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Successful treatment of mucosa-associated lymphoid tissue lymphoma in a patient with gastric and rectal lesions with metachronous and ectopic development

A 75-year-old female, who had an abnormal stomach x-ray finding, was admitted to the hospital for further examination and therapy. Upper GI endoscopy showed reddish and swollen folds on the greater curvature of the gastric body and a biopsy was of this lesion revealed malignant lymphoma (small cell type or mucosa-associated lymphoid tissue (MALT) lymphoma suspected). The patient was infected with Helicobacter pylori (H. pylori), however, in response to the patient's wishes, a total gastrectomy, omentectomy and splenectomy were performed and the histological diagnosis was gastric MALT lymphoma. Two courses of CHOP therapy (cyclophosphamide (CPM) 750 mg/m2/day, day 1, adriamycin (ADM) 50 mg/m2/day, day 1, vincristine sulfate (VCR) 1.4 mg/m2/day, day 1, prednisolone 100 mg/body, day 1–5) were administered as adjuvant chemotherapy. A colonoscopic examination performed about 4.5 yr after the operation revealed rectal submucosal tumors and the biopsied specimens were diagnosed as malignant lymphoma. A transanal focal resection was performed and the histological diagnosis was metachronous and ectopic development of MALT lymphoma. The histological finding was similar to the gastric lesion. About 4 and 7 yr after the first development of rectal MALT lymphoma, MALT lymphomas developed repeatedly in the rectal lesion, however, these were resected repeatedly and no developmenthas occurred during the past two years. This report presents a very rare case of metachronous and ectopic MALT lymphoma development in the gastric and rectal lesions.


Introduction
Mucosa-associated lymphoid tissue (MALT) lymphoma is a lymphoma derived from B-cells originating from the marginal zone of the MALT in an extra-nodal organ in the presence of chronic inflammations in the gastrointestinal tract, thyroid gland, salivary gland, lung and so on. 1,2 Many cases of MALT lymphoma of the stomach have been reported to date in association with an Helicobacter pylori (H. pylori) infection, however, the development of MALT lymphoma in the colon and rectum without the apparent etiology such as an H. pylori infection is comparably rare. Anecdotal reports in which MALT lymphomas develop metachronously in the same or different organs have been reported to date. [3][4][5][6][7][8][9] In the present case, a focal resection was performed for MALT lymphoma developed metachronously and ectopically in the rectum 3 years after a total gastrectomy for gastric MALT lymphoma followed by 2 courses of adjuvant chemotherapy. MALT lymphomas developed repeatedly in the rectal lesion, however, these were focally resected repeatedly and no recurrence has occurred over the past two years. This report presents a very rare case of successfully treated MALT lymphomas that developed metachronously and ectopically in gastric and rectal lesions.

Case Report
A 75-year-old woman showed an abnormality in the findings of barium X-ray screening for gastric cancer and was transferred to our hospital (Medical Hospital, The Nippon Dental University School of life Dentistry at Niigata) for further examination and therapy in October 1995. Upper GI endoscopy revealed swollen giant folds of the body ( Figure 1A, 1B). A biopsy was performed and malignant lymphoma (small cell type or MALT lymphoma) was suspected. The background mucosa of the stomach was positive for an H. pylori infection in a retrospective pathological examination. We did not perform any chromosomic study at that time. Very recently, we performed the FISH assay to evaluate the translocation of t (11;18) in formalin fixed tissues of gastric and colonic tumors, however, we could not perform any proper examination on this translocation because the tumor tissues with formalin fixation were in bad condition. A computed tomography (CT) scan of the chest, abdomen and pelvic lesion demonstrated no swollen lymph nodes. Although there were several options for treatment, the patient and her family requested that the lesion be treated surgically. A total gastrectomy, omentectomy and splenectomy (D2 resection of regional lymph nodes and Roux-en-Y gastrojejunostomy) were thus performed in November 1995 (Figure 2 A, B). The histopathological diagnosis was MALT lymphoma (Figure 3 A,B) with a slight invasion into the spleen. Lymphoepithelial lesion (LEL), positive immunoreactivity for CD20 (L26) and CD79a, and negative immunoreactivity for cyclin D1 and CD5 were observed (figure not shown). A Positive IgG-rearrangement and monoclonal proliferation were confirmed (figure not shown). The depth of greatest invasion of the tumor was the muscularis propria. No metastatic lymph nodes and no vestigial remnant of the tumor were seen. Therefore, the patient was diagnosed as stageⅡE by Ann Arbor classification, 10 as stageⅡE1 by Lugano International classification 11 and as stageⅡ1 by Blackledge Staging System. 12 Two courses of CHOP therapy (cyclophosphamide (CPM) 750 mg/m 2 /day, day 1, adriamycin (ADM) 50 mg/m 2 /day, day 1, vincristine sulfate (VCR) 1.4 mg/m 2 /day, day 1, prednisolone 100 mg/body, day 1-5) were administered as an adjuvant chemotherapy, beginningDecember 11, 1995. Afterward, the patient was followed as an out- The patient is currently being followed as an outpatient without additional adjuvant chemotherapy, however, the patient shows no sign of recurrence of MALT lymphoma and her serum IL2-recepter levels remain within the normal limits.

Discussion
MALT lymphoma is a low grade malignant Bcell lymphoma that develops from mucosaassociated lymphoid tissue (MALT). The concept of MALT lymphoma was first introduced by Isaacson et al. 13    ic B-cells and into the follicles; iii) tumor cells likely to be differentiated into the plasma cells (lymphoplasmacytoid cells); iv) lymphoepithelial lesions (LEL) and so on. [13][14][15] Centrocyte-like cells, diffuse proliferation in the marginal zone of monocytic B-cell lymphoma cells, LEL, positive IgG-reconstruction and monoclonal proliferation were observed in the current case. In addition, the histopathological examinations revealed positive immunoreactivity for CD20 (L26) and CD79a and negative immunoreactivity for cyclin D1 and CD5. Therefore, with the case herein presented many of the above-mentioned features of MALT lymphoma. The surgical specimen in the last (third) focal resection showed that the tumor cells appeared to be well differentiated plasma cells, partly because a lymphoma cell characterized as a MALT lymphoma may develop and proliferate monoclonally over an extended time through metachronous development. Since many of metachronous and multiple MALT lymphoma cases can arise from identical cells, the MALT lymphoma which developed metachronously in the gastric and rectal lesions may have arisen from identical lymphoma cells and was more likely to be differentiated into plasma cells.
MALT lymphoma is likely to develop from inflammatory lesions after a prior infection, not only an H. pylori infection of the stomach, but also autoimmune diseases, such as, Torsten Sjogren's syndrome of salivary gland and thymus and Hashimoto's disease (hypothyroidism) of thyroid have been associated with the development of MALT lymphoma. 2 While MALT lymphomas in the gastrointestinal tract are likely to develop from gastric lesions associated with H. pylori infection; MALT lymphoma development in the colon and rectum in which H. pylori infection and other apparent inflammation are not seen, is comparatively rare. Patients with MALT lymphoma have a higher incidence of colonic involvement than previously reported.
Furthermore, Yoshino et al. 16 and Thieblemont et al. 17  There are various macroscopic forms of MALT lymphoma. Most gastric MALT lymphoma show surface-accretive lesions with groveling progress in the mucosa because the mucosal invasive type accounts for many of the gastric MALT lymphoma cases. In contrast, because colonic MALT lymphomas are likely to progress mainly in the submucosal layers, most colonic MALT lymphomas appear to be a macroscopic form of submucosal tumor (SMT). 18,19 In the present case, the gastric lesion showed swollen and reddish folds on the greater curvature and the colonic lesion showed a flat elevation like a SMT. These macroscopic forms were characteristic of MALT lymphoma as described above.
MALT lymphomas also show characteristic chromosomal and genetic features. Most MALT lymphomas have API2/MALT1 chimeric DNA resulting from a translocation of t (11;18). 20,21 These chromosomal changes are recognized in about 50% of all MALT lymphomas and in 10-20% of all gastric MALT lymphomas. 22 Additional chromosomal changes include trisomy 3 23 and t(1;14) with a translocation of the Bcl10-gene. 24 Many of the MALT lymphoma cases with the t(11;18) translocation are resistant to eradication of H. pylori and show multiorgan involvement, 25,26 although, there is little or no concern of their developing malignant potential. However, several previous reports indicate that, in most MALT lymphoma patients with multiple organ involvement, the multiple lesions consisted of an identical clone. [27][28][29] Iwano et al. reported that most API2-MALT1-positive gastric MALT lymphomas with multiple lesions or multiple organ involvement appear to originate from a single lesion and disseminate to other lesions or organs. 30 In the present case, the presence of t(11;18), API2-MALT1 fusion transcripts and the monoclonality of CDR3 was not determined, partly because there was no frozen sample of the tumor lesions. Therefore, it is impossible to determine whether the primary lesion metastasized to the rectum or whether the MALT lymphomas developed metachronously from the background so common in the gastric and rectal lesions. In the current case, the rectal MALT lymphoma developed about 3 and a half years after the operation for the gastric lesion. The incidence of metastasis from a gastric lesion to the rectum is very low, with respect to the metastatic pathway. The background factors common to gastric and rectal lesions are not known nor is the association between the infection and the inflammation caused from the infection or other factors. However, anecdotal reports have indicated that antibiotics were effective for treating colonic MALT lymphoma regardless of the presence of an H. pylori infection in the gastric lesion. 18,19,31 These reports suggested the possibility of a correlation between colonic MALT lymphoma development and colonic bacteria.
In  report suggested that H. pylori-eradication or antibiotic treatment targeting H. pylori was ineffective for treatment of extra-gastric MALT lymphomas. 32 In the past, the first line of therapy for the limited type of malignant lymphoma has been a resection of the tumor including the gastric lesion. Adjuvant chemotherapy has been administered in Japan and adjuvant radiotherapy in Western countries and the United States for cases with positive lymph node metastasis and focal progression. The concept of MALT lymphoma was introduced in the 1980s 1,13 and the correlation with H. pylori infections was initially suggested in 1995. [33][34][35] Eradication of H. pylori is now considered to be an internationally accepted standard therapy for the limited type of gastric MALT lymphoma. In particular, in those cases with positive H. pylori infections, eradication of the infection has been shown to improve the cure rate from 80% to 90%. Even if the patients are negative for H. pylori infections, eradication is advantageous in the cases positive for H. heilmani or false-negative for H. pylori infections, however, most cases negative for H. pylori infections have the API2/MALT1 transcripts produced by the translocation of t(11;18), 22 reveal multiorgan involvements and show no effect of H. pylori eradication.
A salvage operation is the standard therapy for patients who do not respond to eradication, however, radiation therapy, 36,37 administration of CHOP therapy, 38 single drug therapy with cyclophosphamide,39 cladribine, 40 etc. and Rituximab (anti-CD20 antibody) [41][42][43] are other selected forms of treatment.
No therapy has been established for colonic MALT lymphoma. Anecdotal reports have described effective eradication for colonic MALT lymphoma as with gastric lesions, regardless of H. pylori infection status in the stomach, 19,31,44,45 and it would seem appropriate to perform eradication therapy because it involves simple oral therapy for 7 days. However, it has been reported that eradication therapy was not effective for extra-gastric MALT lymphoma in one study 32 and there are a number of questions of its therapeutic effect. Surgical resection is the most frequent therapeutic procedure for rectal MALT lymphoma in Japan. Further more, CHOP therapy and oral cyclophosphamide, 39 etc., or Rituximab etc. are used as they are with gastric MALT lymphoma.
In the present case, eradication seems appropriate to the initially selected therapeutic procedure, because the patient was positive for H. pylori infection. Ho wever, in 1995, when the correlations between MALT lymphoma and H. pylori were initially reported, the patient and her family strongly requested a surgical resection. Therefore, a total gastrectomy was performed. The pathological examination suggested the involvement of the regional lymph nodes and the invasion into the spleen, thus two courses of CHOP therapy were added as adjuvant chemotherapy, however, rectal MALT lymphomas thereafter developed metachronously and repeatedly. Anecdotal reports on the effectiveness of eradication for colonic MALT lymphomas have been published 19,31,44,45 and eradication therapy could have been administered, however, because the patient and her family requested a surgical operation, we judged that the advantages due to a preservation of a quality of life by not performing a colostomy were therefore greater than the disadvantages due to a relapse after a focal resection and thus selected a trans-anal focal resection of the tumor. It was strongly suggested that MALT lymphomas are likely to develop due to some background factor common in the stomach and rectum.
These common factors in the stomach and rectum are unknown, however, because several cases in which antibiotics for eradication were effective, have been reported to date, 19,31,44,45 such factors may be an infection of some kind other than H. pylori.
Eradication therapy was administered in August 2006, to prevent further metachronous developmentof MALT lymphoma. In the current case, careful observations, including periodical endoscopic examinations, computed tomography (CT) scans, measurement of the levels of serum interleukin-2 (s-IL-2) receptor, are needed. Further experimental and clinical research on the most appropriate treatments for colonic MALT lymphoma is awaited with great interest.