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CASE REPORT

Helicobacter-Independent,Chemotherapy-Resistant, Radiosensitive Gastric

MALT Lymphoma with Massive Depositsof Amyloidlike Substance

HIROSHI MATSUMOTO, MD,* HIDEKI KOGA, MD,* MITSUO IIDA, MD,* † HIROSHI SUEKANE, MD,*KEN-ICHI TARUMI, MD,* KAZUNORI HOSHIKA, MD,* YOSHIKI MIKAMI, MD, ‡ and KEN HARUMA, MD*

KEY WORDS: gastric MALT lymphoma;Helicobacter pylori; eradication therapy; chemotherapy; radiation therapy; amyloidlike substance.

Gastric lymphoma is a heterogeneous group of variousclinicopathologic conditions. Mucosa-associated lym-phoid tissue (MALT) lymphoma, which was first de-scribed by Isaacson and Wright (1) in 1983, has becomea distinct entity in gastric lymphoma. For a long time, thetreatment for gastric lymphoma has been surgical resec-tion regardless of the clinicopathologic features (2). Asfor gastric MALT lymphoma, a causal relationship withHelicobacter pylori(Hp) infection has been indicated (3,4), and antibiotic therapy to eradicate Hp has become thetreatment of choice (5, 6). However, some gastric MALTlymphomas do not respond to Hp eradication. It remainscontroversial what the approach should be when Hp erad-ication proves ineffective.

Recently, it has been reported that radiation therapy,which has been used frequently as an adjuvant therapyto other treatments, might become a primary therapy forgastric MALT lymphoma (7). Because radiation has moreadverse effects than Hp eradication, the indications for ra-diation therapy should be carefully determined. We usedradiation therapy for a patient with a gastric MALT lym-phoma that had not responded to Hp eradication therapy,and which had further resisted single-agent chemother-apy and combined chemotherapy. Herein, we describe the

Manuscript received March 27, 2002; accepted December 15, 2002.From the *Division of Gastroenterology, Department of Medicine,

and‡Department of Pathology, Kawasaki Medical School, Kurashiki,Japan; and†Department of Medicine and Clinical Science, GraduateSchool of Medical Sciences, Kyushu University, Fukuoka, Japan.

Address for reprint requests: Dr. Hiroshi Matsumoto, Divisionof Gastroenterology, Department of Medicine, Kawasaki MedicalSchool, Matsushima 577, Kurashiki, Okayama 701-0192, Japan; e-mail:hirom@med.kawasaki-m.ac.jp.

clinical course of this patient and the clinicopathologicfeatures of her MALT lymphoma in detail.

CASE REPORT

In June 1996, a 68-year-old Japanese woman underwent anupper gastrointestinal series during a medical checkup, and cir-cumferential rigidity of the gastric body was incidentally noted.Esophagogastroduodenoscopy revealed multiple depressed le-sions mimicking early IIc-type gastric cancer, and extensivelyrough and hyperemic mucosa with a lack of extension after airinjection of the gastric body (Figure 1). Microscopic examinationof biopsy specimens disclosed an excess of lymphocytes, lym-phoepithelial lesions, and the presence of centrocytelike cells(Figure 2A). Based on these clinicopathologic findings, a diag-nosis of gastric MALT lymphoma was made. Interestingly, aneosinophilic amorphous substance was massively deposited inthe tumor (Figure 2B). Congo red stain did not impart a uniquegreen birefringence when stained tissue sections were viewedusing a polarizing microscope. Therefore, the material appearedto be a nonamyloidal substance. The deposits were further la-beled negatively for immunoglobulins. On October 17, 1998,the patient was admitted to our hospital for treatment of thiscondition.

On admission, physical and laboratory examinations revealedno abnormal findings except mild anemia. Histologic and cul-tural examinations of biopsy specimens and the urea breath testshowed them to be positive for Hp.

Initially, we attempted to eradicate Hp by the following reg-imen: a two-week course of 30 mg of lansoprazol, 1000 mg ofamoxicillin, and 500 mg of metronidazole daily. Eight weeksafter the treatment, eradication of Hp was achieved, as assessedby a negative culture, histology, and the urea breath test. How-ever, lymphoma cells were observed histologically. Because theMALT lymphoma remained unchanged after further follow-upof several months, the patient underwent oral monochemother-apy with 100 mg of cyclophosphamide daily. Although themonochemotherapy was continued for 12 months, her lymphoma

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Fig 1. Esophagogastroduodenoscopy disclosed multiple depressed le-sions mimicking early IIc-type gastric cancer.

cells never disappeared. Therefore, combination chemotherapywas carried out with pirarubicin, cyclophosphamide, vincristin,and prednisolone (THP-COP). However, her MALT lymphomahad never changed.

Finally, radiation was applied to the lymphoma as the soletherapy. A total radiation dose of 30 Gy was delivered to thestomach in 1.5-Gy fractions over a 20-days period. No adverseeffect was observed during the therapy. Endoscopy disclosedonly a few erosions in the IIc-like lesions. Surprisingly, micro-scopic evaluation of biopsy specimens revealed complete dis-appearance of lymphoma cells. The amyloidlike substance hadalso disappeared completely. The patient underwent endoscopicevaluation and biopsy at three-month intervals for one year andthereafter at six-month intervals. No recurrence of the MALTlymphoma has been noted during the last 2.5 years.

Serial Endosonographic Findings.In June 1996, initial en-dosonography disclosed a significant thickening of the secondand the third layers (Figure 3A). Disappearance of differen-tiation between the layers was noted. Endosonography afterHp eradication revealed no changes (Figure 3B). Followingmonochemotherapy and combined chemotherapy, endosono-graphic findings still remained unchanged. After radiation, how-ever, thickening of the second and third layers was dramaticallyreduced (Figure 3C). The differentiation between the layers be-came obvious. To date, the thickness of the second and thirdlayers remains as thin as it was immediately after radiation.

DISCUSSION

At present, antibiotic therapy to eradicate Hp is the treat-ment of choice for gastric MALT lymphoma. Various stud-ies have found an association between Hp infection andgastric MALT lymphoma (3, 4, 8, 9). Eidt et al (9) reportedthat the presence of Hp was verified on biopsy specimens

Fig 2. Histologic examination of biopsy specimens revealed an ex-cess of lymphocytes, lymphoepithelial lesions, and the presence ofcentrocyte-like cells (A). An eosinophilic amorphous substance wasmassively deposited in the tumor (B).

of all 121 patients with gastric MALT lymphoma theyinvestigated by Warthin-Starry silver staining. Does Hpinfection actually cause gastric MALT lymphoma in ev-ery case? Steinbach et al (10) reported that 6 of 34 pa-tients with gastric MALT lymphoma were Hp-negativeand that none of them responded to Hp eradication ther-apy. In a larger series by Nakamura et al (11), a histologicanalysis of 237 patients with primary gastric lymphomashowed the frequency of Hp positivity to be only 63%in patients with MALT lymphoma. These studies suggestthat more Hp-unrelated gastric MALT lymphomas may bepresent than we may have imagined. In our case, Hp erad-ication therapy also proved ineffective, although the pres-ence of Hp had been verified by the histologic and culturalexaminations of biopsy samples and by the urea breathtest. The above-mentioned report by Steinbach et al (10)also described 4 of 28 Hp-positive patients with gastric

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Fig 3. Endosonography initially disclosed a 10.5 mm thickening of thesecond and third layers (A). Disappearance of differentiation between thelayers was also observed. Following Hp eradication, there was no changein the endosonographic findings (B). However, after radiation therapy,endosonography demonstrated a significant reduction in the thickeningof these two layers to 5.5 mm in thickness (C), and the differentiationbetween the layers was restored.

MALT lymphoma who did not respond to Hp eradicationtreatment. Sackmann et al (12) also reported no tumor re-sponse to Hp eradication therapy was observed in 5 of 22patients with Hp-positive gastric MALT lymphoma. Wepreviously investigated the efficacy of Hp eradication ther-apy against gastric MALT lymphoma in 22 patients, andfound that 6 patients did not respond (13). Of the 6 pa-tients, 4 were Hp-positive, but the quantity of Hp, whichwas immunohistochemically assessed in accordance withthe updated Sydney system (14), was significantly lessthan that in patients who responded to Hp eradication. Inthe present case, as expected, the quantity of Hp was small.

Although chemotherapy is a well-recognized optionof the treatment of primary gastric lymphoma, only lim-ited information is available regarding its use as primaryor adjuvant theapy in treating gastric MALT lymphoma.Blazquez et al (15) reported 14 patients with low-gradegastric MALT lymphoma who were treated with single-agent chemotherapy. All of these patients initially re-sponded to an oral cyclophosphamide alone. Hammel et al(16) also treated 24 patients with low-grade gastric MALTlymphoma with continuous single-agent chemotherapy oforal cyclophosphamide or chlorambucil. However, only18 of these patients completely responsed, and 5 of themrelapsed. In our patient, monochemotherapy was also in-effective. A detailed analysis of the clinicopathologicalcharacteristics of nonresponders to chemotherapy is re-quired to clarify what kind of patient is a suitable candidatefor chemotherapy.

Radiation therapy was a unique modality for treatinggastric MALT lymphoma in our patient successfully. Al-though gastric lymphoma has long been known to oftenbe radiosensitive, radiation therapy has been recognizedas a complementary therapy to primary surgical therapyor chemotherapy. Regarding the primary effect of radi-ation therapy, Burgers et al (17) treated non-Hodgkin’slymphoma of the stomach with radiation therapy alone,and reported a four-year disease-free survival rate of 83%.Schechter et al (7) evaluated the efficacy of radiation ther-apy alone in 17 patients with gastric MALT lymphoma anddescribed a surprising result of an event-free survival rateof 100% at a median follow-up time of 27 months. Theyconcluded that radiation therapy alone might become analternative to surgery in treating gastric MALT lymphomain its early stages. In our case, radiation therapy was theonly beneficial option, and the patient has been in com-plete remission for the last 33 months. To the best of ourknowldege, this is the first reported case in which radia-tion therapy has proven effective following verification ofresistance to Hp eradication therapy, monochemotherapy,and combination chemotherapy. Therefore, we intend tocarry out a comparative study of the success of radiation

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therapy and eradication therapy or chemotherapy in treat-ing gastric MALT lymphoma.

The most characteristic histologic feature of our pa-tient’s MALT lymphoma was massive deposits of aneosinophilic amorphous substance (EAS). Such materialwithin lymphomas is occasionally amyloid protein (18).However, this was histologically ruled out in our caseby the negative specific staining for amyloid protein. Todate, few reports have referred to non amyloidal EAS(19, 20). Akaza et al (19) sometimes observed hyalinesclerosis with amyloid-like material in the submucosalinfiltration of lymphoma cells. Aihara et al (20) immuno-histochemically and ultrastructurally investigated EAS ina patient with extramedullary plasmacytoma of the thy-roid, and identified the EAS in their patient as consistingof polytypic immunoglobulins, major histocompatibilityantigens, electron-lucent collagen fibers, and nonfibrillarmaterials. In some MALT lymphomas, plasma cell differ-entiation is very predominant. Such a MALT lymphomaappears to be of a lymphoplasmacytic cell predominanttype (21). Considering the biological characteristics ofplasma cells and the previously analyzed features of EAS,this type of MALT lymphoma may easily produce non-amyloidal EAS. In our case, in which plasma cell dif-ferentiation was significant, the massive deposits of non-amyloidal EAS may have played an inhibitory role in thetreatment of this condition. Although we checked out pre-vious studies carefully, a possible relation between EASdeposists and resistance to medical treatments has neverbeen noted. Further analyses are therefore required.

EUS is useful in the diagnosis, staging, and predic-tion of regression in gastric MALT lymphoma (12, 22,23). Our patient underwent serial radiologic, gastroscopic,and EUS examinations, and the EUS findings correlatedwith histologic findings more faithfully than those of anyother examinations. After Hp eradication, endoscopic ex-amination disclosed fading of the hyperemic mucosa ofthe lesion, whitish mucosa, but the lymphoma cells re-mained. At that time, the EUS findings, like those of thehistologic examinations, remained unchanged. When thelymphoma cells disappeared following successful radia-tion therapy, the endoscopic findings scarely changed. Incontrast, EUS disclosed a reduced thickening of the mu-cosubmucosal layer and clearness of the layer structure.Regarding follow-up of patients with gastric MALT lym-phoma, it may be necessary to pay much more attentionto changes in EUS findings.

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