lymphoma Lymphoblastic lymphoma

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)

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

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. Burkitt’s 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

Entità clinicopatologica Presentazione Evoluzione istologica e clinica Linfomi indolenti Linfoma linfocitico 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 linfoma del mantello linfoma B diffuso a grandi cellule linfoma a grandi cellule con sclerosi del mediastino linfomi T periferici 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

Survival Patterns are Different for Indolent and Aggressive NHL Indolent NHL (e.g. Follicular lymphoma) Probability of survival (%) Aggressive NHL (e.g. Diffuse large B-cell lymphoma) Key Point: The clinical features of the various lymphoma types were remarkably different, as were the survivals.1 Although aggressive NHL can have a more rapid mortality outcome than indolent NHL, it can be cured with treatment. In contrast, indolent NHL is rarely cured with current treatments: Relapses are common The prognosis worsens after each relapse Often becomes refractory to treatment. Using overall survival the various lymphoma types could be divided into four broad groups for prognostic purposes:1 NHLs with a 5-year survival of >70% (including follicular lymphoma and marginal zone B-cell lymphoma of MALT type) NHLs with a 5-year survival of 50% to 70% (including small lymphocytic, lymphoplasmacytoid and nodal marginal zone B-cell lymphomas) NHLs with a 5-year survival of 30% to 49% (including diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, Burkitt lymphoma) NHLs with a 5-year survival of <30% (including peripheral T-cell lymphoma, precursor T-lymphoblastic lymphoma and mantle cell lymphoma). 1. The Non-Hodgkin’s Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. Blood 1997;89(11):3909–3918. Years The Non-Hodgkin’s Lymphoma Classification Project. Blood 1997;89:3909–3918

Therapy Depends on Age and performance status Histogic features low-grade vs high grade, specific types (B vs T, Burkitt’s) Tumor dissemination (Staging) Is compete remission a reasonable goal?

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

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

Outcome of advanced DLCL with various chemotherpy regimens

GELA Trial: Survival R-CHOP CHOP R-CHOP CHOP Event- Free Survival 0.5 1.0 1.5 2.0 2.5 3 Years 0.0 0.2 0.4 0.6 0.8 R-CHOP CHOP 0.5 1.0 1.5 2.0 2.5 3 Years 0.0 0.2 0.4 0.6 0.8 R-CHOP CHOP Event- Free Survival P < 0.001 Survival P = 0.007 Median follow-up of 2 years

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