Primary non-Hodgkin Lymphomas of the Gastrointestinal Tract (GI-NHL)

Emanuele Zucca, M.D.

Istituto Oncologico della Svizzera ItalianaOncology Institute of Southern Switzerland

Portorož, Slovenia, June 15 - 16, 2007Falk Symposium 160Pathogenesis and Clinical Practice in Gastroenterology

GI tract is the most frequent extranodal site in NHL (20%-40% in clinical series)

GI involvement: 50%-70% in postmortem studies

The stomach represents 50-75% of the GI tract localisations in western countries

The incidence of gastric lymphoma is ~0.7-0.8 cases per 100,000 inhabitants in Western Europe

Lymphoma affecting the stomach, but not other sites, is associated with previous H. pylori infection

IPSID is associated with Campylobacter jejuni

GI-NHL Epidemiology

Relaxed criteria for gastric NHL (Levin, 1978; Herrmann, 1980)

contiguous involvement of liver, spleen, bowel, diaphragm, regional nodesgastric lymphomas as a sole or dominant site of involvement

Strict criteria for gastric NHL(Dawson, 1961)

predominant gastric lesionno lymph nodesno liver or spleennormal blood count

Definition of Primary GI Lymphoma

General criteria for extranodal NHL (D’Amore, 1991)

clinically dominant extranodal component after routine stagingproceduresno lymph nodes or only “minor” nodal involvement (i.e., ≤25% of total tumor volume)

GI-NHL: Histologic Classification

GI-NHL do not fit into a single category but correspond to the different subtypesdescribed by the WHO classification (only the EATCL is strictly typical of the GIT)

B-cellExtranodal Marginal Zone B-cell lymphoma of MALT type (including IPSID)DLCL (including those arising at MALT sites)Mantle cell (Lymphomatous polyposis)Burkitt’sFollicular lymphoma other types corresponding to nodal equivalents

T-cellEnteropathy associated T-cell lymphoma (EATCL)Other types not associated with enteropathy

Koch et al. JCO, 2005

German Multicenter Study GIT NHL 02/96

Distribution of histologic subtypes in 393 patients with localized primary gastric lymphoma

Intestine Stomach (N=91) (N=85)

DLCL 70% 60%

MALT type 7% 35%

Follicular 17% ---

Other types 6% 5%TN Shenkier and JM Connors, 2006

Distribution of WHO histologic types in localized GI-NHL at BCCA 1981-2003

MALT lymphoma(Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid-Tissue )

HISTOLOGICAL FEATURES AND PHENOTYPE

centrocyte-like cells (usually)lymphoepithelial lesions plasma cell differentiationscattered transformed blastsadmixed non-neoplastic T-cellfollicular colonisationsIg (usually IgM + and IgD - ) CD20, CD21, CD35 positive; CD5, CD10, CD23 negative

72-90% prevalence of H. pylori infection in gastric MALT lymphoma (Wotherspoon 1991, Nakamura 1997)high prevalence of both H. pylori infection and gastric MALT lymphomas in North-eastern Italy (Doglioni 1992)eradication of H. pylori leads to histological regression of low-grade gastric lymphoma (Wotherspoon 1993)previous H. pylori infection more likely in gastric lymphomathan in matched non-gastric lymphoma controls (Parsonnet1994)molecular detection in previous gastritis specimens of theclonal B-cell that will give rise to the MALToma (Zucca 1998)

The H. pylori and Gastric MALT Lymphoma Story

H. pylori and MALT lymphomaa model of tumor progression

BB B

B

BBBB

BB B T

T

strain-specificstimulation

mucosal T-cell proliferation

H. pylori-dependentMALT lymphoma B-cell proliferation

contact-dependent B-cell stimulation

neutrophils activations with release of

genotoxic free radicals

antigen selectionautoimmunity

geneticalterations

T

additional genetic damages

B

T

T

diffuse large B-cell lymphoma

B BB

H. pylori chronic gastritis

H. pylori-independentMALT lymphoma

BB

Antibiotic-resistantgastric lymphoma

raret(1;14)BCL10

deregulation

common t(11;18)

CagA+ strainsAPI2/MALT1

fusion

at non-GI sitest(14;18)

MALT 1deregulation

NF-kB activation

Different chromosomal translocationsaffecting the same signalling pathway in MALT lymphoma

more recentlydescribed

t(3;14)

FOXP1overexpression

poorer outcome and higher risk of histological transformation

?

MALT lymphoma, one and the same:

Extranodal Marginal Zone B-Cell Lymphoma of mucosa-associated lymphoid-tissue

Low-grade MALT lymphoma

MALToma

Not the same: DLBCL arising at a MALT site(with or without any „low-grade“ MALT component)

NB: The term „High-grade MALT“ should not be used!

Stage I and II– Antibiotics– Surgical excision– Radiation – Chemotherapy– Rituximab

Stage III and IV– Chemotherapy– Rituximab

Treatment options forgastric MALT lymphoma

Non-randomised trials provide some evidence of activity for:

Stage I gastric MALT lymphoma:Response to antibiotics

Reference n staging % CR time No. of procedure to CR relapses

(months)

Wotherspoon, 1993 6 US 83 --- ---Savio, 1996 12 CT 84 2-4 0Pinotti, 1997 45 CT 67 3-18 2Neubauer, 1997 50 CT±EUS 80 1-9 5Nobre Leitao, 1998 17 CT+EUS 100 1-12 1Steinbach, 1999 23 CT±EUS 56 3-45 0Montalban, 2001 19 CT±EUS 95 2-19 0Ruskone-Formestraux, 2001 24 CT+EUS 79 2-18 2Bertoni, 2002 189 CT 56 3-24 15

Neubauer A, J Natl Cancer Inst 1997

• Complete histologic remission (CR)residual lymphoma cells cannot be detected and an empty lamina propria is found with only small basal clusters of lymphocytes and plasma cells

• Partial remission (PR)partial depletion of lymphoid cells from the lamina propria or focal lymphoepithelial destruction

Response evaluation in gastric MALToma following anti-helicobacter therapy

Wotherspoon’s Histologic score for gastric MALT lymphoma (Lancet 1993)

Score Description Histological features

0 normal scattered plasma cells in lamina propria

1 chronic active gastritis small clusters of lymphocytes in laminapropria; no lymphoid follicles; no LELs

2 chronic active gastritis prominent lymphoid follicles withwith lymphoid follicles surrounding mantle zone and plasma cells;

no LELs

3 suspicious infiltrate, lymphoid follicles surrounded by smallprobably reactive lymphocytes that infiltrate in lamina propria

and occasionally into epithelium

4 suspicious infiltrate, lymphoid follicles surrounded byprobably lymphoma CCL cells that infiltrate diffusely in lamina

propria and into epithelium in small groups

5 Low Grade MALT dense diffuse infiltrate of CCL cells inlymphoma lamina propria with prominent LELs

LEL = lymphoepithelial lesion; CCL = centrocyte-like

CR

PR

NC

GELA score for gastric MALT lymphoma (Copie-Bergmann et al, Gut 2003)

Dense, diffuse or nodular lymphoid infiltrate, LEL usually present

NCno change

Focal empty LP and/or fibrosis with dense, diffuse or nodular lymphoid infiltrate, extending around glands in the LP, focal LEL or absent

rRDresponding residual disease

Empty LP and/or fibrosis with aggregates of lymphoid cells or lymphoid nodules in the LP/MM and/or SM, no LEL

pMRDprobable minimal residual disease

Normal or empty LP and/or fibrosis with absent or scattered plasma cells and small lymphoid cells in the LP, no LEL

CRcomplete histological remission

GI-NHL follow-up

Endoscopic and histological remission does not mean “cure”PCR assay for the detection of monoclonal B-cells remainedpositive in approximately 50% of histological CRclinical relevance and prognostic significance of molecular remission still to be ascertained

Thiede, 2001Bertoni, 2002

The neoplastic clone can re-expand but without the H. pylori stimulus this may remain a self-limiting eventtransient histological and molecular relapses and/orpersistent clonality without lymphoma progression or histologic transformation

Isaacson, 1999 Fischbach, 2002Wundisch, 2005wait-and-see policy:

safe if a close follow-up can be performed

LY03 Trial

3-year 5-year 5 yearrelapse relapse-free overallrate survival survival

Observation 14% 79 % 98 %

Chlorambucil 16 % 78 % 91 %Hancock et al. 9-ICML Lugano 2005

233 patients registered, H.pylori eradicated with antibiotics in 97%

63% of patients with abnormal mucosa at registration achieved macroscopically normal gastric mucosa

56% histological lymphoma regression rate

median time to lymphoma regression: 3-24 mos

IELS

G

www.ielsg.org

locally advanced disease (EUS)

H. pylori-negative status

t(11;18), nuclear BCL10

increased numberof blasts and/or focalhigh-grade areas?

concomitant autoimmune diseases?

Prognostic factors (predicting a poor response to antibiotics)

EUS staging in gastric MALT lymphoma

Depth of parietal CR rate [95%CI] infiltration

Mucosal 78% [52-94]Submucosa 43% [10-82]Muscularis propria 20% [0.5-71]Serosa 25% [0.6-80]

No response in pts with nodal involvement

Ruskone-Formestraux et al. 2001

Second-line Therapy

Front-line antibiotics> 90% H.Pylori eradication~ 50-100% histological CR < 10% recurrence ?

(problems with definition, increasing recurrences with longer follow-up?)

How should we treat persistent or recurrent lymphoma after eradication therapy?

Consensus on 2nd line Therapy?

RT SX CT7 Dutch centres 5 1 1

7 European centres 0 5 2

3 non-European 1 1 1

De Jong et al. Ann Oncol,1999

89% (76-96)74%12 72Total

80% (20-97)100%1 5Combined modality b75% (32-93)50%3 8Chemotherapy

92% (57-99)100%3 14Local treatment a94% (65-99)67%5 45Antibiotics

5-year OS (95% CI)

CRrate

additional tumors

(n of pts)

nTreatment

Excellent prognosis regardless of treatment in patients with stage IE gastric MALT lymphoma

a surgery ± RT b surgery+ adjuvant chemotherapy

Pinotti et al, 1997

in the studies that take account of the MALT concept the results of surgical resection alone are excellentwith 5-year survival rates of 85%-95%

Cogliatti et al, 1991Ruskone-Formestraux et al, 1991

but a total gastrectomy should be considered since MALT lymphoma is often multifocal

Wotherspoon et al, 1992

Surgical therapy of gastricMALT lymphoma

→ Acute complications→ Long-term morbidity

(e.g., dumping syndrome)

Radiotherapy in gastric MALToma

Author n RT dose (Gy) FFP

Burgers, 1988 24 20 WA+ 20 boost 83% at 4 yr

Schechter, 1998 17 28-43 100% at 27 mo

Tsang, 2001 9 20-30 100% at 5 yr

Yahalom, 2002 51 30 median 89% at 4 yr

Hitchcock, 2002 9 34 median 78%, 100% local

Questions regarding RT

Optimal RT volume, dose and technique? Does RT provide durable local control?Does this really translate to cure?In a very indolent condition, is the potential toxicity cost acceptable? (gastric and renal damage, risk of second malignancy)

RT Toxicity can be reducedusing 3D conformal techniques

and minimizing the RT dose to the kidneys and the liver

Continuous oral administration of single alkylating agents in MALT lymphoma

24 patients, 17 stage I and 7 stage IV

Cyclophosphamide or Chlorambucil for 8-24 mos.

100% ORR (75%CR)

5-year EFS: 50%5-year OS: 75%

5 relapses at initial sites (1 with transformation)

Hammel et al. JCO, 1995

Phase II study of Cladribine (2-CdA, 0.12 mg/kg/d x5, q28 d)

26 patients, 19 gastric and 7 non-gastric MALToma100% ORR (84% CR); higher CR rate in gastric (100%) than extragastric (43%)hematologic toxicity grade 3 in 35%Disease-free survival at 6.7 years was 78% for the patients with gastric disease, and 33% for those with extragastric The use of purine analogs might however be associated with an increased risk of secondary MDS

Jäger et al., 2002 and 2006

Questions regarding CTNo randomised trials publishedThe combination of Chlorambucil, Mitoxantrone and Prednisone as well as the classic CVP have been reported to be active and well-tolerated and Fludarabine in combination with Mitoxantrone has also been found to be extremely active

(Wohrer 2003; Zinzani 2004)Aggressive anthracycline-containing regimens are usually reserved for patients with histological transformations or with bulky masses

Given the indolent course of gastric MALT lymphomas the need for aggressive regimens

remains controversial.

Rituximab in Gastric MALT NHL

good clinical activity of rituximab in gastric MALT lymphomasresistant/refractory to antibiotics or H. pylori-negative11 of 12 CRs had stage I or II disease at study entryThe t(11; 18)(q21; q21) was not a predictive marker of response.

Martinelli et al. J Clin Oncol 2005

Response to treatment with single agent Rituximab (375 mg/m2/weekly x4)

No of pts. (%)

Complete response 12 46Partial Response 8 31Stable Disease 6 23

Provisional guidelines for thetreatment of (gastric) MALToma

Optimal therapy remains unresolved, but prognosisis usually excellent regardless of treatment:

Initial antibiotic therapy in localized H.pylori-positive

RT, CT and rituximab can be used in patientswho do not respond to antibiotics. The choiche should consider the less toxic option for every single situation.

Role of surgery to be redefined

Rituximab to be further evaluated

IELSG-19 Randomized trial in MALT lymphoma Chlorambucil alone

vs Chlorambucil+ Rituximab

vs Rituximab alone

IELS

G

www.ielsg.org

IELSG 25 phase II study of Bortezomib in pretreated MALT lymphomasIE

LSG

www.ielsg.orgBortezomib 1,3 mg/m2 day 1, 4, 8, 11

in relapsed/refractory MALT lymphoma≥1 prior systemic treatment

(chemotherapy and/or immunotherapy)any extranodal site, any stage

INTERNATIONAL EXTRANODAL LYMPHOMA STUDY GROUP

Problems with surgery in GI- NHL

5-10% postoperative mortality rate with substantial immediate morbidity and long-term complications or discomfort related to gastrectomyPrimary resectability rate of the study population is an important factor of positive selection:Surgery is possible only in 60-70% of cases because of disseminate disease or poor condition and only 50% of them can be completely resected

Salles et al. Am J Med 90: 77-84, 1991Law MM et al. J surgery Oncol 61:199-204, 1996

Bartlett DL et al. Ann surgery 223: 53-62, 1996

Management of Diffuse Large B-Cell Lymphoma of the Stomach

Surgery has, historically, been the initial procedure of choice because it simultaneously solved diagnostic and therapeutic problems. Since endoscopy and CT scan have become generally available, the necessity of surgery for biopsy and staging has disappeared. Having conservative approaches proven successful, the need for routine gastrectomy has been eliminated. Surgery does not necessarily prevent complications, as episodes of bleeding or perforation have also been reported despite surgical resection Risk of bleeding or perforation during chemotherapy generally overestimated

Treatment of gastric DLBCL at the IOSI

Localised stages3-4 cycles R-CHOP followed by IF-RT or 6–8 cycles of R-CHOP (conformational techniques to reduced RT toxicity)

Antibiotic therapy alone is investigational but can be added to chemotherapy at the clinician’s discretion.

Advanced-stage patients6–8 cycles of R-CHOP

Special situations

Mantle cell lymphoma and follicular lymphoma of small intestine can both present with multiple lesions (multiple lymphomatous polyposis). The prognosis for mantle cell lymphoma is poor in spite of aggressive chemotherapy, similar to its nodal equivalent.

Rectal presentations are less common than other sites in the lower intestinal tract. Treatment usually includes chemotherapy and RT. Abdominoperineal resection should be discouraged, as there is no evidence that it improves local control or survival.

Special situations (cont.)

The clinical course of EATCL is very unfavourable with death usually resulting from multifocal intestinal perforations due to ulcerating lymphoma. Very aggressive treatment is usually needed.

Resolution of early-stage IPSID after antimicrobial therapy is possible and Campylobacter jejuni has been recently associated with this disease