Casus 2

• Een 40 jarige man bezoekt de huisarts i.v.m. sinds een half jaar bestaande klachten van zuurbranden en pijn midden in de bovenbuik, vooral na de maaltijd.

• De huisarts schrijft een protonpomp remmer voor. Dit resulteert wel in enige verbetering, maar de klachten blijven bestaan.

• Patiënt wordt verwezen voor een gastroscopie. In het antrum wordt een ulcererende zwelling gezien van 1,5x 2 cm. Er worden multipele biopten genomen

Immunohistochemische kleuring met anti CD20 antistoffen.

HE kleuring

Casus 2

Vragen:

• Welke diagnose overweegt U en wat zijn hiervoor belangrijke argumenten?

• Welk micro-organisme speelt een belangrijke rol in de pathogenese?

• Wat is de behandeling?

Gastric MALT lymphomakey messages

• Distinct disease entity

• Pivotal role of chronic antigenic stimulation by H. pylori

• Can be cured by antibiotic treatment

• Good prognosis (5 yrs OS 82-93%)

MALT Lymphoma

• MALT: Mucosa-Associated Lymphoid Tissue

– Can be induced/expanded by chronic antigenic

stimulation• Lymphomas of MALT-type : ~8% of all NHL

• Two subgroups

– Gastric MALT Lymphomas (70%)– Non-Gastric MALT Lymphomas (30%)

Gastric MALT Lymphoma:History

• 1991 Wotherspoon et al.

– Association H.Pylori gastritis and Gastric MALT lymphoma

• 90% H.Pylori infection,• 98% H.Pylori positive serology

• 1993 Wotherspoon et al.

– Remission of MALT lymphoma after H.pylori eradication

• 1996 Hussell et al.

– H.Pylori strain specific T-cells involved in lymphomagenesis

Gastric MALT Lymphoma:Gastroscopy

Gastric MALT Lymphoma:Histology

• LEL’s (Lymphoepithelial lesions)

• monoclonal small/meduim sized B cells (“marginal zone cells”)

• CD20+,CD79a+,CD5-,CD10-, CD23-, CD21+, CD35+,IgM+

•Plasmacytoid differentiation

t(11;18)t(11;18)

t(14;18)t(14;18)

t(1;14)t(1;14)

Unknown!Unknown!n=252

13.5%

10.8%

1.6%

74.1%

Translocations in MALT lymphomaTranslocations in MALT lymphoma

Streubel et al., Leukemia 2004

All result in antigen-independent NFkB activation- proliferation- Inhibition of apoptosis

Pathogenesis Gastric MALT Lymphoma:

B-cell

MALT lymphoma

HP Infection acquired MALT

HP-specificT-cell

APC

HP dependent NFkB activation of B cells- proliferation- Inhibition of apoptosis

Chromosomal translocations → HP independent NFkB activation

-

Gastric MALT Lymphoma: assessment of localisations

• Gastroscopy with multiple biopsies (H.Pylori culture)

• Endosonography of the stomach

• CT-chest and abdomen (gastric protocol)

• Ophthalmologic and ENT-examination

• Bone Marrow investigation

• Further Investigation of GI-tract depending on

symptoms

25 % also extragastric localisation !

Gastric MALT Lymphoma Therapy local disease

• H.Pylori eradication with strict Follow-Up

• Omeprazole 20 mg bid d1-7,• Amoxycillin 1000 mg bid d1-7, CR 70-80%• Clarithromycin 500 mg bid d1-7

• Similar OS with different treatments : 5yrs OS 82%

• chemotherapy, surgery, surgery with additional

chemotherapy or radiation therapy or H.Pylori eradication

Effect of eradication of H.Pylori

Before Hp eradication

2 weeks post-eradication

10 months post-eradication

Dr Naomi Uemura, Hiroshima Japan

Gastric MALT LymphomaTherapy II

• Radiotherapy: • Chemotherapy (mild, oral)• Immunotherapy: Rituximab

Advanced disease:• Comparable with follicular lymphoma:

– CVP-R or FCR

Non Gastric MALT lymphomas:

Primary site: Percentage: Antigen:

Head & Neck 30 Sjögren Syndrome

Ocular Adnexa 24 Chlamydia Psittaci

Lung 12

Skin 12 Borrelia Burgdorferi

Intestinal tract 8 IPSID: Campylobacter Jejuni

Thyroid 7 Hashimoto’s thyreoiditis

Breast 2

Genitourinary tract 1

Pathogenesis non-gastric MALT ymphoma

B-cell

MALT lymphoma

Bacterial Infection

T-cell

Auto-antigenAPC

Multistage development of gastric MALT lymphoma

Isaacson et al. Nature Rev. Cancer 2004:4;644-653

Paris Staging system of Gastric MALT Lymphoma

m.mucosa

submucosa

mucosa

m.propria

T1T2

T3 T4

Adjacent structures or organs

N1 regional

N2 intra-abdominal

N3 extra-abdominal M1 separate GI site

M2 separate non-GI site

serosa

B0

B1

BM neg

BM pos

Predictors of response toHelicobacter Pylori eradication

• Depth of invasion of gastric wall

• Helicobacter status at diagnosis

• Presence/absence of large cell component

• Immunocytochemistry

• nuclear bcl-10

• nuclear NF-kB

• Molecular abnormalities

• API-2/MALT-1 fusion t(11;18)

• t(1;14)

• Trisomy 3

Non Gastric MALT Lymphoma:Therapy and Prognosis

No randomized controlled trials

Patient tailored therapy

•Local disease:

•Radiotherapy

•Chemotherapy, Immunotherapy, Surgery

•Advanced disease: “indolent lymphomas”

•Prognosis: 5 year survival 82-93%