Digestive Endoscopy

(2003)

15

, 174–178

ORIGINAL ARTICLE

Blackwell Science, LtdOxford, UKDENDigestive Endoscopy0915-56352003 Blackwell Science Asia Pty Ltd

153July 2003240.doc

EUS ASSESSMENT OF GASTRIC MALT LYMPHOMAS YOSHIDA

ET AL.

10.1046/j.0915-5635.2003.240.doc.xOriginal Article174178BEES SGML

Correspondence: Shinji Tanaka, Department of Endoscopy,Hiroshima University Medical Hospital, 1-2-3 Kasumi, Minami-ku,Hiroshima 734-8551, Japan. Email: colon@hiroshima-u.ac.jp

Received 11 September 2002; accepted 2 December 2002.

ENDOSCOPIC ULTRASONOGRAPHY FOR ASSESSMENT OF MEDICAL TREATMENT IN PATIENTS WITH GASTRIC MUCOSA-ASSOCIATED

LYMPHOID TISSUE LYMPHOMA

S

HIGETO

Y

OSHIDA

,* K

EN

H

ARUMA

,

†

S

HINJI

T

ANAKA

,* Y

UTAKA

M

ITSUOKA

,

‡

M

UTSUHIRO

H

ARA

,

‡

H

IROSHI

M

ASUDA

,

‡

T

OMOARI

K

AMADA

,

†

H

IROAKI

K

USUNOKI

,

†

Y

ASUHIKO

K

ITADAI

,

‡

J

IRO

H

ATA

,

‡

N

ORIHIKO

H

AYAKAWA

§

AND

K

AZUAKI

C

HAYAMA

‡

*

Department of Endoscopy, Hiroshima University Medical Hospital,

‡

Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences,

Hiroshima University,

§

Department of Epidemiology, Division of Bio-Medical Informatics, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima and

†

Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan

Background

: Although gastric mucosa-associated lymphoid tissue (MALT) lymphoma often regresses after medical treat-ment, it is not known whether submucosal lymphomatous involvement persists. Because sampling error is a problemassociated with histological evaluation and endoscopic ultrasonography (EUS) is appropriate for assessing the depth ofinfiltration in cases of gastric lymphoma, we investigated the value of EUS for assessing the effectiveness of medicaltreatment.

Methods

: Twelve patients with gastric MALT lymphoma were treated with

Helicobacter pylori

eradication therapy and/or chemotherapy. Endoscopic ultrasonography was done at initial staging and after treatment. We used EUS to measurethe distance from the surface layer to the deepest part of the hypoechoic area; a distance of less than 1.3 mm was considerednormal.

Results

: The mean depth of the hypoechoic area in MALT lymphoma-positive biopsy specimens was significantly greaterthan that in MALT lymphoma-negative biopsy specimens. In many cases in which MALT lymphoma disappeared aftertreatment, the depth of the endoscopic ultrasonographic hypoechoic area also decreased to normal. In two cases, however,in which the MALT lymphoma biopsy results were negative but there was no decrease to normal depth, recurrence occurredduring follow up.

Conclusion

: Our results show that measurement of the depth of the hypoechoic area via EUS is useful in assessing theresponse of gastric MALT lymphoma to treatment. When the depth of the hypoechoic area does not decrease to normal,careful follow up and frequent biopsies are required.

Key words: endoscopic ultrasonography, mucosa-associated lymphoid tissue lymphoma.

INTRODUCTION

Mucosa-associated lymphoid tissue (MALT) lymphoma wasfirst described by Isaacson and Wright in 1983.

1

This lym-phoma has a morphology corresponding to that of low-gradelymphoma and the type of lesions once referred to as reactivelymphoreticular hyperplasia of the stomach.

1,2

The tumorsare most frequently localized in the gastrointestinal (GI)tract, and more than 90% of all gastric MALT lymphomasare related to

Helicobacter pylori

-associated chronic gastri-tis.

2,3

Patients with gastric MALT lymphoma treated viaeradication of

H.

pylori,

4,5

chemotherapy

6

or radiotherapy

7

generally show lymphoma regression as assessed by endo-

scopic biopsy. Whether lymphomatous involvement persistssubmucosally is uncertain, however, because sampling erroris a problem in histological evaluation. Endoscopic ultra-sonography (EUS) is an appropriate modality for assessingthe depth of tumor infiltration of primary gastric lymphoma.The aim of the present study was to determine the value ofEUS examination for assessing the effectiveness of medicaltreatment of gastric MALT lymphoma.

METHODS

Our subjects comprised 12 patients with primary gastricMALT lymphoma (four men and eight women; age 48–68years, median 58 years) who underwent EUS during initialtumor staging and post-treatment examinations at our insti-tution at Hiroshima University between 1995 and 2001. Afterendoscopic observation, the intragastroduodenal air wasaspirated and 300–500 mL de-aerated water, which improvesultrasound transmission, was instilled. In the best scanning

EUS ASSESSMENT OF GASTRIC MALT LYMPHOMA 175

conditions, a tumor was identified by thickening and disrup-tion of the layers of the gastric wall and shown as a hypo-echoic mass, which is the typical EUS appearance of gastricMALT lymphoma.

8,9

The distance from the surface layer tothe deepest part of the hypoechoic area was measured viaEUS (Fig. 1) with an ultrasonic mechanical radial scanningminiprobe (SP-701, frequency 12 or 20 MHz; Fuji PhotoOptical Co., Ltd, Saitama, Japan) and/or a conventional ech-oendoscope with a radial sector scan transducer (UM200,frequency 7.5 or 12 MHz; Olympus Co., Ltd, Tokyo, Japan).A depth of the hypoechoic area of less than 1.3 mm wasconsidered normal. Diagnosis was confirmed by endoscopicbiopsy after EUS examination in all cases. The Ann Arborsystem

10

as modified by Musshoff

11

was used for tumor stag-ing. The staging procedure included a physical examination,abdominal ultrasound examination, endoscopy, EUS, com-puted tomography of the abdomen and thorax, and bonemarrow biopsy. All 12 patients were treated medically; 11patients with low-grade MALT lymphoma underwent

H. pylori

eradication therapy for 1 or 2 weeks (40 mg/dayomeprazole, 2000 mg/day amoxicillin, and 800 mg/dayclarithromycin). One patient with tumors beyond the EIIstage underwent chemotherapy (750 mg/m

2

cyclophospha-mide, 50 mg/m

2

doxorubicin, 1.4 mg/m

2

vincristine, 100 mgprednisolone (CHOP) regimen). One patient who showed noresponse to

H. pylori

eradication therapy was treated furtherwith chemotherapy (CHOP regimen). Complete regressionof tumor was defined as the disappearance of endoscopiclesions with negative biopsy specimens. The mean depth ofthe hypoechoic area in MALT lymphoma-positive biopsyspecimens and in MALT lymphoma-negative biopsy speci-mens is expressed as mean

±

standard deviation (SD). Forcomparison of the depth of the hypoechoic area in MALTlymphoma-positive biopsy specimens versus that in MALTlymphoma-negative biopsy specimens, we used the non-parametric Mann–Whitney

U

-test. A

P

-value of less than0.05 was considered statistically significant.

Fig. 1.

(a) Pretreatment endoscopic image of gastric mucosa-associated lymphoid tissue (MALT) lymphoma showsdiscolored and irregular mucosa. (b) Pretreatment endoscopicultrasonographic image of gastric MALT lymphoma showshypoechoic thickening of tissue. *Distance from the surfacelayer to the deepest part of the hypoechoic area (depth) wasmeasured.

a

b

Fig. 2.

Mean difference between the depth of thehypoechoic area of mucosa-associated lymphoid tis-sue (MALT) lymphoma-positive biopsy specimensand MALT lymphoma-negative biopsy specimens.

�

,MALT lymphoma-positive biopsy specimens(

n

=

30);

�

, MALT lymphoma-negative biopsy spec-imens (

n

=

26).

P < 0.001

2.1 ± 1.0

1.2 ± 0.6

3

2

1

0

Dep

th o

f th

e hy

poec

hoic

are

a (m

m)

176 S YOSHIDA

ET AL.

RESULTS

The mean depth of the hypoechoic area in MALT lymphoma-positive biopsy specimens was significantly greater than themean depth of the hypoechoic area in MALT lymphoma-

negative biopsy specimens (Fig. 2). The depth of the hypo-echoic area before and after medical treatment is shown inFig. 3. The median follow-up period was 22 months (range,4–50 months). Endoscopic ultrasonography after treatmentshowed that the depth of the hypoechoic area had decreased

Fig. 3.

Depth of the hypoechoic areas after medical treatment. Positive mucosa-associated lymphoid tissue lymphoma biopsyresults are shown by solid symbols, and negative biopsy results are shown by open symbols. (a) Endoscopic ultrasonography (EUS)findings during follow up of eight patients in complete regression.

�

, Patient 1: eradication therapy;

★

, Patient 2: eradication therapy;, Patient 3: eradication therapy;

�

, Patient 4: eradication therapy; , Patient 5: eradication therapy; , Patient 6: eradication ther-apy;

�

, Patient 7: eradication therapy;

�

, Patient 8: eradication therapy; (b) EUS findings during follow up of four patients withoutcomplete regression after initial treatment.

�

, Patient 9: eradication therapy;

�

, Patient 10: chemotherapy after eradication therapy;

�

, Patient 11: eradication therapy;

�

, Patient 12: eradication therapy.

Dep

th o

f th

e hy

poec

hoic

are

a (m

m)

(a)

Chemotherapy

Dep

th o

f th

e hy

poec

hoic

are

a (m

m)

(b)

EUS ASSESSMENT OF GASTRIC MALT LYMPHOMA 177

to normal during follow-up examinations in seven patients(patients 1–7) who were treated with

H. pylori

eradicationtherapy and in one patient (patient 8) treated with chemo-therapy. In all cases, the post-treatment biopsy specimens alsoappeared MALT lymphoma negative during follow-up exam-ination. In two patients (patients 6 and 7), remission asassessed by EUS was earlier compared with histologicalremission: the depth of the hypoechoic area had decreasedto normal at the 2-month and 4-month follow-up EUS exam-inations, respectively, whereas MALT lymphoma did notdisappear in the biopsy specimens. Despite the MALT lym-phoma-negative biopsy specimen in patient 8, the depth ofthe hypoechoic area did not decrease to normal within 6months after the start of medical treatment, but it did decreaseto normal by the time of the 7-month follow-up examination.In two patients (patients 9 and 11), the biopsy specimens wereMALT lymphoma negative, but there was not a decrease tonormal in the depth of the hypoechoic area, and recurrenceof the lymphoma was discovered (patient 9, 18-month follow-up examination; patient 11, 14-month follow-up examina-tion). One patient (patient 10) initially showed a decrease inthe depth of the hypoechoic area after

H. pylori

eradicationtherapy but it was not to normal; the depth of the hypoechoicarea later increased to 10 mm at the time of the 5-monthfollow-up examination. This patient was given additional che-motherapy; the depth of hypoechoic area decreased to normalafter this second course of treatment, and another biopsyspecimen was negative for MALT lymphoma. In one patient(patient 12) who showed no decrease to normal in the depthof the hypoechoic area after

H. pylori

eradication therapy,MALT lymphoma was found in the post-treatment biopsy.

DISCUSSION

Gastric MALT lymphoma arises from the mucosal lymphoidtissue normally acquired as a reaction to

H. pylori

infection.Eradication of

H. pylori

with antibiotics leads to regressionand cure of the lymphoma in 75% of cases,

4,12

but 20–30% ofMALT lymphomas associated with

H. pylori,

including manyt(11;18)-positive MALT lymphomas, do not regress aftereradication therapy.

13

A previous study showed that after

H. pylori

eradication, complete regression of MALT lym-phoma occurs significantly more often in tumors restricted tothe mucosa than in those deeply invading the submucosa.

14

With early accurate diagnosis, treatment, and follow up, theprognosis of gastric MALT lymphoma is usually good.Patients treated with

H. pylori

eradication therapy showgood lymphoma regression as assessed by endoscopic biopsy.However, although resolution of

H. pylori

infection and itsassociated inflammatory changes may occur in the superficialmucosa, whether lymphomatous involvement persists sub-mucosally is not easily determined. Endoscopy alone isunsatisfactory in evaluating locoregional extension and isthus insufficient for assessing stage, determining prognosisand planning therapy.

15,16

Endoscopic ultrasonographyappears to be effective in evaluating the depth of gastric wallinvasion, infiltration into adjacent organs and lymph nodeinvolvement,

15–17

and it may be useful for initial staging andplanning of non-surgical therapy of the stomach because itpermits visualization of the intramural area of the gastricwall. A previous report on non-Hodgkin’s lymphoma pro-posed that EUS evaluation of the gastric wall may overcome

the problem of sampling error associated with histologicalspecimens.

18

Our results show the depth of the hypoechoicarea to be greater when MALT lymphoma is present inbiopsy specimens than when MALT lymphoma is not presentin specimens. In many cases in which MALT lymphoma dis-appeared after medical treatment, the size of the hypoechoicarea also decreased to normal. However, we discovered arecurrence of lymphoma at the follow-up examination of thetwo patients who did not show a decrease to normal in thedepth of the hypoechoic area after treatment and negativeMALT lymphoma biopsy results. This finding suggests thatwhen EUS shows no decrease to normal in the depth of thehypoechoic area, careful follow up and frequent biopsies maybe necessary. This may minimize histological sampling errors.

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