Regression of gastric lymphoma of mucosa-associated lymphoid tissue with antibiotic therapy for Helicobacter pylori

GASTROENTEROLOGY

1994;107:1835-1838

Regression of Gastric Lymphoma of Mucosa-Associated Lymphoid Tissue With Antibiotic Therapy for Helicobacter pylori DONNA M. WEBER,* MELETIOS and GIDEON STEINBACHT

A. DIMOPOULOS,*

DARSHAN

P. ANANDU,?

WILLIAM

C. PUGH?

*Department of Hematology, ?Department of Gastrointestinal Medical Oncology and Digestive Diseases, and “Department The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Regression of low-grade B cell gastric lymphoma of mucosa-associated lymphoid tissue after eradication of Helicobacter pylotiwith antibiotic therapy was recently shown in a small number of patients with low-volume tumors. A patient with a >lO cm nodular gastric mucosa-associated lymphoid tissue lymphoma that caused hematemesis and weight loss is described. Antibiotic therapy of H. py/ori resulted in full clinical recovery and resolution of the mass lesion and morphological features of lymphoma on routine histological examination. However, monotypic immunostaining of plasma cells persisted in a separate and grossly normal-appearing region of the stomach. Antibiotic therapy may be of benefit in patients with mucosa-associated lymphoid tissue lymphoma with mass lesions and significant signs and symptoms, but periodic search for residual lymphoma is needed.

Case Report A 49-year-old woman had a lo-month history of epigastric discomfort. Initial endoscopy showed two ulcers on the lesser curvature induration

aspect of the antrum

suspicious

a dense mononuclear cralfate

with heaped margins

of carcinoma.

Biopsy specimens

cell infiltrate.

Despite

and ranitidine

for 11 months,

pounds and developed

progressive

temesis

two hospitalizations

that required

ulcers. Four subsequent gression

of the ulcers

examinations

and mass,

monomorphic

coma was made, and the patient On evaluation reported

diagnosis

G

tissue

(MALT)

generally

follows

is a clonal

an indolent

to chemotherapy,’

although

to large cell lymphoma

had orthostatic

lightheadedness,

hypotension

and epigastric

has been

MALp’5

and the subsequent stimulation

course and responds

well

in the midlesser

associated

lymphoma.6S7 Dependence

with

the

shown,

be responsive

to withdrawal

development

suggesting

of low-grade

lymphoma

B cell gastric of patients

It is unknown

if large

resulted

may

Eradication in regression

of MALT type in

with low-volume tumors

on

T lymphocytes

of this stimulus.8 therapy

of

tumors.9z’0

are also responsive

The

She

but no

hemoglobin

level was 49 mg/dL,

curvature

(Figure

monomorphous

revealed a poorly expandable

thickened

l), and a 4 cm antral

of malignant

that early tumors

of H. pylori with antibiotic a small number

acquisition

of early MALT lymphoma

by H. pylori-specific

was recently

examination

ach with markedly

examination

and melena. tenderness

or hepatosplenomegaly.

that

or progression

plasmacytic of plasmacy-

Cancer Center, the patient

postural

B cell malignancy

metastases

gastric

showed pro-

level was 1.3 mg/dL.

Endoscopic

also occurs.2S3 Helicobactwpriori

infection

growth

lymphoid

15

was referred to our institution

at M.D. Anderson

weakness,

and creatinine

of mucosa-associated

lost

and hema-

for treatment.

lymphadenopathy

lymphoma

with su-

for bleeding

endoscopic

and H. pyfori.A presumptive

infiltrates,

therapy

and

showed

the patient

nausea, vomiting,

level was 8.1 g/dL, blood urea nitrogen

astric

of Pathology,

folds, a >lO

with a >3 cm bleeding

mass with 2) revealed

infiltrate

cm nodular

stommass

ulcer (Figure

a 2 cm ulcer. Histological a mucosal

and submucosal

of plasma cells with monotypic

stain-

ing of plasma cells for h light chains and H. pyhri organisms in areas of chronic

active

scans showed a thickened and biopsy specimens

gastritis. stomach

Computed

tomographic

wall. Bone marrow aspirate

were normal.

The diagnosis of gastric lymphoma of MALT type, stage IE, associated with H. pylori was made. Therapy was initiated with

oral bismuth

metronidatole mg four times

subsalicylate

(250 mg three daily),

(624 mg four times times

daily),

and omeprazole

tetracycline

daily), (500

(40 mg every day).

to

antibiotic treatment. We describe a patient with a >lO cm nodular gastric MALT lymphoma that caused hematemesis and weight loss who was treated with antibiotics.

Abbreviations used in this paper: MALT, mucosa-associated lymphoid tissue. 0 1994 by the American Gastroenterologkal Association 0018-5085/94/$3.00

1836

WEBER ET AL.

GASTROENTEROLOGY Vol. 107. No. 6

Figure l. Endoscopic view of the gastric lesser curvature ulcer and mass in a patient with MALT lymphoma before antibiotic treatment.

Within

2 weeks, all symptoms

copy revealed normal gastric

resolved. After 6 weeks, endosfolds and complete

the ulcers and masses (Figure with

“jumbo”

and patchy

forceps)

showed

polymorphic

trates that were polytypic tion fragment These

findings

regression

clarithromycin,

were consistent

viously

normal

The patient

metronidazole,

infil-

initial

treatment

Australia) ever,

(CLOtest;

Delta

and no morphological

immunocytochemistry

West

Pty Ltd., Bentley,

evidence of lymphoma. showed

plasma

cells in biopsy

of B cell clonality.

pearing

area on the distal greater

and

of H. pylmi by histology

showed eradication

and urease testing

Restric-

H. pylori infection

specimens

a focus

How-

of monotypic

from a grossly

normal

ap-

curvature.

Laboratory Methods

was then treated with

and bismuth

from previously

areas of the stomach

(n > 20

and plasmacytic

no evidence with

of

H. pyfwi infection

persistent

by immunocytochemistry.

analysis detected

2 weeks. Biopsy specimens

resolution

3). Biopsy specimens

lymphocytic

of the lymphoma.

Figure 3. Endoscopic view of the gastric lesser curvature at the region of the previous ulcer and mass after treatment with antibiotics.

subsalicylate involved

at 12 weeks from

the

Staining

lmmunohistochemistty.

for

and pre-

chains

was performed

on paraffin

for K and h light

sections

as previously

de-

tailed.” Molecular

extracted

studies.

tional proteinase individually

K digestion.

digested

gels, transferred and hybridized lin heavy-chain genes (Oncor,

Aliquots

to completion

BumHI, EcoRI, and HindIII,

subjected

High molecular

weight

DNA was

from the residue of frozen section blocks by convenof purified

with restriction

size-fractionated

to nylon supports

DNA were enzymes

on 0.7% agarose

by the Southern

technique,

with 32P-labeled probes for the immunoglobujoining region and K light-chain Gaithersburg,

to autoradiography

joining region

MD). The resulting

filters were

for 4 days.

Histopathologic Results Histological mens

Figure 2. Monomorphic plasma cell population and lymphoepithelial lesions on histology of the gastric mass before antibiotic treatment. Note the presence of Dutcher bodies within plasmacytic nuclei (H& E; original magnification 200x).

showed

examination

a dense

and

of the initial

monomorphous

biopsy

speci-

proliferation

of

plasma cells and occasional lymphoid cells expanding the gastric lamina propria and infiltrating glandular epithelium to produce typical lymphoepithelial lesions (Figure 2). Some plasma cells contained Dutcher bodies (intranuclear pseudoinelusions). In several biopsy specimens, reactive-appearing germinal centers with preserved mantles were surrounded by the

REGRESSION OF GASTRIC MALT LYMPHOMA

December 1994

1837

Rgure 4. Benign follicle centers with preserved follicular mantles were interspersed within the plasmacytic proliferation in pretreatment biopsy specimens.

plasmacytic

monotypic

(Figure

proliferation

4).

h light chain expression nature

Plasma

cells

showed

by immunostaining,

of the lesion.

sup-

porting

the neoplastic

In view of the

extreme

degree of plasmacytic differentiation, an alternative

diagnosis of plasmacytoma was considered; however, the presence of germinal centers and prominent lymphoepithelial lesions favored the diagnosis

of low-grade

B cell lymphoma

of

MALT. Subsequent resolution

biopsy specimens

of the abnormal

appearing

at 6 weeks showed substantial

infiltrate

lymphoplasmacytic

lymphocytic

permeation

ever, well-developed

infiltrates

remaining.

of gastric epithelium

lymphoepithelial

fied. There was polytypic immunoglobulin

with only mild, reactiveFocal

was found; how-

lesions were not identi-

immunostaining

of the infiltrates

light chains, and restriction

fragment

sis was negative

for immunoglobulin

gene rearrangement.

opsy specimens

at 12 weeks showed

further

lymphoplasmacytic

infiltrates.

However,

imens (from the distal greater mulation could

resolution

showed a focal accu-

of plasma cells that showed monotypic

not be shown

of the sensitivity

proximately

5%) or sampling.

immunostain-

5B and C). Clonal populations

by restriction

consequence

Biof the

one set of biopsy spec-

curvature)

ing for h light chains (Figure

for

analy-

analysis,

threshold

presumably

as a

of the procedure

(ap-

DiSCUSSiOIl Although lymphoid

normal

gastric

tissue, lymphoid

&-induced

mucosa

contains

no

follicles develop with H. py-

chronic active gastritis,495*‘2 and low-grade

B cell lymphoma This hypothesis

of MALT is postulated is supported

gastric

H. pyhi

MALT

lymphoma6

colonization

to arise in these.

by the high prevalence in patients

and by histological

tween

the two entities.

gastric

MALT

lymphoma

Recently,

Figure 5. A residual focus of plasma cells, some with Dutcher bodies (A; arrow), in a posttreatment biopsy specimen of the distal greater curvature. Plasma cells in this focus continue to show monotypic h lightchain staining (B = h; C = Y; original magnification 400x).

with

similarities

the proliferation

in cell culture

of

gastric beof

was shown to

be stimulated

by specific H. pylori strains.8 The stimula-

tion was mediated lated cytokines.

by H. pylori-specific

T cells and re-

The responses were found in cells from

stage IE , I&, and IIIr low-grade gastric MALT lymphoma but not in cells from high-grade

gastric

lymphoma.

1838

WEBER ET AL.

GASTROENTEROLOGY Vol. 107, No. 6

Based on the hypothesis ation by

in gastric

H. pyiori-induced

patients

with

that malignant

MALT

lymphoma

inflammation,

gastric

MALT

be sustained

manuscript,

the patient

number

of evidence

of MALT

a small

lymphoma

tripotassium sults

combined

support

treated

with either metronidazole

dicitrobismuthate the in vitro

or omeprazole.’ findings

of

not associated

with mass lesions or large ulcers were successfully with ampicillin

that

and

These re-

tumor

B-cell

H. pylori-specific

T-

proliferation

may be dependent

on

cell signals Withdrawal

such as interleukin of the proliferative

2 or other cytokines.8 stimulus by eradication

of

H. pylori

Whether

is postulated

complete

MALT

to cause

and permanent

lymphoma

is unknown.

It

lymphoma,

which is responsive

an early stage in tumor tion of autonomous lymphoma

This after

H. pylon

cause MALT

numerous

deep biopsy

ular studies

histological subsequent trolled

features.

follow-up,

routine

Further

Whether

and -independent

histology residual

or molecis not typical

lymphoma

of the initial

regression

was

gross and

may occur with lymphoma

with antibiotic

and needs to be studied of

H.

are most commonly

resolution

subsets

There-

and obtain

from areas where

but the course of MALT

is yet unknown

Be-

and multifocal,

to document.

immunocytochemistry

resolution

to apparent

trials.

the need for

in this manner.

follicles

By this method,

shown after apparent

ment

treated

specimens

even when

of lymphoma.

of a MALT

mass and large ulcers

to map the stomach

lymphoid

found’* and to perform

longer

is not achieved has occurred.14

can be patchy

fore, it may be advisable

at

mucosa

disease may be difficult

pylori-associated

therapy

but underscores

lymphoma

acquisi-

Mediterranean

the regression

of patients

represents

preceding

remission

with a tumor

treatment

careful follow-up persistent

shows

if MALT

to tetracycline

of the muscularis

associated

antibiotic

to antibiotics,

growth.13 By analogy,

case report

of gastric

with

unclear

development

an early stage, but complete

lymphoma

regression.

resolution

is also

can be responsive

once invasion

tumor

can also be achieved

treatment

treatin con-

H. pylori-dependent

MALT lymphomas

exist also remains

to be determined. Therapy

for gastric

lymphoma

associated

with

scopic

lymphoma

ultrasonographic,

and 9 months

submission

has been reexamined

from initial

by endoscopic,

and pathological

of the

and is free criteria

endoat 6

treatment.

References 1. lsaacson PG, Spencer J. Malignant lymphoma of mucosa-associated lymphoid tissue. Histopathology 1987;11:445-462. 2. lsaacson PG, Wright DH. Extranodal malignant lymphoma arising from mucosa-associated lymphoid tissue. Cancer 1984; 53: 2515-2524. 3. Chan JK, Ng CS, lsaacson PG. Relationship between high-grade lymphoma and low-grade B-cell mucosa-associated lymphoid tissue lymphoma (MALToma) of the stomach. Am J Pathol 1990; 136:1153-1164. 4. Wyatt JI, Rathbone BJ. Immune response of the gastric mucosa to Campylobacter pyhi. Stand J Gastroenterol Suppl 1988; 142:44-49. 5. Stolte M, Eidt S. Lymphoid follicles in antral mucosa: immune response to Campylobacterpylori? J Clin Pathol1989;42:12691271. 6. Wotherspoon AC, Ortiz Hidalgo C, Falzon MR, lsaacson PG. He/icobacter pylon’-associated gastritis and primary B-cell gastric lymphoma. Lancet 1991;338:1175-1176. 7. Stolte M. Helicobacter py/ori gastritis and gastric MALTlymphoma (letter). Lancet 1992;339:745-746. 8. Hussell T, lsaacson PG, Crabtree JE, Spencer J. The response of cells from low-grade Ecell gastric lymphomas of mucosa-asso ciated lymphoid tissue to Helicobacter pylori. Lancet 1993; 342:571-574. 9. Wotherspoon AC, Doglioni C, Diss TC, Pan L, Moschini A, de Boni M, lssacson PG. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter py/ori. Lancet 1993;342:575-577. 10. Stolte M, Eidt S. Healing gastric MALT lymphomas by eradicating H pylori? Lancet 1993; 342:568. 11. Osborne BM, Butler JJ, Pugh WC. The value of immunotyping on paraffin sections in the identification of T cell rich B cell large cell lymphomas. Am J Surg Pathol 1990; 14:933-938. 12. Genta RM, Hamner HW, Graham DY. Gastric lymphoid follicles in Helicobacter py/ori infection: frequency, distribution, and response to triple therapy. Hum Pathol 1993; 24:577-583. 13. Thomas GA, Williams D. Gastric lymphomas (letter). Lancet 1993; 342:1182. 14. Al-Bahrani ZR, Al-Mondhiry H, Bakir F, Al-Saalem T. Clinical and pathologic subtypes of primary intestinal lymphoma: experience with 132 patients over a 14year period. Cancer 1983;52:16661672. 15. Taal BG, Burgers JVM. Primary non-Hodgkins lymphoma of the stomach: endoscopic diagnosis and the role of surgery. Stand J Gastroenterol 1991;26(suppl 188):33-37.

large

ulcers often entails gastrectomy because primary chemotherapy and/or radiotherapy have been associated with an increased incidence of perforation in this setting.15 The results suggest that antibiotic treatment of H.pylori may substantially reduce tumor and reduce associated morbidity.

Note added in proof: After

B cell prolifer-

could

bulk in lieu of surgery

Received February 28, 1994. Accepted July 22, 1994. Address requests for reprints to: Gideon Stelnbach, M.D., Department of Gastrointestinal Oncology and Digestive Diseases, Box 78, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030. Fax: (713) 7451163. The authors thank Dr. Raymond Alexanian for clinical and sclentlfic advice.