1. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Gastrointestinal Lymphomas

2. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria „Extranodal Lymphomas“ Definition: „....presenting with the main disease bulk at an extranodal site....“ Incidence: »24 – 48% of all lymphomas »Considerable geographic variation

3. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Extranodal Lymphomas: Incidence USA:24% Canada:27% Hong Kong:29% Israel:36% Denmark:37% Holland:41% Lebanon:44% Italy:48% Zucca et al, Ann Oncol 1997

4. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria MALT: Mucosa Associated Lymphoid Tissue GALT: Gut associated...... a priori: Peyer’s patches BALT: Bronchus associated Salivary glands, thyroid gland, skin

5. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Histological Classification B-Cell: Mucosa associated lymphoid tissue Diffuse large B-cell lymphoma (+/- MALT-component) Mantle cell lymphoma (Lymphomatous polyposis) Burkitt‘s lymphoma Other types corresponding to nodal equivalents (follicular, lymphocytic) Immunodeficiency related lymphomas T – Cell: Enteropathy type T-cell lymphoma Other types not associated with enteropathy

6. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Frequency of gastric lymphoma: Vienna Lymphoma Registry 1997 – 9/2002 Initial diagnosis: MALT lymphoma: n = 100 Diffuse large B-cell lymphoma:n = 113 (18)

7. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Predominant sites of MALT-lymphoma Stomach GI-Tract Lung Salivary Glands Ocular Adnexa Skin

8. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Standardized staging: Ophthalmologic investigation Ear, nose and throat (incl Sono/MR) Endosonography + Gastroscopy (multiple biopsies) Enteroklysma (-CT) Colonoskopy CT-Thorax + Abdomen Bone marrow biopsy (?)

9. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Gastric Lymphoma Resected patients:n = 1609 Perioperative deaths: n = 75 (4.7 %) Unresected patients: n = 587 Major complications:n = 27 (4.6 %) Gobbi et al; Haematologica 2000

10. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Conservative management plus surgery vs conservative alone Koch et al, J Clin Oncol 2001

11. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Warren JR, Marshall B. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1983; 1: 1273-5

12. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Factors associated with acquired MALT Helicobacter pylori Helicobacter Heilmanii Chronic infection / inflammation Borrelia Burgdorferi Autoimmune conditions: Sjögren’s Syndrome Hashimoto’s Thyroiditis........................................

13. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Time to Remission after HP-Eradication Isaacson et al.: 4 weeks – 14 months Sackmann et al.:6 – 14 months Neubauer et al.:4 – 18 months Montalban et al.: 2 – 7 months „The cases of late remission encourage us to wait for at least one year after eradication of H. pylori.“ A. Savio, Recent Results Cancer Res 2000

14. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Factors predicitive of response Staging / Endosonographic assessment: Stage EI1 vs more advanced stages Probability of complete response stage EI1 (n=22): 6 mos60% 12 mos79% 14 mos100% Sackmann et al, Gastroenteroloy 1997

15. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria t(11;18) (q21;q21) Characteristic translocation for MALT-lymphomas  found in up to 50% of gastric MALT-lymphomas Not detected in other MZBL and extranodal DLBCL Fusion of the apoptosis inhibitor gene API2 (11q21) and the novel MALT1 gene (18q21) Fusion product inhibits apoptosis by caspase pathways

16. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria t(11;18) translocation in gastric MALT-lymphoma Number of patients: 111 Response to eradication: 48 t(11;18) positive: 2 / 48 responders 42 / 63 non-responders Liu et al, Gastroenterology 2002

17. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Helicobacter eradication: Facts..... HP is a major factor in the development of MALT-lymphoma. Eradication leads to durable remissions in about 80% of selected patients. t(11;18)+ patients seem to be unresponsive to HP eradication. Relapse triggered by re-infection with HP remains sensitive to eradication. A high percentage of patients (-50%) remain PCR-positive even in case of pathological complete remission.

18. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria................ and speculations Role of HP-eradication following extragastric spread of the lymphoma? Benefit of additional therapy following eradication? Does underlying autoimmune disease impair response to HP-eradication? Is persisting positive PCR an indicator for relapse? Regression of DLCL following eradication?

19. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Non-surgical management of gastric lymphoma Radiotherapy (stage I – II 1 ): „Low grade“: – 100% CR 5-year-survival: > 90% „High grade“: 80% CR 5-year-survival: > 60% Chemotherapy (stages II 2 – IV): „Low grade“: - 75% CR 5-year-survival: > 80% „High grade“: - 80% CR 5-year-survival: 40 – 93%

20. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Treatment for gastric lymphoma: MALT-type Stage I1: HP-eradication Stage I2 – II2: HP eradication + radiation? HP-eradication + chemotherapy? Stage III/IV: HP-eradication + chemotherapy Chemotherapeutic options: Cyclophosphamide, Chlorambucil, 2 CdA, MCP Surgery as an emergency procedure (bleeding, perforation)

21. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Treatment for gastric lymphoma: Difuse large cell lymphoma Stage I - IV: HP-eradication + chemotherapy Stage I – II 2 : HP eradication + chemotherapy (+ radiation?) Chemotherapeutic options: CHOP, R-CHOP,......?

22. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria “...for all gastric lymphomas, surgery probably belongs to the history of medicine...” E. Roggero et al. J Natl Cancer Inst 1997; 89:1328-30