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胃MALTリンパ腫

著者: 中村昌太郎 岩手医科大学医学部 内科学講座消化器内科 消化管分野

監修: 上村直実 国立国際医療研究センター 国府台病院

著者校正/監修レビュー済:2020/07/09
参考ガイドライン:
  1. 日本胃癌学会編:胃癌治療ガイドライン 医師用2018年1月改訂(第5版). 金原出版、2018
  1. Ruskone-Fourmestraux A, et al: EGILS consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT. Gut 60: 747-758, 2011
  1. Zucca E, et al: Gastric marginal zone lymphoma of MALT type: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol Suppl.6:vi 144-148, 2013
  1. NCCN Guidelines Version 1.2020. Extranodal Marginal Zone B-Cell Lymphoma: Gastric MALT lymphoma.
患者向け説明資料

概要・推奨   

  1. H. pylori陽性胃MALTリンパ腫の患者には、H. pylori除菌を第1選択の治療とすることが勧められる(推奨度1)。
  1. 胃MALTリンパ腫におけるH. pylori除菌治療に対する抵抗性の予測因子として、H. pylori感染の有無、t(11;18)/BIRC3-MALT1転座、深達度などがある(推奨度1)。
  1. H. pylori除菌で寛解が得られない胃MALTリンパ腫に対する二次治療は、PDの有無と病期に応じて決定すべきである(推奨度2)。
  1. 限局期(I/Ⅱ1期)のH. pylori除菌治療抵抗性胃MALTリンパ腫には放射線治療が勧められる(推奨度2)。
  1. 化学療法と抗体療法は、病期にかかわらず、H. pylori除菌治療抵抗性胃MALTリンパ腫に有効である(推奨度2)。
  1. 胃MALTリンパ腫に対するH. pylori除菌治療後の長期予後はきわめて良好である(推奨度1)。
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
中村昌太郎 : 特に申告事項無し[2021年]
監修:上村直実 : 未申告[2021年]

改訂のポイント:
  1. 定期レビューを行い、下記について改訂を行った。
  1. 特徴的な染色体(遺伝子)転座の名称が変更〔「API2」→「BIRC3」〕された。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. MALTリンパ腫(extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue)は、節外臓器に生じる粘膜関連リンパ組織の辺縁帯B細胞由来の低悪性度リンパ腫であり、消化管に好発する[1][2]
  1. 胃MALTリンパ腫は胃悪性腫瘍の1~5%、全MALTリンパ腫の30~40%、胃悪性リンパ腫の40~50%を占める[1][2][3]
  1. 胃MALTリンパ腫の約90%はHelicobacter pylori感染による慢性胃炎を基盤に発生し、15~20%で特異的な染色体転座t(11;18)(q21;q21)/ BIRC3-MALT1を認める[4]
  1. 予後はきわめて良好で、診断後5年生存率は90~96%である。原病死はまれであるが、2~5%の例でびまん性大細胞型B細胞リンパ腫に形質転換し、死に至る例もある[5]
 
問診・診察のポイント  
  1. 以前の胃の内視鏡・X線検査歴とH. pyloriの診断・除菌歴の有無を確認する。
  1. 症状は、胃癌と同様、非特異的で、腹痛、悪心・嘔吐、消化管出血などがみられるが、無症状の例も少なくない[2]。 症状(発熱、体重減少、盗汗)の有無を確認する。
  1. 有症状または検診などで胃の異常が疑われる場合、鑑別疾患としてMALTリンパ腫の可能性も念頭に置き、内視鏡検査を行う。

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文献 

著者: S Nakamura, M Iida
雑誌名: Nihon Shokakibyo Gakkai Zasshi. 2001 Jun;98(6):624-35.
Abstract/Text
PMID 11436279  Nihon Shokakibyo Gakkai Zasshi. 2001 Jun;98(6):624-35.
著者: Angelo Zullo, Cesare Hassan, Alessandro Andriani, Francesca Cristofari, Vincenzo Cardinale, Gian Paolo Spinelli, Silverio Tomao, Sergio Morini
雑誌名: J Clin Gastroenterol. 2010 May-Jun;44(5):340-4. doi: 10.1097/MCG.0b013e3181b4b1ab.
Abstract/Text GOAL: To assess the clinical and endoscopic presentation of primary gastric lymphoma.
BACKGROUND: Remission rate and long-term survival in patients with gastric lymphoma mainly depend on disease stage at diagnosis. Series reporting clinical and endoscopic presentation of gastric lymphoma are generally small and heterogeneous.
STUDY: Systematic review with pooled-data analysis assessing clinical and endoscopic presentation of primary gastric lymphoma.
RESULTS: Data regarding 2000 patients were collected. Overall, males were slightly more prevalent, alarm symptoms were absent in near half of the patients, lymphoma was diagnosed in a stage >I in one-third of the patients, and Helicobacter pylori infection was present in 88.8% of considered patients. At endoscopy, the ulcerative type was the most frequent presentation, although low-grade lymphoma was diagnosed on normal/hyperemic gastric mucosa in 9% of cases. Patients with high-grade lymphoma presented alarm symptoms (anemia and/or melena and/or hemorrhage, persistent vomiting, weight loss), an exophytic or ulcerative lesion, a stage III-IV, and a H. pylori negative status more frequently than low-grade lymphoma cases.
CONCLUSIONS: Our pooled-data analysis showed that gastric lymphoma is still disappointingly diagnosed in an advanced stage in a large number of patients. This is probably due to presence of nonspecific symptoms at initial clinical presentation and/or a normal appearing mucosa at endoscopic observation in the early stages.

PMID 19745757  J Clin Gastroenterol. 2010 May-Jun;44(5):340-4. doi: 10・・・
著者: Shotaro Nakamura, Hongtao Ye, Chris M Bacon, Alison Goatly, Hongxiang Liu, Alison H Banham, Roland Ventura, Takayuki Matsumoto, Mitsuo Iida, Yutaka Ohji, Takashi Yao, Masazumi Tsuneyoshi, Ming-Qing Du
雑誌名: Gut. 2007 Oct;56(10):1358-63. doi: 10.1136/gut.2007.123729. Epub 2007 May 24.
Abstract/Text BACKGROUND AND AIMS: There is a need for genetic biomarkers to guide prognosis and management of gastric mucosa-associated lymphoid tissue (MALT) lymphomas. We assessed the incidence and clinical significance of the MALT lymphoma-associated genetic abnormalities t(11;18)/API2-MALT1, t(1;14)/BCL10-IGH, t(14;18)/IGH-MALT1, t(3;14)/FOXP1-IGH, and extra copies of MALT1 and FOXP1 in gastric MALT lymphomas from Japan.
METHODS: The presence of translocations and copy number changes involving MALT1, IGH and FOXP1 were assessed in 90 cases of gastric MALT lymphoma using interphase fluorescence in situ hybridisation (FISH). In cases carrying a MALT1 translocation, FISH for API2-MALT1 was performed, whereas in those carrying an IGH translocation, FISH was performed for BCL10, BCL6, BCL2, c-MYC and/or CCND1.
RESULTS: t(11;18)/API2-MALT1 was detected in 18 of 87 (21%) cases and was significantly associated with Helicobacter pylori-negativity, resistance to H pylori eradication and Bcl10 nuclear expression. Four of 68 (6%) cases carried a translocation involving IGH and FOXP1 (n = 1), BCL2 (n = 1) or an unknown partner (n = 2). Neither t(1;14)/BCL10-IGH nor t(14;18)/IGH-MALT1 was detected. Extra copies of MALT1 and FOXP1 were detected in 18 of 71 (25%) cases and 10 of 59 (17%) cases, respectively. The presence of extra copies of MALT1 was significantly associated with progression or relapse of lymphoma, and was an independent adverse prognostic factor for event-free survival as determined by multivariate analysis.
CONCLUSIONS: t(11;18)/API2-MALT1 is frequent, whereas IGH-involved translocations are rare in gastric MALT lymphoma in Japan. The presence of extra copies of MALT1, often suggestive of partial or complete trisomy 18, is a frequent genetic aberration in gastric MALT lymphoma, which appears to predict adverse clinical behaviour.

PMID 17525089  Gut. 2007 Oct;56(10):1358-63. doi: 10.1136/gut.2007.123・・・
著者: Shotaro Nakamura, Toshiro Sugiyama, Takayuki Matsumoto, Katsunori Iijima, Shouko Ono, Masahiro Tajika, Akira Tari, Yasuhiko Kitadai, Hiroshi Matsumoto, Tadanobu Nagaya, Toshiro Kamoshida, Norihiko Watanabe, Toshimi Chiba, Hideki Origasa, Masahiro Asaka, JAPAN GAST Study Group
雑誌名: Gut. 2012 Apr;61(4):507-13. doi: 10.1136/gutjnl-2011-300495. Epub 2011 Sep 2.
Abstract/Text OBJECTIVE: A multicentre cohort follow-up study of a large number of patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma was conducted to elucidate the long-term outcome of the disease after Helicobacter pylori eradication.
METHODS: 420 patients with gastric low-grade MALT lymphoma who had undergone successful H pylori eradication and been followed up for at least 3 years were registered from 21 participating institutes. Responders to treatment were defined as patients whose post-treatment biopsies showed complete histological response (ChR) or probable minimal residual disease (pMRD). Treatment failure was defined as the status of progressive disease or lymphoma relapse after ChR/pMRD.
RESULTS: 323 patients (77%) responded to H pylori eradication. A logistic regression analysis showed that absence of H pylori, submucosal invasion determined by endoscopic ultrasonography and t(11;18)/API2-MALT1 were independent predictors of resistance to H pylori eradication. During the follow-up periods ranging from 3.0 to 14.6 years (mean 6.5 years, median 6.04 years), the disease relapsed in 10 of 323 responders (3.1%) while progressive disease was found in 27 of 97 non-responders (27%). Thus, 37 of 420 patients (8.8%) were regarded as treatment failures. Of these 37 patients, transformation into diffuse large B cell lymphoma occurred in nine patients. Among the non-responders and relapsed patients, 17 patients were subjected to a 'watch and wait' strategy while 90 patients underwent second-line treatments including radiotherapy (n=49), chemotherapy (n=26), surgical resection (n=6), chemoradiotherapy (n=5), antibiotic treatment (n=2), rituximab monotherapy (n=1) or endoscopic resection (n=1). Probabilities of freedom from treatment failure, overall survival and event-free survival after 10 years were 90%, 95% and 86%, respectively. Cox multivariate analysis revealed endoscopic non-superficial type to be an independent prognostic factor for adverse freedom from treatment failure, overall survival and event-free survival.
CONCLUSIONS: The excellent long-term outcome of gastric MALT lymphoma after H pylori eradication was confirmed by this large-scale follow-up study.

PMID 21890816  Gut. 2012 Apr;61(4):507-13. doi: 10.1136/gutjnl-2011-30・・・
著者: A Ruskoné-Fourmestraux, W Fischbach, B M P Aleman, H Boot, M Q Du, F Megraud, C Montalban, M Raderer, A Savio, A Wotherspoon, EGILS group
雑誌名: Gut. 2011 Jun;60(6):747-58. doi: 10.1136/gut.2010.224949. Epub 2011 Feb 11.
Abstract/Text This consensus report of the EGILS (European Gastro-Intestinal Lymphoma Study) group includes recommendations on the management of gastric extranodal marginal zone B-cell lymphoma of MALT. They are based on data from the literature and on intensive discussions and votings of the experts during their annual meetings.

PMID 21317175  Gut. 2011 Jun;60(6):747-58. doi: 10.1136/gut.2010.22494・・・
著者: A C Wotherspoon, C Doglioni, T C Diss, L Pan, A Moschini, M de Boni, P G Isaacson
雑誌名: Lancet. 1993 Sep 4;342(8871):575-7.
Abstract/Text Certain features of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue (MALT) suggest the tumour is antigen-responsive. Given the close association between gastric MALT lymphoma and Helicobacter pylori, these organisms might be evoking the immunological response, and eradication of H pylori might inhibit the tumour. 6 patients in whom biopsies showed histological and molecular-genetic evidence of low-grade gastric B-cell MALT lymphoma with H pylori infection were treated with antibiotics. In all cases H pylori was eradicated and in 5, repeated biopsies showed no evidence of lymphoma. These results suggest that eradication of H pylori causes regression of low-grade B-cell gastric MALT lymphoma, and that anti-H-pylori treatment should be given for this lymphoma.

PMID 8102719  Lancet. 1993 Sep 4;342(8871):575-7.
著者: A Rohatiner, F d'Amore, B Coiffier, D Crowther, M Gospodarowicz, P Isaacson, T A Lister, A Norton, P Salem, M Shipp
雑誌名: Ann Oncol. 1994 May;5(5):397-400.
Abstract/Text It was considered timely to review the pathological and staging classifications of GI tract lymphoma. This meeting specifically did not address the question of treatment; the management of GI tract lymphoma could perhaps form the basis for a further workshop. The following recommendations were made: to adopt the Isaacson histological classification, that all patients with GI tract lymphoma be investigated uniformly, to record the prognostic factors described above, to use the staging classification shown above. It is hoped that these recommendations will be taken into account in the design of future clinical trials of therapy for GI tract lymphoma.

PMID 8075046  Ann Oncol. 1994 May;5(5):397-400.
著者: Angelo Zullo, Cesare Hassan, Francesca Cristofari, Alessandro Andriani, Vincenzo De Francesco, Enzo Ierardi, Silverio Tomao, Manfred Stolte, Sergio Morini, Dino Vaira
雑誌名: Clin Gastroenterol Hepatol. 2010 Feb;8(2):105-10. doi: 10.1016/j.cgh.2009.07.017. Epub 2009 Jul 22.
Abstract/Text BACKGROUND & AIMS: Different remission rates of gastric low-grade, B-cell, mucosa-associated lymphoid tissue (MALT) lymphoma have been reported after Helicobacter pylori eradication. We assessed the long-term remission and relapse rates of early stage MALT lymphoma in patients treated only by H pylori eradication and identified factors that might predict outcome.
METHODS: This systematic review analyzed data from 32 studies, including 1408 patients.
RESULTS: The MALT lymphoma remission rate was 77.5% (95% confidence interval, 75.3-79.7), and was significantly higher in patients with stage I than stage II(1) lymphoma (78.4% vs 55.6%; P = .0003) and in Asian than in Western groups (84.1% vs 73.8%; P = .0001). Neoplasia confined to the submucosa regressed more frequently than that with deeper invasion (82.2% vs 54.5%; P = .0001); patients with lymphoma localized to the distal stomach experienced regression more frequently than those with lymphoma of the proximal stomach (91.8% vs 75.7%; P = .0037). The remission rate was higher among patients without the API2-MALT1 translocation than in those with this translocation (78% vs 22.2%; P = .0001). In an analysis of data from 994 patients, 7.2% experienced lymphoma relapse during 3253 patient-years of follow-up evaluation, with a yearly recurrence rate of 2.2%. Infection and lymphoma were cured by additional eradication therapy in all patients with H pylori recurrence (16.7%). Five (0.05%) of the patients initially cured of lymphoma developed high-grade lymphoma within 6 to 25 months of therapy.
CONCLUSIONS: H pylori eradication is effective in treating approximately 75% of patients with early stage gastric lymphoma. Long-term follow-up evaluation of these patients is needed to detect early lymphoma relapse or progression.

Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
PMID 19631287  Clin Gastroenterol Hepatol. 2010 Feb;8(2):105-10. doi: ・・・
著者: M Raderer, B Streubel, S Wöhrer, M Häfner, A Chott
雑誌名: Gut. 2006 May;55(5):616-8. doi: 10.1136/gut.2005.083022. Epub 2005 Nov 18.
Abstract/Text BACKGROUND AND AIMS: The role of antibiotic treatment in early stage gastric mucosa associated lymphoid tissue (MALT) lymphoma not associated with Helicobacter pylori infection has not been investigated.
PATIENTS AND METHODS: Six patients with localised gastric MALT lymphoma underwent antibiotic treatment with clarithromycin, metronidazole, and pantoprazole. Staging, including endosonography plus gastroscopy, computed tomography of the thorax and abdomen, colonoscopy, magnetic resonance imaging of the salivary glands, and bone marrow biopsy were performed to rule out distant spread of the disease. In addition, MALT specific genetic changes, including reverse transcriptase-polymerase chain reaction for t(11;18)(q21;q21), were tested in all patients. H pylori infection was ruled out by histology, urease breath test, serology, and stool antigen testing.
RESULTS: All six patients had MALT lymphoma restricted to the stomach, and no evidence of infection with H pylori was found. Only one patient tested positive for t(11;18)(q21;q21) while the remaining five displayed no genetic aberrations. Following antibiotic treatment, endoscopic controls were performed every three months. Five patients responded with lymphoma regression between three and nine months following antibiotic treatment (one partial remission and four complete responses). One patient had stable disease for 12 months and was then referred for chemotherapy.
CONCLUSIONS: Patients with early stage gastric MALT lymphoma negative for H pylori might still benefit from antibiotic treatment as the sole treatment modality.

PMID 16299027  Gut. 2006 May;55(5):616-8. doi: 10.1136/gut.2005.083022・・・
著者: P Malfertheiner, F Megraud, C O'Morain, F Bazzoli, E El-Omar, D Graham, R Hunt, T Rokkas, N Vakil, E J Kuipers
雑誌名: Gut. 2007 Jun;56(6):772-81. doi: 10.1136/gut.2006.101634. Epub 2006 Dec 14.
Abstract/Text BACKGROUND: Guidelines on the management of Helicobacter pylori, which cover indications for management and treatment strategies, were produced in 2000.
AIMS: To update the guidelines at the European Helicobacter Study Group (EHSG) Third Maastricht Consensus Conference, with emphasis on the potential of H pylori eradication for the prevention of gastric cancer.
RESULTS: Eradication of H pylori infection is recommended in (a) patients with gastroduodenal diseases such as peptic ulcer disease and low grade gastric, mucosa associated lymphoid tissue (MALT) lymphoma; (b) patients with atrophic gastritis; (c) first degree relatives of patients with gastric cancer; (d) patients with unexplained iron deficiency anaemia; and (e) patients with chronic idiopathic thrombocytopenic purpura. Recurrent abdominal pain in children is not an indication for a "test and treat" strategy if other causes are excluded. Eradication of H pylori infection (a) does not cause gastro-oesophageal reflux disease (GORD) or exacerbate GORD, and (b) may prevent peptic ulcer in patients who are naïve users of non-steroidal anti-inflammatory drugs (NSAIDs). H pylori eradication is less effective than proton pump inhibitor (PPI) treatment in preventing ulcer recurrence in long term NSAID users. In primary care a test and treat strategy using a non-invasive test is recommended in adult patients with persistent dyspepsia under the age of 45. The urea breath test, stool antigen tests, and serological kits with a high accuracy are non-invasive tests which should be used for the diagnosis of H pylori infection. Triple therapy using a PPI with clarithromycin and amoxicillin or metronidazole given twice daily remains the recommended first choice treatment. Bismuth-containing quadruple therapy, if available, is also a first choice treatment option. Rescue treatment should be based on antimicrobial susceptibility.
CONCLUSION: The global burden of gastric cancer is considerable but varies geographically. Eradication of H pylori infection has the potential to reduce the risk of gastric cancer development.

PMID 17170018  Gut. 2007 Jun;56(6):772-81. doi: 10.1136/gut.2006.10163・・・
著者: William D Chey, Benjamin C Y Wong, Practice Parameters Committee of the American College of Gastroenterology
雑誌名: Am J Gastroenterol. 2007 Aug;102(8):1808-25. doi: 10.1111/j.1572-0241.2007.01393.x. Epub 2007 Jun 29.
Abstract/Text Helicobacter pylori (H. pylori) remains a prevalent, worldwide, chronic infection. Though the prevalence of this infection appears to be decreasing in many parts of the world, H. pylori remains an important factor linked to the development of peptic ulcer disease, gastric malignanc and dyspeptic symptoms. Whether to test for H. pylori in patients with functional dyspepsia, gastroesophageal reflux disease (GERD), patients taking nonsteroidal antiinflammatory drugs, with iron deficiency anemia, or who are at greater risk of developing gastric cancer remains controversial. H. pylori can be diagnosed by endoscopic or nonendoscopic methods. A variety of factors including the need for endoscopy, pretest probability of infection, local availability, and an understanding of the performance characteristics and cost of the individual tests influences choice of evaluation in a given patient. Testing to prove eradication should be performed in patients who receive treatment of H. pylori for peptic ulcer disease, individuals with persistent dyspeptic symptoms despite the test-and-treat strategy, those with H. pylori-associated MALT lymphoma, and individuals who have undergone resection of early gastric cancer. Recent studies suggest that eradication rates achieved by first-line treatment with a proton pump inhibitor (PPI), clarithromycin, and amoxicillin have decreased to 70-85%, in part due to increasing clarithromycin resistance. Eradication rates may also be lower with 7 versus 14-day regimens. Bismuth-containing quadruple regimens for 7-14 days are another first-line treatment option. Sequential therapy for 10 days has shown promise in Europe but requires validation in North America. The most commonly used salvage regimen in patients with persistent H. pylori is bismuth quadruple therapy. Recent data suggest that a PPI, levofloxacin, and amoxicillin for 10 days is more effective and better tolerated than bismuth quadruple therapy for persistent H. pylori infection, though this needs to be validated in the United States.

PMID 17608775  Am J Gastroenterol. 2007 Aug;102(8):1808-25. doi: 10.11・・・
著者: G Pinotti, E Zucca, E Roggero, A Pascarella, F Bertoni, A Savio, E Savio, C Capella, E Pedrinis, P Saletti, E Morandi, G Santandrea, F Cavalli
雑誌名: Leuk Lymphoma. 1997 Aug;26(5-6):527-37. doi: 10.3109/10428199709050889.
Abstract/Text The purpose of this paper is to report the clinical characteristics and treatment outcome following different therapeutic approaches in a large series of patients with primary low-grade MALT lymphoma of the stomach. A total of ninety-three patients (median age 63 years) were reviewed. The patients were treated by different modalities (local treatment alone, combined treatment, chemotherapy, antibiotics alone); seven patients refused any treatment. The antibiotic-treated group of patients was prospectively followed with regular endoscopic biopsies, and their responses were histologically evaluated. The 5-years projected overall survival is 82% (95% C.I.; 67%-91%) in the series as a whole. Second tumors were observed in 21.5% of the patients in this series (95% CI 14%v to 31%). There was no apparent difference in overall survival and event-free survival between patients who received different treatments. In the antibiotic-treated group histologic regression of MALT lymphoma was documented in 67% of patients (95% CI 51% to 80%). In conclusion the indolent nature of the disease justifies a conservative approach. The use of antibiotics as first-line therapy may avert or at least postpone the indication for surgical resection in the majority of patients.

PMID 9389360  Leuk Lymphoma. 1997 Aug;26(5-6):527-37. doi: 10.3109/10・・・
著者: Shotaro Nakamura, Takayuki Matsumoto, Hiroshi Suekane, Shigeo Nakamura, Hiroshi Matsumoto, Motohiro Esaki, Takashi Yao, Mitsuo Iida
雑誌名: Cancer. 2005 Aug 1;104(3):532-40. doi: 10.1002/cncr.21152.
Abstract/Text BACKGROUND: The goals of the current study were to elucidate the long-term outcome of Helicobacter pylori eradication therapy for gastric mucosa-associated lymphoid tissue (MALT) lymphoma and to clarify the therapeutic efficacy of stomach-conserving treatments for patients not responding to eradication therapy.
METHODS: Ninety-six patients with gastric MALT lymphoma, including 17 patients with areas of diffuse large B-cell lymphoma, were treated by H. pylori eradication. Patients not responding to eradication therapy underwent either a gastrectomy, multiagent chemotherapy, oral monochemotherapy (OMC), or radiotherapy (RT). Predictive factors for the response to eradication therapy, overall survival (OS), and event-free survival (EFS) were determined by the Kaplan-Meier analysis with the log-rank test. The efficacy of second-line treatment was compared between OMC and RT.
RESULTS: After eradication therapy, 62 (65%) patients achieved complete disease remission (CR). Transient histologic disease recurrence was confirmed in 4 (6.5%) of 62 patients with CR during the follow-up (median, 37.5 months). The OS and EFS probabilities after 5 years were 0.96 and 0.80, respectively. Second-line treatment was performed in 31 patients; gastrectomy in 4 patients, multiagent chemotherapy in 5 patients, OMC in 12 patients, and RT in 10 patients. There were no differences in the CR rate, OS, EFS, or toxicity between the OMC and RT groups.
CONCLUSIONS: H. pylori eradication therapy was an effective first-line treatment for patients with gastric MALT lymphoma, which led to a favorable long-term outcome. OMC and RT had an equivalent efficacy as a second-line treatment in nonresponding patients to eradication therapy.

(c) 2005 American Cancer Society.
PMID 15937928  Cancer. 2005 Aug 1;104(3):532-40. doi: 10.1002/cncr.211・・・
著者: C Thiede, T Wündisch, B Alpen, B Neubauer, A Morgner, M Schmitz, G Ehninger, M Stolte, E Bayerdörffer, A Neubauer, German MALT Lymphoma Study Group
雑誌名: J Clin Oncol. 2001 Mar 15;19(6):1600-9.
Abstract/Text PURPOSE: Cure of Helicobacter pylori infection is associated with remission induction in the majority of patients with low-grade gastric mucosa associated lymphoid tissue (MALT) lymphoma in localized stages; however, limited data exist as to whether these patients may be cured of their lymphoma. The present study was performed to investigate whether the polymerase chain reaction (PCR) for the rearranged immunoglobulin heavy chain region may be used to define "molecular" remission.
PATIENTS AND METHODS: Ninety-seven patients who suffered from low-grade gastric MALT lymphoma stage I(E) were observed with central pathology and molecular biology after cure of H pylori infection. PCR was performed with the use of consensus primers for the framework regions 1, 2, and 3 and monoclonality was corroborated by sequence analysis. In selected cases, microdissection was performed to study the origin of the monoclonal B cells.
RESULTS: Of the 97 patients, 77 obtained complete endoscopic and histologic remission (CR). Twenty of 44 patients with PCR monoclonality at diagnosis and with sufficient molecular follow-up displayed monoclonal bands for a median time of 20.5 months after CR (range, 0 to 50.4 months). These B cells were related to the original lymphoma clone by sequence analysis. Microdissection analysis identified basal lymphoid aggregates as the source of these monoclonal B cells. Local relapse occurred in and was observed by PCR in four patients. All four patients displayed monoclonal PCR before relapse, and three of these four showed ongoing PCR monoclonality throughout their course, indicating the persistence of malignant cells.
CONCLUSION: Half of all patients with gastric MALT lymphoma show long-term PCR monoclonality up to several years after cure of H pylori infection and CR. Patients with monoclonal PCR should be observed closely, whereas long-term PCR negativity may indicate cure of the disease.

PMID 11250988  J Clin Oncol. 2001 Mar 15;19(6):1600-9.
著者: A Andriani, A Miedico, L Tedeschi, C Patti, F Di Raimondo, M Leone, L Schinocca, A Romanelli, G Bonanno, C Linea, M Giustini, C Hassan, M Cottone, A Zullo
雑誌名: Dig Liver Dis. 2009 Jul;41(7):467-73. doi: 10.1016/j.dld.2008.09.009. Epub 2008 Oct 21.
Abstract/Text BACKGROUND/AIM: Data on management and long-term follow-up of Helicobacter pylori-associated MALT-lymphoma in clinical practice are scanty. We evaluate the long-term efficacy of H. pylori eradication on low-grade MALT-lymphoma, and the efficacy of further therapies in refractory patients.
METHODS: This study enrolled patients with stages I-II(1) MALT-lymphoma and H. pylori infection. H. pylori eradication was attempted in all patients. Patients with lymphoma persistence or progression following H. pylori treatments received further lymphoma treatments. Both 5-year and disease-free survivals were calculated.
RESULTS: Sixty patients (stage I/II(1): 50/10) were followed up for a median time of 65 months (range 7-156). H. pylori infection was successfully eradicated in 53 (88.3%) patients following three consecutive therapeutic attempts, and lymphoma regressed in 42 (79.2%) of these patients. Sixteen patients received anti-neoplastic treatments due to either lymphoma persistence or progression, and lymphoma was cured in 14 (87.5%) cases. At follow-up, lymphoma relapsed in 13/42 (30.9%) patients within a median time of 19 months (range 3-41), and all but 1 patient were cured with further therapies. Overall, lymphoma regression was achieved in 56 patients (93.3%). The 5-year and disease-free survivals were 94.7% and 74.6%, respectively.
CONCLUSIONS: In clinical practice, a conservative approach with antibiotic eradication seems to be appropriate management for early-stage MALT-lymphoma, with oncologic therapy being reserved for those patients who fail to respond to H. pylori therapy.

PMID 18945654  Dig Liver Dis. 2009 Jul;41(7):467-73. doi: 10.1016/j.dl・・・
著者: A Stathis, C Chini, F Bertoni, I Proserpio, C Capella, L Mazzucchelli, E Pedrinis, F Cavalli, G Pinotti, E Zucca
雑誌名: Ann Oncol. 2009 Jun;20(6):1086-93. doi: 10.1093/annonc/mdn760. Epub 2009 Feb 4.
Abstract/Text BACKGROUND: Treatment aimed at eradicating Helicobacter pylori infection results in lymphoma remission in most localized gastric mucosa-associated lymphoid tissue (MALT) lymphomas. The aim of this survey is to investigate the long-term effect of this therapeutic approach in a large series of patients.
METHODS: One hundred and five patients with localized gastric MALT lymphoma were initially treated only with H. pylori eradication regimens. Lymphoma responses were graded using the Wotherspoon score.
RESULTS: Helicobacter pylori, detected by histology in 81% of cases, was eradicated in all positive patients. Histological regression of the lymphoma was achieved in 78 of 102 assessable patients [76%, 95% confidence interval (CI): 67% to 84%] with complete remission (score 0-2) in 66 and partial remission (score 3) in 12. At a median follow-up time of 6.3 years, histological remission was consistently confirmed in 33 of 74 assessable patients, while 25 had score fluctuations (from 0 to 4) and 13 presented a lymphoma relapse (score 5). Only one patient had a distant progression. Transformation to a large-cell lymphoma was seen in two cases. The 5- and 10-year overall survival is 92% (95% CI: 84% to 96%) and 83% (95% CI: 70% to 91%), respectively. Only one patient died of lymphoma after transformation to a high-grade lymphoma.
CONCLUSIONS: Helicobacter pylori eradication resulted in complete lymphoma remission in the majority of cases. Long-term clinical disease control was achieved in most patients. A watch and wait policy appears to be safe in patients with minimal residual disease or histological-only local relapse.

PMID 19193705  Ann Oncol. 2009 Jun;20(6):1086-93. doi: 10.1093/annonc/・・・
著者: Hiroshi Inagaki, Tsuneya Nakamura, Chunmei Li, Toshiro Sugiyama, Masahiro Asaka, Jyunichi Kodaira, Masahiro Iwano, Tsutomu Chiba, Kazuichi Okazaki, Atsunaga Kato, Ryuzo Ueda, Tadaaki Eimoto, Shiro Okamoto, Naomi Sasaki, Naomi Uemura, Taiji Akamatsu, Hideharu Miyabayashi, Yoko Kawamura, Hidemi Goto, Yasumasa Niwa, Takio Yokoi, Masao Seto, Shigeo Nakamura
雑誌名: Am J Surg Pathol. 2004 Dec;28(12):1560-7.
Abstract/Text Gastric MALT lymphoma shows unique features including regression by Helicobacter pylori eradication and API2-MALT1 fusion. We performed a molecular and clinicopathologic study for 115 cases. All eradication-responsive cases were devoid of API2-MALT1 fusion. All tumors positive for the fusion and all negative for H. pylori infection were nonresponsive to the eradication. Consequently, gastric MALT lymphomas were divided into three groups: Eradication-responsive and fusion-negative (group A, n = 72), eradication-nonresponsive and fusion-negative (group B, n = 22), and eradication-nonresponsive and fusion-positive (group C, n = 21). Group A tumors were characterized by low clinical stage and superficial gastric wall involvement, and group C tumors by low H. pylori infection rate, advanced clinical stage, and nuclear BCL10 expression. All group C tumors showed exclusively low-grade histology. Group B tumors, which have not been well recognized, frequently showed nodal involvement, deep gastric wall involvement, and advanced clinical stage, and sometimes an increased large cell component. A multivariate discriminant analysis revealed that responsiveness to the eradication could be predicted accurately by negative API2-MALT1 fusion, positive H. pylori infection, low clinical stage, and superficial gastric wall invasion, the former being the most important factor for the prediction. This 3-group categorization may be helpful for a comprehensive understanding of gastric MALT lymphoma.

PMID 15577674  Am J Surg Pathol. 2004 Dec;28(12):1560-7.
著者: Angelo Zullo, Cesare Hassan, Alessandro Andriani, Francesca Cristofari, Chiara Bassanelli, Gian Paolo Spinelli, Silverio Tomao, Sergio Morini
雑誌名: Med Oncol. 2010 Jun;27(2):291-5. doi: 10.1007/s12032-009-9207-y. Epub 2009 Mar 24.
Abstract/Text The most favourable therapeutic strategy for gastric MALT-lymphoma not responding to Helicobacter pylori eradication still remains unclear, neither official guidelines nor randomised studies being available. We therefore performed a systematic review of the literature to evaluate the efficacy of different therapeutic approaches in these patients. Data regarding 315 patients were valuable, and lymphoma remission following the first therapeutic attempt was achieved in 90.1% cases. The most used therapy was radiotherapy (112 patients), followed by surgery (80 patients) and chemotherapy (68 patients), whilst a combination therapy was less frequent. Radiotherapy achieved a higher remission rate as compared to chemotherapy (97.3 vs. 85.3%; P = 0.007), being similar to surgery (97.3 vs. 92.5%; P = 0.2). No difference emerged when comparing lymphoma remission rate achieved by a single therapy with that of combined treatments (89.6 vs. 96.4%; P = 0.6). This is the first pooled-data analysis assessing the efficacy of different oncologic therapeutic approaches to treat gastric MALT-lymphoma unresponsive to H. pylori eradication. Radiotherapy seems to be the most suitable treatment in these patients.

PMID 19308737  Med Oncol. 2010 Jun;27(2):291-5. doi: 10.1007/s12032-00・・・
著者: Richard W Tsang, Mary K Gospodarowicz, Melania Pintilie, Woodrow Wells, David C Hodgson, Alexander Sun, Michael Crump, Bruce J Patterson
雑誌名: J Clin Oncol. 2003 Nov 15;21(22):4157-64. doi: 10.1200/JCO.2003.06.085.
Abstract/Text PURPOSE: Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is a distinct lymphoma with unique clinicopathologic features. We report the clinical outcome of stage I and II MALT lymphoma treated with involved field radiation therapy (RT).
PATIENTS AND METHODS: From 1989 to 2000, 103 patients with stage IE and IIE disease were referred. Their median age was 60 years, with a 2:1 female predominance. Presenting sites were stomach (17 patients), orbital adnexa (31 patients), salivary glands (24 patients), thyroid gland (13 patients), and other sites (18 patients). Ninety-three patients received RT--85 received RT alone, and eight received chemotherapy and RT--with a median dose of 30 Gy. The median follow-up time was 5.1 years.
RESULTS: A complete response (CR) to RT alone was achieved in 84 of 85 patients. Among CR patients, 14 experienced relapse. Relapse sites were mostly contralateral paired-organ or distant MALT locations and, infrequently, lymph nodes. The crude local control rate with RT was 95.3% (81 of 85 patients). No relapses were observed in patients with stomach or thyroid lymphoma, whereas 14 of 63 patients (22%) experienced relapse in the other sites. The overall 5-year survival rate was 98%, and the disease-free survival rate was 77%. Transformed lymphoma was observed in 14% of patients (two of 14) experiencing relapse.
CONCLUSION: Moderate-dose RT achieved excellent local control in localized MALT lymphomas and had curative potential for three fourths of the patients. Gastric and thyroid MALT lymphomas had better outcome, whereas distant failures were common for other sites. Despite relapse, the disease often maintained an indolent course.

PMID 14615444  J Clin Oncol. 2003 Nov 15;21(22):4157-64. doi: 10.1200/・・・
著者: Conny Vrieling, Daphne de Jong, Henk Boot, Jan Paul de Boer, Froukje Wegman, Berthe M P Aleman
雑誌名: Radiother Oncol. 2008 Jun;87(3):405-11. doi: 10.1016/j.radonc.2008.02.012. Epub 2008 Mar 17.
Abstract/Text PURPOSE: To evaluate long-term results of stomach-conserving therapy and to assess the value of histological probable minimal residual disease (pMRD) in predicting outcome in patients with gastric MALT lymphoma.
MATERIALS AND METHODS: We studied 115 patients with stage I-II(2) gastric MALT lymphoma treated between 1975 and 2002. Initially, first-line treatment consisted of radiotherapy only. Since 1994 most patients were primarily treated with Helicobacter pylori eradication; radiotherapy was used in case of eradication failure. To assess the value of pMRD, first follow-up biopsy samples classified as compete remission (CR) according to classical clinico-pathological criteria and biopsy samples 1 year after assessment of histological CR were reviewed; results were related to outcome.
RESULTS: Following radiotherapy only (n=56) 96% achieved a clinical CR; 10-year cancer-specific survival rate was 94%. Following H. pylori eradication only (n=35) CR-rate was 43% and after additional treatment 89%; 5-year cause-specific survival was 93%. There was no difference in relapse rate following initial histological CR or pMRD.
CONCLUSIONS: Patients with early stage gastric MALT lymphoma have a favorable long-term outcome following conservative treatment. Outcome after H. pylori eradication followed by delayed radiotherapy on indication was excellent. In our series pMRD was not associated with increased risk of recurrence.

PMID 18343513  Radiother Oncol. 2008 Jun;87(3):405-11. doi: 10.1016/j.・・・
著者: Michaël Lévy, Christiane Copie-Bergman, Christine Gameiro, Marie-Thérèse Chaumette, Marie-Hélène Delfau-Larue, Corinne Haioun, Antoine Charachon, François Hemery, Philippe Gaulard, Karen Leroy, Jean-Charles Delchier
雑誌名: J Clin Oncol. 2005 Aug 1;23(22):5061-6. doi: 10.1200/JCO.2005.05.660.
Abstract/Text PURPOSE: To determine the impact of translocation t(11;18) on response to oral alkylating agents in gastric mucosa-associated lymphoid tissue lymphoma (GML).
PATIENTS AND METHODS: Fifty-three patients with a GML were studied. Helicobacter pylori-positive patients (n = 34) received anti-H pylori treatment and H pylori-negative patients (n = 19) or patients who failed to respond to anti-H pylori treatment received oral alkylating agents. t(11;18) was detected by reverse transcription polymerase chain reaction from frozen gastric biopsies.
RESULTS: t(11;18) was detected in 32% of patients. It was more prevalent in H pylori-negative as compared with H pylori-positive patients (12 of 19 v five of 34 patients; P = .0005). Among 31 H pylori-eradicated patients, t(11;18) was detected in three patients, all of whom experienced treatment failure, and it was absent in 28 patients: 21 patients (75%) were in remission and seven patients (25%) experienced treatment failure (P = .03). Among 21 patients who received an alkylating agent, t(11;18) was detected in 12 patients: five patients (42%) were in remission and seven patients (58%) experienced treatment failure. t(11;18) was absent in nine patients: eight patients (89%) were in remission and one patient (11%) experienced treatment failure by the end of treatment. Four patients in remission relapsed during follow-up (median, 7 years): they all had t(11;18). Durable remission was obtained in eight (89%) of the nine patients without t(11;18) versus one of the 12 patients (8%) with t(11;18) (P = .0003).
CONCLUSION: Presence of t(11;18) in GML is predictive of resistance to oral alkylating agents, with less than 10% of durable remission at long-term follow-up.

PMID 16051953  J Clin Oncol. 2005 Aug 1;23(22):5061-6. doi: 10.1200/JC・・・
著者: Mathias J Rummel, Salah E Al-Batran, Soo-Z Kim, Manfred Welslau, Ralf Hecker, Dorothea Kofahl-Krause, Klaus-M Josten, Heinz Dürk, Andreas Rost, Michael Neise, Ulrich von Grünhagen, Kai U Chow, Martin-L Hansmann, Dieter Hoelzer, Paris S Mitrou
雑誌名: J Clin Oncol. 2005 May 20;23(15):3383-9. doi: 10.1200/JCO.2005.08.100.
Abstract/Text PURPOSE: The aim of this multicenter-study was to evaluate the progression-free survival, response rate and toxicity of the combination of bendamustine and rituximab (BR) in patients with mantle cell or low-grade lymphomas in first to third relapse or refractory to previous treatment.
PATIENTS AND METHODS: A total of 245 courses (median, four courses per patient) were administered to 63 patients. Bendamustine was given at a dose of 90 mg/m2 as a 30-minute infusion on days 1 and 2, combined with 375 mg/m2 rituximab on day 1, for a maximum of four cycles every 4 weeks. Histologies were 24 follicular, 16 mantle cell, 17 lymphoplasmacytoid, and six marginal zone lymphoma.
RESULTS: Fifty-seven of 63 patients responded to BR, corresponding to an overall response rate of 90% (95% CI, 80% to 96%) with a complete remission rate (CR) of 60% (95% CI, 47% to 72%). The median time of progression-free survival was 24 months (range, 5 to 44+ months), and the median duration of overall survival has not yet been reached. In mantle cell lymphomas, BR showed a considerable activity, achieving a response rate of 75% (95% CI, 48% to 93%) with a CR rate of 50%. Myelosuppression was the major toxicity, with 16% grade 3 and 4 leukocytopenia. Thrombocytopenia was rare, with only 3% grade 3 and 4.
CONCLUSION: These results demonstrate that the BR combination is a highly active regimen in the treatment of low-grade lymphomas and mantle cell lymphomas.

PMID 15908650  J Clin Oncol. 2005 May 20;23(15):3383-9. doi: 10.1200/J・・・
著者: Antonio Salar, Eva Domingo-Domenech, Cristina Estany, Miguel A Canales, Fernando Gallardo, Octavio Servitje, Guadalupe Fraile, Carlos Montalbán
雑誌名: Cancer. 2009 Nov 15;115(22):5210-7. doi: 10.1002/cncr.24605.
Abstract/Text BACKGROUND: Currently, there are no consensus guidelines regarding the best therapeutic option for patients with extranodal marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT) type.
METHODS: Patients with systemically untreated or de novo extranodal MALT lymphoma received rituximab 375 mg/m(2) intravenously on Day 1 and fludarabine 25 mg/m(2) intravenously on Days 1 through 5 (Days 1-3 in patients aged >70 years) every 4 weeks, for 4 to 6 cycles. After the first cycle, oral fludarabine could be given orally at 40 mg/m(2) on the same schedule. After 3 cycles, a workup was done. Patients who achieved a complete remission (CR) received an additional cycle, and patients who achieved a partial remission (PR) received a total of 6 cycles.
RESULTS: Twenty-two patients were studied, including 12 patients with gastric lymphoma and 10 patients with extragastric MALT lymphoma. Six patients (27%) had stage IV disease. In total, 101 cycles were administered (median, 4 cycles per patients). After the third cycle, 13 patients (62%) achieved a CR, and 8 patients (38%) achieved a PR. Primary extragastric disease was an adverse factor to achieve CR after 3 cycles of chemotherapy (hazard ratio, 23.3; 95% confidence interval, 2.0-273.3). At the end of treatment, the overall response rate was 100%, and 90% of patients achieved a CR. The progression-free survival rate at 2 years in patients with gastric and extragastric MALT lymphoma was 100% and 89%, respectively. Toxicities were mild and mainly were hematologic.
CONCLUSIONS: Combination therapy with rituximab and fludarabine is a very active treatment with favorable safety profile as first-line systemic treatment for patients with extranodal MALT lymphoma.

PMID 19672998  Cancer. 2009 Nov 15;115(22):5210-7. doi: 10.1002/cncr.2・・・

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