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Transcript of Lymphomes de la zone marginale (MALT et non MALT) DES/DES  · PDF file Lymphomes de la...

  • Lymphomes de la zone marginale

    (MALT et non MALT)

    Catherine Thieblemont

    Hôpital Saint-louis, Paris - France

    DES d’hématologie

    14 Février 2014

  • Cas clinique 1

    • Mme. M., 87 ans, présente un oedème de la paupière gauche

    • PS = 0

    • Aucun antécédent, en particulier oculaire

    • IRM : infiltration des tissus mous à gauche. Oeil droit est normal.

    - Infiltrat diffus de cellules centrocytes monomorphes de

    petite taille sans différentation plasmocytaire

    -Immuno : CD5 neg CCND1 neg CD10 neg and bcl6 neg

    = Lymphome de MALT

  • Cas clinique 1

    • Quel bilan d’extension recommendez-vous?

    1. Scanner TAP seul

    2. Scanner TAP et BOM

    3. Colonoscopie, gastroscopie

    4. Scanner TAP, BOM, gastroscopie

    • Quel traitement proposez – vous?

    1. Radiotherapie sur la partie résiduelle post-biopsique

    2. Chlorambucil

    3. R-CVP

    4. Antibiotiques

    5. surveillance

    6. autre

  • Cas clinique 2

    Mme. M., 79 ans, est adressée pour douleur du flanc gauche associée à une

    thrombopenie. Elle n’a aucun antécédent. Le PS est à 1. L’examen clinique retrouve

    une SMG à 3 cm du rebord costal.

  • Cas clinique 2

    • Quel est votre bilan pour porter le diagnostic de lymphome de la zone

    marginale splénique ?

    • Quel est votre bilan d’extension ?

    • Quel traitement proposez – vous?

    – Observation et surveillance

    – Rituximab seul

    – R-CHOP

    – R-FC

    – Splenectomie

    – Splenectomie suivie par du Rituximab or R-chimio

  • Marginal zone

    Secondary follicule

    • Mainly present in spleen

    • Present in extranodal MALT (Peyer patches, crypt epithelium of tonsils)

    • Rare in nodes

    • Immune response

    • T- dependant or T- independant response :

    -> innate and adaptative immune response

    Ly B m

    Marginal zone Marginal zone B-cells

     Memory B-cells

    Immune response for a protective response

    against highly pathogenic encapsulated

    bacteria that do not trigger classical T-

    dependent responses

    Naive B cells

    Weill JC, Weller S, Reynaud CA. Human marginal zone B cells. Annu Rev Immunol. 2009

    Marginal zone B-cells

  • WHO Classification 2008

    Marginal Zone B-Cell Lymphomas

    Extranodal Marginal Zone Lymphoma of mucosa-associated lymphoid-tissue (MALT Lymphoma)

    ~ 8% of all NHLs

    Splenic Marginal Zone Lymphoma ~ 2% of all NHLs

    Nodal Marginal Zone Lymphoma ~ 1% of all NHLs

  • Small cell

    2,4%

    T-cell Large L.

    3,4%

    T cells small cell

    5,4%

    T small cell L. (angioim.)

    0.5%

    Lymphoblastic L.

    0,5%

    Burkitt

    0,5%

    DLBCL

    38,0%

    FL

    8,8%

    MALT

    7,3%

    MZL

    18,5%

    SLL

    6,3%

    MCL

    4,9%

    Waldenstrom

    3,4%

    MZL

    30%

    MZL

    17% MCL

    6%

    DLCL

    31%

    LL

    1% BL

    3%

    HIV/PTL

    2%

    Unclassified

    2% SLL/LPL

    10% CTCL

    1%

    FL

    21%

    ALCL

    1%

    PTCL

    6%

    MALT 43% MZL

    17%

    Chez l’ adulte Chez le sujet âgé > 80 ans

     2ème lymphome chez le sujet très âgé

    Nathwani 1999; Sonoki 2001; Berger F 2000; Thieblemont C. 2007

    MZL : A frequent disease

  • Auto-antigens - Thyroid Hashimoto thyroiditis

    - Salivary gland Myoepithelial sialoadenitis +/ - Sjögren S.

    - Lung Lymphoid interstitial pneumopathy

    MZL: associated with a chronic antigenic stimulation

    MALT Lymphomas

    Site Infectious agents

    - Stomac Helicobacter pylori

    - Intestin Campylobacter jéjuni

    - Ocular adnexa Chlamydia psittaci

    - skin Borrelia burgdorferi

    Hepatite C Virus

    Microbial pathogens

    1.

    2.

    +

    Splenic Nodal

     Lung : Achromobacter (Alcaligenes) Xylosoxidans in BALT-Lymphoma?

  • HELICOBACTER PYLORI in STOMACH

    chronic antigen stimulation -> chronic inflammation

  • chronic antigen stimulation -> chronic inflammation

    INFECTION AUTOANTIGEN

    Acquisition of MALT

    Ag-dependant

    MALT lymphoma

    Ag-independant

    MALT lymphoma

    Epithelium of

    extranodal sites

    MALT CONCEPT

    C.Thieblemont et al. Semin Cancer Biol. 2014

    Isaacson P, Wright DH. Cancer 1983

  • lymphoma progression

    antibiotic-resistant gastric lymphoma

    rare t(1;14)

    BCL10 deregulation

    common t(11;18) API2/MALT1

    fusion

    at non-GI sites t(14;18) MALT 1

    deregulation

    NF-kB

    activation

    Different chromosomal translocations affecting the same signalling pathway in MALT lymphoma

    more recently

    described

    t(3;14) FOXP1

    overexpression

    poorer outcome

    and higher risk

    of histological

    transformation

    ?

    Wild-type MALT 1 synergizes with BCL 10 to activate NF-B

  • Chromosomal abnormalities in marginal zone lymphoma

    +3, +18, + 12, del 6q

    - No diagnostic value

    - No pronostic value

    - Therapeutic implication for t(11;18) / ATB , Alkylating agents

    Review in Gascoyne RD, Hematology 2005

  • MALT lymphoma

  • Mucosal sites Non mucosal sites

    Gastro-Intestinal tract

    - Stomach

    - Intestin

    Respiratory tract

    - lung

    - pharynx, larynx

    Urinary tract

    Breast

    Thyroid

    Salivary Gland

    - Skin

    - Meninges

    - Orbit

    Very diverse sites of involvement

    Thieblemont C. Hematology Am Soc Hematol Educ Program. 2005

  • Thieblemont C. et al. J Clin Oncol 1997

    Non GIT: 50% GIT : 50%

    non GIT

    3%

    Lung

    9%

    Breast

    3%

    Orbit

    10%

    Head and Neck

    11%

    Thyroid

    4%

    Skin

    10%

    Stomach

    34%

    Intestin

    8%

    Stomach + Intestin

    4% GIT + non GIT

    4%

    SKIN

    GIT = Gastro - Intestinal tract

    THYROID

    LUNG

    ORBIT

    STOMACH

    INTESTIN

    Very diverse sites of involvement

  • Endoscopic aspects Gastric MALT lymphoma

    Pseudogastritis

    30%

    Nodular

    infiltration

    25%

    Ulcers

    45%

    JC Delchier – Henri Mondor Hospital, Créteil

    Endoscopic aspect of gastric MALT lymphoma

  • In the non-gastric sites

    Skin Lung Thyroid Orbit

    - Conjonctiva

    - Lacrymal gland

    - Soft tissue

  • Clinical presentation at initial diagnosis

    • Indolent disease

    • Good performance status

    • Absence of B-symptoms

    • Normal LDH and B2-microglobulin

    • Localized disease : 70%

    • Dissemination : 30%

    – multiple mucosal and non mucosal extranodal sites

    – Nodal involvement : 25%

    – Bone Marrow involvement : 20%

    Thieblemont et al , Blood 2000 Zucca et al, Blood 2003 Raderer et al, JCO 2006

    de Boer et al. Haematologica 2008 Papaxoinis et al , Ann Oncol 2008

    Sretenovic et al, Eur J Haematol. 2009

  • The dissemination does not confer a worse prognosis

    Localized disease

    Disseminated disease

    Years

    0.0

    0.2

    0.4

    0.6

    0.8

    1.0

    0 5 10 15 20 25

    p NS 0.0

    0.2

    0.4

    0.6

    0.8

    1.0

    5 10 15 20 25

    Years

    p NS

    Localized disease

    Disseminated disease

    Overall Survival Progression free survival

    C Thieblemont, Blood 2000

    N=158 patients

  • Transformation into DLBCL

    • In 3-18% of the MALT lymphomas

    • At first recurrence or at further relapses

    • Genetic alterations

    – p53 allelic loss and mutation

    – Hypermethylation of p15 and p16

    – p16 deletion

    Thieblemont C et al. 1997 – Zucca E et al. 2003 – Thieblemont C et al. 2000

    Du M. et al. Blood1995 – Martinez-Delgado et al. Leukemia 1998 – Neumiester P et al. Gastroenteroly 1997

  • STAGING procedures

    for MALT lymphoma

    Dreyling M, Thieblemont C. et al. ESMO guidelines Ann Oncol 2013

    Lymphoma Specific to the organ

    Mandatory • physical exam

    • complete blood counts

    • basic biochemical studies (renal and liver

    fu