LNHCosa occorre sapere

Classificazione REAL con tipo di aggressività clinica per ogni forma

Cellula d’origine

BTLivello maturativo della cellula d’origine (se noto)

Eziopatogenesi Fattori eziologiciFattori predisponenti

Modello EBV e linfoma di BBurkitt, linfoma MALT

Patogenesi citogenetico-molecolare

Stadiazione

Quadri di presentazionee concetti di terapia

Principali danni genetici

Ann Arbor

Relazione coi principali istotipi

Quadro di presentazione generale

Linfoadenopatie in 2/3 dei casi

1.Adenopatia persistente (> 1 cm per >4 settimane)2.Non dolente3.Andamento del volume delle adenopatie fluttuante nelle forme indolenti

Da differenziare 1.Adenopatie infettive2.(Batteri, Mononucleosi CMV, HIV,Toxoplasmosi, Istoplasmosi)3.Sarcoidosi (mediastino)4.Adenopatie metastatiche

Sintomi correlati a linfoadenopatie

Mediastino

Addome

Extranodali

1.Tosse persistente2.Senso di fastidio retrosternale3.Sindrome medistinica

4.Senso di gonfiore, dolore,5.Splenomegalia6.Linfedema

7.SNC, midollo spinale8.Gastrico9.Orbita10.ossa11.Testicolo12.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

Section of a normal hyperplastic lymph node

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

Follicular lymphomaCell of origin: centrobasts/centrocytes in the follicole centre which have encountered the AgImmunophenotype: sIgM>IgG+ sIgD+; cyIg+/-; CD19+; CD5-; CD10+/-; CD43-

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

The lymph node architecture is replaced by centrocyte-like cells

Residual germinalcentre 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 AgImmunophenotype: CD19+; CD5+; sIgM>D+CD10-/+; CD23-; CD43+

Marginal zone Lymphoma Small lymphocytic lymphoma

Cell origin of B-lymphoid neoplasia

B-precursor cellNaive B-cell

(no Ag)

Germinal centre

Diffuse large B cell lymphomaMantle cellLymphoma

Multiple myeloma

Plasma cell

Lymphoplasmacyticlymphoma

Pre-plasma cell

Lymphoblastic NHL

Pre-germinal centre (no IGVH mutation)

Burkitt’s lymphoma

MemoryB-cell

Bone marrow blood LYMPH NODE

(post)-germinal centre (IGVH mutation)

Mantle zone

Mar

ginal

zone

Follicular lymphoma

Angiocentric NHLIntestinal NHL

Angiocentric NHLIntestinal NHL

Cell origin of T-lymphoid neoplasiaCell origin of T-lymphoid neoplasia

T-ALL

BM T-precursorcell

THYMUS

Per

iphe

ral b

lood

ALCLPTCL

ALCLPTCL

Mycosis fungoidesSezary’s syndrome

Mycosis fungoidesSezary’s syndrome

skinT-cell CLL/PLLT-cell CLL/PLL

CD4+ lymphocytes

CD8+ lymphocytes

LGL expansionLGL expansion

Mucosae

Bow

el

Germinal centre

Hepato-splenicγδ NHL

Hepato-splenicγδ NHL

Lymph

node

Spleenliver

AITLFollicular

helper T-cells

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.

NHL

Non lymphoidHemopoietic tumors

Myeloma

Hodgkin’s lymphoma

Copyright ©2006 American Society of Hematology. Copyright restrictions may apply.

Morton, L. M. et al. Blood 2006;107:265-276

Incidence of lymphoid neoplasms by subtype and race, 12 SEER registries, 1992-2001

Causative factors

VirusEBV 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

• Follicular lymphoma

• Marginal zone B-cell lymphoma

• Small lymphocytic lymphoma/CLL

• Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia)

Clinically Indolent- B-cell type

extranodal (gastric)Splenicnodal

- T-cell type

• Peripheral T-cell lymphoma (some)• Mycosis fungoides• LGL expansion (T or NK)

Most frequent types of non Hodgkin’s lymphoma

• Diffuse large B-cell lymphoma

• Mantle cell lymphoma

• Anaplastic large cell lymphoma

• Burkitt’s lymphoma

• Lymphoblastic lymphoma

Clinically aggressive

- T-cell type

• Anaplastic large cell lymphoma (ALK+)

• Peripheral T-cell lymphoma (some)

• Sezary’s syndrome

• T- Prolymphocytic leukemia

• Lymphoblastic lymphoma

• Angioimmunoblastic lymphoma

- B-cell type

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 a) Linfoma linfocitico

b) linfoma marginale

c) linfoma centrofollicolare

Frequentissimo coinvolgimento ematico (LLC)

Variante extranodale (MALT)Linfomi gastrici, bronchiali, gh. salivariVariante linfonodaleVariante 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 PBMalattia 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 cutaneomalattia 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

0

25

50

75

100

0 1 2 3 4 5 6 7 8

Pro

bab

ility

of

surv

ival

(%

)

Years

Indolent NHL(e.g. Follicular lymphoma)

Aggressive NHL(e.g. Diffuse large B-cell lymphoma)

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)

Follicular lymphoma

(Stage 1)

Watchfulwaiting

Consider age

Involved fieldradiotherapy

Localized

(Stage 2)

ChemotherapyCVP, chlorambucil

Anti CD20 monoclonal antibody (?)

DisseminatedStage II bulky

Stage 3,4

Consider age

<60 >60

CHOP+/- anti CD20high dose therapyin selected cases withautologous BMT

CVP or CHOP +/-anti CD20

Radiactive anti CD20in relapsedor resistant

Radiactive anti CD20in relapsedor resistant

Flow chart for treatment of large cell lymphoma (aggressive lymphoma)

Large cell lymphoma

(Stage 1)

CHOP -/+ RTCVP if unfit

Consider age

Localized

(Stage 2)

Chemotherapy+/- RT

Anti CD20 monoclonal antibody

DisseminatedStage II bulky

Stage 3,4

Consider age

<60 >60

Aggressive regimens + anti CD20 +/- autologous BMT

CHOP +anti CD20

Radiactive anti CD20 (?)in relapsedor resistant

Radiactive anti CD20 (?)in relapsedor resistant

Outcome of advanced DLCL with various chemotherpy regimens

Event- Free Survival P < 0.001

0 0.5 1.0 1.5 2.0 2.5 3 Years

0.0

0.2

0.4

0.6

0.8

1.0

R-CHOP

CHOP

Survival P = 0.007

GELA Trial: Survival

0 0.5 1.0 1.5 2.0 2.5 3 Years

0.0

0.2

0.4

0.6

0.8

1.0

R-CHOP

CHOP

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