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