J Gastrointest Canc DOI 10.1007/s12029-014-9606-y
CASE REPORT
Metastatic Gastric MALT Lymphoma Masquerading as Pulmonary Infiltrates, with a Dramatic Response to Chemotherapy Sami Samiullah & Hadi Bhurgri & Madiha Tufail & Fatima Samad & Sheenal Patel & Marium Marium & Lillian Pliner & Zamir Brelvi & Weizheng Wang
# Springer Science+Business Media New York 2014
Introduction In 1983, Isaacson and Wright described the entity mucosaassociated lymphoid tissue lymphoma [1]. It is a type of nonHodgkin’s lymphoma, now classified as an extranodal marginal zone B cell lymphoma [2]. By definition, a low-grade lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma is thought to develop as a result of chronic antigenic stimulation. Epidemiologic models indicate that over 90 % of gastric MALT lymphomas arise in the presence of Helicobacter pylori infection and that eradication of H. pylori infection leads to endoscopic and histologic remissions in the majority of those cases [3, 4]. Autoimmune diseases may also create a setting of chronic inflammation and antigenic stimulation leading to MALT lymphoma [5]. It is also postulated that elements of the innate immune system play a role in the defense against lymphoproliferative diseases, and particularly, natural killer cell dysfunction is seen in high-grade nonHodgkin’s lymphomas [6]. Genetic abnormalities, notably certain high-risk chromosomal translocations such as t(11;18), t(1;14), and t(14;18), to name a few, have also been implicated as a cause of antigenindependent proliferation, particularly in cases not associated with or not responsive to H. pylori eradication [7]. On H. Bhurgri (*) : M. Tufail : F. Samad : S. Patel : M. Marium Department of Medicine, Rutgers—New Jersey Medical School, 150 Bergen Street, UH I-248, Newark, NJ 07003, USA e-mail: [email protected] S. Samiullah : Z. Brelvi : W. Wang Department of Gastroenterology, Rutgers—New Jersey Medical School, 150 Bergen Street, UH I-248, Newark, NJ 07003, USA L. Pliner Department of Medical Oncology, Rutgers—New Jersey Medical School, 150 Bergen Street, UH I-248, Newark, NJ 07003, USA
immunophenotype analysis, MALT lymphoma demonstrates B cell markers, CD19, CD20, and CD45 [8]. Predominantly found in gastric tissue, it can virtually arise in any epithelial tissue. Some sites worth mentioning include the lung, eye, skin, salivary glands, and breast. Systemic screening is therefore essential when MALT lymphoma is suspected. A good history and physical exam are key, followed by definitive histopathologic diagnosis via biopsies. Endoscopic biopsies for gastric MALT lymphoma are diagnostic in more than 75 % of the patients and should include evaluation for H. pylori infection [9]. Here, we report a case of metastatic gastric MALT lymphoma with a dramatic response to treatment.
Case A 60-year-old Asian man with a medical history significant for undiagnosed pulmonary infiltrates for 7 years presented with abdominal pain, hematemesis, and one episode of syncope. After initial resuscitation, an esophagogastroduodenoscopy (EGD) was performed, which showed a large fundic ulcer with raised margins (Fig. 1). The biopsy of the gastric ulcer demonstrated a dense mucosal and submucosal infiltrate by small marginal zone-type cells; positive for CD20 and bcl-2, CD43, and MUM-1; and negative for CD3, CD5, CD10, CD23, bcl-6, and cyclin D1 (Fig. 2). Kappa and lambda stains revealed scattered polyclonal plasma cells, with a slight kappa excess. This was consistent with an extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue. H. pylori was not seen on histology, with Steiner staining showing no bacilli. To evaluate for metastases, a PET/CT scan was performed (Fig. 3) which showed diffusely increased FDG uptake in the anterior segments of both upper lungs and in the right upper
J Gastrointest Canc
Fig. 1 Ulcer in the gastric body
lobe, corresponding to the pulmonary infiltrates along with moderately increased uptake in the fundus of the stomach. Endoscopic ultrasound (EUS) revealed a normal gastric wall without evidence of muscularis invasion. To evaluate for the resolution of the gastric ulcer, a repeat EGD was performed 6 weeks later which revealed a healed gastric ulcer. Biopsies however, despite being consistent with a healed ulcer, negative for H. pylori, were consistent with persistent MALT lymphoma. The patient’s long-standing history of pulmonary infiltrates had been evaluated in the past with multiple Fig. 2 a Gastric mucosa with atypical lymphocytic infiltrates (H and E histology, ×10). b Lymphoepithelial lesion is present (H and E histology, ×40). c Small lymphoid cells showing monocytoid appearance with round nuclear contours, condensed chromatin, inconspicuous nucleoli, and abundant clear (H and E histology, ×100). d Immunohistochemical stains reveal the atypical cells to be positive for CD20
Fig. 3 Pretreatment and posttreatment PET/CT images
bronchoscopies, which were non-diagnostic. To obtain a definitive diagnosis, the patient underwent a video-assisted thoracoscopy (VATS) with a wedge resection of the left
J Gastrointest Canc
upper lobe. Immunohistochemical stains were positive for Pax-5, CD3, CD5, and CD43 and negative for CD10, CD23, and cyclin D1. The histopathology was consistent with an extranodal marginal zone cell lymphoma. He was thus restaged from stage 1E to stage IV CD20-positive gastric MALT and subsequently underwent chemotherapy with cyclophosphamide (750 mg/m2 IV, day 1), vincristine (1.4 mg/m2 IV, day 1), and prednisone (40 mg/m2 PO, day 1), every 3 weeks for six cycles. Because the patient had a serology consistent with resolved hepatitis B, rituximab was initially not given. After chemotherapy, the patient continued to have shortness of breath and a cough. A repeat PET/CT showed persistent uptake in lungs, with no improvement. A second chemotherapy regimen consisting of rituximab (375 mg/m 2, day 1) and bendamustine (90 mg/m2 IV, day 1 and 2) every 28 days for four cycles, including lamivudine for prevention of HBV reactivation, was then initiated. After four cycles, the patient reported a significant improvement in his pulmonary symptoms. A follow-up PET/ CT scan (Fig. 3) showed dramatically decreased uptake with some residual infiltrates. Follow-up EGDs were also performed twice, which revealed gross resolution of ulcer, along with biopsies showing no evidence of MALT lymphoma.
Discussion For local disease, MALT associated with H. pylori infection, treatment consists of H. pylori eradication with endoscopic follow-up to assess resolution. However, in patients nonresponsive to H. pylori eradication, those who are H. pylori negative, and those with MALT lymphoma in other organs, treatment has to be individualized based on the site, symptoms, and stage. In patients with gastric MALT lymphoma associated with H. pylori who receive eradication treatment with a proton pump inhibitor and antibiotics, eradication rates vary between 60 and 90 % [10]. If H. pylori persists after initial therapy, the course can be repeated with alternative therapy until H. pylori is eradicated. Treatment failure after antibiotic therapy is defined as a lack of regression on endoscopy after 12 months of therapy [11]. In patients positive for H. pylori but with no response to antibiotic therapy, those who are H. pylori negative, and those who have MALT lymphoma in other organs, the treatment is based on the site, symptoms, and stage of the cancer. With localized disease, local treatment via either radiotherapy or surgery can usually achieve excellent disease control [12-14]. With pulmonary involvement, treatment may involve surgery, radiation, or chemotherapy, with similar median times to progression, but in order to avoid the risks involved with surgery, chemotherapy is preferable [15].
In patients with disseminated disease at presentation, chemotherapy remains the mainstay, although no standard regimens exist to date. Alkylating agent-based regimens have been shown to be efficacious along with nucleoside analogs [16]. In cases with histologic transformation or high tumor burdens, anthracycline-based regimens have also been used [17]. Complete remission rates for these regimens are similar and vary from 70 to 75 %. More recently, rituximab has been studied as monotherapy with an overall objective response in approximately 77 %, and trials are underway studying its efficacy in combination with bendamustine and chlorambucil [18, 19]. Immunotherapy using rituximab has been studied in the treatment of aggressive B cell lymphomas and may be considered in aggressive MALT lymphomas [20]. The 5-year overall survival rate with treatment from the time of diagnosis of MALT lymphoma is approximately reported between 95 and 86 % with little difference between GI or non-GI sites and also between localized and disseminated disease [21, 22]. But the 5-year progression-free survival has been estimated at around 5 years, being significantly higher for GI locations compared to non-GI locations (8.9 versus 4.9 years, respectively; P=0.01) [23]. In our patient, an initial alkylating agent-based regimen consisting of six cycles of cyclophosphamide, vincristine, and prednisone failed to show a response. A second regimen of consisting of bendamustine and rituximab with lamivudine showed a dramatic clinical and radiographic response, with no MALT recurrence to date.
Conclusion No standard chemotherapy regimens exist for the treatment of metastatic gastric MALT lymphoma. In the absence of standardized treatment guidelines and sparse literature on the subject, the management of these tumors poses a challenge, necessitating efforts to develop a consensus on treatment strategies. Rituximab has recently shown promising results, and phase II clinical trials of rituximab in combinations with bendamustine and chlorambucil are underway and they may shed new light on chemotherapeutic options in the near future.
Conflict of Interest Authors declare no conflicts of interest for this article.
References 1. Isaacson P, Wright DH. Malignant lymphoma of mucosa-associated lymphoid tissue. A distinctive type of B-cell lymphoma. Cancer. 1983;52(8):1410–6. 2. Swerdlow SHCE, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008.
J Gastrointest Canc 3. Neubauer A, Thiede C, Morgner A, Alpen B, Ritter M, Neubauer B, et al. Cure of Helicobacter pylori infection and duration of remission of low-grade gastric mucosa-associated lymphoid tissue lymphoma. J Natl Cancer Inst. 1997;89(18):1350–5. 4. Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, Isaacson PG. Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet. 1991;338(8776):1175–6. 5. Wohrer S, Troch M, Streubel B, Zwerina J, Skrabs C, Formanek M, et al. MALT lymphoma in patients with autoimmune diseases: a comparative analysis of characteristics and clinical course. Leukemia. 2007;21(8):1812–8. 6. Konjevic G, Jurisic V, Banicevic B, Spuzic I. The difference in NKcell activity between patients with non-Hodgkin’s lymphomas and Hodgkin’s disease. Brit J Haematol. 1999;104(1):144–51. 7. Burke JS. Lymphoproliferative disorders of the gastrointestinal tract: a review and pragmatic guide to diagnosis. Arch Pathol Lab Med. 2011;135(10):1283–97. 8. Kost CB, Holden JT, Mann KP. Marginal zone B-cell lymphoma: a retrospective immunophenotypic analysis. Cytometry B Clin Cytom. 2008;74(5):282–6. 9. Taal BG, Boot H, van Heerde P, de Jong D, Hart AA, Burgers JM. Primary non-Hodgkin lymphoma of the stomach: endoscopic pattern and prognosis in low versus high grade malignancy in relation to the MALT concept. Gut. 1996;39(4):556–61. 10. Montalban C, Norman F. Treatment of gastric mucosa-associated lymphoid tissue lymphoma: Helicobacter pylori eradication and beyond. Expert Rev Anticancer Ther. 2006;6(3):361–71. 11. Ahmad A, Govil Y, Frank BB. Gastric mucosa-associated lymphoid tissue lymphoma. Am J Gastroenterol. 2003;98(5):975–86. 12. Tsai HK, Li S, Ng AK, Silver B, Stevenson MA, Mauch PM. Role of radiation therapy in the treatment of stage I/II mucosa-associated lymphoid tissue lymphoma. Ann Oncol. 2007;18(4):672–8. 13. Zucca E, Conconi A, Pedrinis E, Cortelazzo S, Motta T, Gospodarowicz MK, et al. Nongastric marginal zone B-cell lymphoma of mucosaassociated lymphoid tissue. Blood. 2003;101(7):2489–95. 14. Martinelli G, Laszlo D, Ferreri AJ, Pruneri G, Ponzoni M, Conconi A, et al. Clinical activity of rituximab in gastric marginal zone nonHodgkin’s lymphoma resistant to or not eligible for anti-Helicobacter pylori therapy. J Clin Oncol: Off J Am Soc Clin Oncol. 2005;23(9): 1979–83.
15. Oh SY, Kim WS, Kim JS, Kim SJ, Kwon HC, Lee DH, et al. Pulmonary marginal zone B-cell lymphoma of MALT type—what is a prognostic factor and which is the optimal treatment, operation, or chemotherapy?: Consortium for Improving Survival of Lymphoma (CISL) study. Ann Hematol. 2010;89(6):563–8. 16. Hammel P, Haioun C, Chaumette MT, Gaulard P, Divine M, Reyes F, et al. Efficacy of single-agent chemotherapy in low-grade B-cell mucosa-associated lymphoid tissue lymphoma with prominent gastric expression. J Clin Oncol: Off J Am Soc Clin Oncol. 1995;13(10): 2524–9. 17. Wohrer S, Drach J, Hejna M, Scheithauer W, Dirisamer A, Puspok A, et al. Treatment of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) with mitoxantrone, chlorambucil and prednisone (MCP). Ann Oncol. 2003;14(12):1758–61. 18. Conconi A, Martinelli G, Thieblemont C, Ferreri AJ, Devizzi L, Peccatori F, et al. Clinical activity of rituximab in extranodal marginal zone B-cell lymphoma of MALT type. Blood. 2003;102(8):2741–5. 19. Zucca E, Conconi A, Laszlo D, Lopez-Guillermo A, Bouabdallah R, Coiffier B, et al. Addition of rituximab to chlorambucil produces superior event-free survival in the treatment of patients with extranodal marginal-zone B-cell lymphoma: 5-year analysis of the IELSG-19 Randomized Study. J Clin Oncol: Off J Am Soc Clin Oncol. 2013;31(5):565–72. 20. Colovic N, Jurisic V, Terzic T, Atkinson HD, Colovic M. Immunochemotherapy for Bcl-2 and MUM-negative aggressive primary cutaneous B-cell non-Hodgkin’s lymphoma. Arch Dermatol Res. 2009;301(9):689–92. 21. Olszewski AJ, Castillo JJ. Survival of patients with marginal zone lymphoma: analysis of the Surveillance, Epidemiology, and End Results database. Cancer. 2013;119(3):629–38. 22. Thieblemont C, Bastion Y, Berger F, Rieux C, Salles G, Dumontet C, et al. Mucosa-associated lymphoid tissue gastrointestinal and nongastrointestinal lymphoma behavior: analysis of 108 patients. J Clin Oncol: Off J Am Soc Clin Oncol. 1997;15(4):1624–30. 23. Thieblemont C, Berger F, Dumontet C, Moullet I, Bouafia F, Felman P, et al. Mucosa-associated lymphoid tissue lymphoma is a disseminated disease in one third of 158 patients analyzed. Blood. 2000;95(3):802–6.
CASE REPORT
Metastatic Gastric MALT Lymphoma Masquerading as Pulmonary Infiltrates, with a Dramatic Response to Chemotherapy Sami Samiullah & Hadi Bhurgri & Madiha Tufail & Fatima Samad & Sheenal Patel & Marium Marium & Lillian Pliner & Zamir Brelvi & Weizheng Wang
# Springer Science+Business Media New York 2014
Introduction In 1983, Isaacson and Wright described the entity mucosaassociated lymphoid tissue lymphoma [1]. It is a type of nonHodgkin’s lymphoma, now classified as an extranodal marginal zone B cell lymphoma [2]. By definition, a low-grade lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma is thought to develop as a result of chronic antigenic stimulation. Epidemiologic models indicate that over 90 % of gastric MALT lymphomas arise in the presence of Helicobacter pylori infection and that eradication of H. pylori infection leads to endoscopic and histologic remissions in the majority of those cases [3, 4]. Autoimmune diseases may also create a setting of chronic inflammation and antigenic stimulation leading to MALT lymphoma [5]. It is also postulated that elements of the innate immune system play a role in the defense against lymphoproliferative diseases, and particularly, natural killer cell dysfunction is seen in high-grade nonHodgkin’s lymphomas [6]. Genetic abnormalities, notably certain high-risk chromosomal translocations such as t(11;18), t(1;14), and t(14;18), to name a few, have also been implicated as a cause of antigenindependent proliferation, particularly in cases not associated with or not responsive to H. pylori eradication [7]. On H. Bhurgri (*) : M. Tufail : F. Samad : S. Patel : M. Marium Department of Medicine, Rutgers—New Jersey Medical School, 150 Bergen Street, UH I-248, Newark, NJ 07003, USA e-mail: [email protected] S. Samiullah : Z. Brelvi : W. Wang Department of Gastroenterology, Rutgers—New Jersey Medical School, 150 Bergen Street, UH I-248, Newark, NJ 07003, USA L. Pliner Department of Medical Oncology, Rutgers—New Jersey Medical School, 150 Bergen Street, UH I-248, Newark, NJ 07003, USA
immunophenotype analysis, MALT lymphoma demonstrates B cell markers, CD19, CD20, and CD45 [8]. Predominantly found in gastric tissue, it can virtually arise in any epithelial tissue. Some sites worth mentioning include the lung, eye, skin, salivary glands, and breast. Systemic screening is therefore essential when MALT lymphoma is suspected. A good history and physical exam are key, followed by definitive histopathologic diagnosis via biopsies. Endoscopic biopsies for gastric MALT lymphoma are diagnostic in more than 75 % of the patients and should include evaluation for H. pylori infection [9]. Here, we report a case of metastatic gastric MALT lymphoma with a dramatic response to treatment.
Case A 60-year-old Asian man with a medical history significant for undiagnosed pulmonary infiltrates for 7 years presented with abdominal pain, hematemesis, and one episode of syncope. After initial resuscitation, an esophagogastroduodenoscopy (EGD) was performed, which showed a large fundic ulcer with raised margins (Fig. 1). The biopsy of the gastric ulcer demonstrated a dense mucosal and submucosal infiltrate by small marginal zone-type cells; positive for CD20 and bcl-2, CD43, and MUM-1; and negative for CD3, CD5, CD10, CD23, bcl-6, and cyclin D1 (Fig. 2). Kappa and lambda stains revealed scattered polyclonal plasma cells, with a slight kappa excess. This was consistent with an extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue. H. pylori was not seen on histology, with Steiner staining showing no bacilli. To evaluate for metastases, a PET/CT scan was performed (Fig. 3) which showed diffusely increased FDG uptake in the anterior segments of both upper lungs and in the right upper
J Gastrointest Canc
Fig. 1 Ulcer in the gastric body
lobe, corresponding to the pulmonary infiltrates along with moderately increased uptake in the fundus of the stomach. Endoscopic ultrasound (EUS) revealed a normal gastric wall without evidence of muscularis invasion. To evaluate for the resolution of the gastric ulcer, a repeat EGD was performed 6 weeks later which revealed a healed gastric ulcer. Biopsies however, despite being consistent with a healed ulcer, negative for H. pylori, were consistent with persistent MALT lymphoma. The patient’s long-standing history of pulmonary infiltrates had been evaluated in the past with multiple Fig. 2 a Gastric mucosa with atypical lymphocytic infiltrates (H and E histology, ×10). b Lymphoepithelial lesion is present (H and E histology, ×40). c Small lymphoid cells showing monocytoid appearance with round nuclear contours, condensed chromatin, inconspicuous nucleoli, and abundant clear (H and E histology, ×100). d Immunohistochemical stains reveal the atypical cells to be positive for CD20
Fig. 3 Pretreatment and posttreatment PET/CT images
bronchoscopies, which were non-diagnostic. To obtain a definitive diagnosis, the patient underwent a video-assisted thoracoscopy (VATS) with a wedge resection of the left
J Gastrointest Canc
upper lobe. Immunohistochemical stains were positive for Pax-5, CD3, CD5, and CD43 and negative for CD10, CD23, and cyclin D1. The histopathology was consistent with an extranodal marginal zone cell lymphoma. He was thus restaged from stage 1E to stage IV CD20-positive gastric MALT and subsequently underwent chemotherapy with cyclophosphamide (750 mg/m2 IV, day 1), vincristine (1.4 mg/m2 IV, day 1), and prednisone (40 mg/m2 PO, day 1), every 3 weeks for six cycles. Because the patient had a serology consistent with resolved hepatitis B, rituximab was initially not given. After chemotherapy, the patient continued to have shortness of breath and a cough. A repeat PET/CT showed persistent uptake in lungs, with no improvement. A second chemotherapy regimen consisting of rituximab (375 mg/m 2, day 1) and bendamustine (90 mg/m2 IV, day 1 and 2) every 28 days for four cycles, including lamivudine for prevention of HBV reactivation, was then initiated. After four cycles, the patient reported a significant improvement in his pulmonary symptoms. A follow-up PET/ CT scan (Fig. 3) showed dramatically decreased uptake with some residual infiltrates. Follow-up EGDs were also performed twice, which revealed gross resolution of ulcer, along with biopsies showing no evidence of MALT lymphoma.
Discussion For local disease, MALT associated with H. pylori infection, treatment consists of H. pylori eradication with endoscopic follow-up to assess resolution. However, in patients nonresponsive to H. pylori eradication, those who are H. pylori negative, and those with MALT lymphoma in other organs, treatment has to be individualized based on the site, symptoms, and stage. In patients with gastric MALT lymphoma associated with H. pylori who receive eradication treatment with a proton pump inhibitor and antibiotics, eradication rates vary between 60 and 90 % [10]. If H. pylori persists after initial therapy, the course can be repeated with alternative therapy until H. pylori is eradicated. Treatment failure after antibiotic therapy is defined as a lack of regression on endoscopy after 12 months of therapy [11]. In patients positive for H. pylori but with no response to antibiotic therapy, those who are H. pylori negative, and those who have MALT lymphoma in other organs, the treatment is based on the site, symptoms, and stage of the cancer. With localized disease, local treatment via either radiotherapy or surgery can usually achieve excellent disease control [12-14]. With pulmonary involvement, treatment may involve surgery, radiation, or chemotherapy, with similar median times to progression, but in order to avoid the risks involved with surgery, chemotherapy is preferable [15].
In patients with disseminated disease at presentation, chemotherapy remains the mainstay, although no standard regimens exist to date. Alkylating agent-based regimens have been shown to be efficacious along with nucleoside analogs [16]. In cases with histologic transformation or high tumor burdens, anthracycline-based regimens have also been used [17]. Complete remission rates for these regimens are similar and vary from 70 to 75 %. More recently, rituximab has been studied as monotherapy with an overall objective response in approximately 77 %, and trials are underway studying its efficacy in combination with bendamustine and chlorambucil [18, 19]. Immunotherapy using rituximab has been studied in the treatment of aggressive B cell lymphomas and may be considered in aggressive MALT lymphomas [20]. The 5-year overall survival rate with treatment from the time of diagnosis of MALT lymphoma is approximately reported between 95 and 86 % with little difference between GI or non-GI sites and also between localized and disseminated disease [21, 22]. But the 5-year progression-free survival has been estimated at around 5 years, being significantly higher for GI locations compared to non-GI locations (8.9 versus 4.9 years, respectively; P=0.01) [23]. In our patient, an initial alkylating agent-based regimen consisting of six cycles of cyclophosphamide, vincristine, and prednisone failed to show a response. A second regimen of consisting of bendamustine and rituximab with lamivudine showed a dramatic clinical and radiographic response, with no MALT recurrence to date.
Conclusion No standard chemotherapy regimens exist for the treatment of metastatic gastric MALT lymphoma. In the absence of standardized treatment guidelines and sparse literature on the subject, the management of these tumors poses a challenge, necessitating efforts to develop a consensus on treatment strategies. Rituximab has recently shown promising results, and phase II clinical trials of rituximab in combinations with bendamustine and chlorambucil are underway and they may shed new light on chemotherapeutic options in the near future.
Conflict of Interest Authors declare no conflicts of interest for this article.
References 1. Isaacson P, Wright DH. Malignant lymphoma of mucosa-associated lymphoid tissue. A distinctive type of B-cell lymphoma. Cancer. 1983;52(8):1410–6. 2. Swerdlow SHCE, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008.
J Gastrointest Canc 3. Neubauer A, Thiede C, Morgner A, Alpen B, Ritter M, Neubauer B, et al. Cure of Helicobacter pylori infection and duration of remission of low-grade gastric mucosa-associated lymphoid tissue lymphoma. J Natl Cancer Inst. 1997;89(18):1350–5. 4. Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, Isaacson PG. Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet. 1991;338(8776):1175–6. 5. Wohrer S, Troch M, Streubel B, Zwerina J, Skrabs C, Formanek M, et al. MALT lymphoma in patients with autoimmune diseases: a comparative analysis of characteristics and clinical course. Leukemia. 2007;21(8):1812–8. 6. Konjevic G, Jurisic V, Banicevic B, Spuzic I. The difference in NKcell activity between patients with non-Hodgkin’s lymphomas and Hodgkin’s disease. Brit J Haematol. 1999;104(1):144–51. 7. Burke JS. Lymphoproliferative disorders of the gastrointestinal tract: a review and pragmatic guide to diagnosis. Arch Pathol Lab Med. 2011;135(10):1283–97. 8. Kost CB, Holden JT, Mann KP. Marginal zone B-cell lymphoma: a retrospective immunophenotypic analysis. Cytometry B Clin Cytom. 2008;74(5):282–6. 9. Taal BG, Boot H, van Heerde P, de Jong D, Hart AA, Burgers JM. Primary non-Hodgkin lymphoma of the stomach: endoscopic pattern and prognosis in low versus high grade malignancy in relation to the MALT concept. Gut. 1996;39(4):556–61. 10. Montalban C, Norman F. Treatment of gastric mucosa-associated lymphoid tissue lymphoma: Helicobacter pylori eradication and beyond. Expert Rev Anticancer Ther. 2006;6(3):361–71. 11. Ahmad A, Govil Y, Frank BB. Gastric mucosa-associated lymphoid tissue lymphoma. Am J Gastroenterol. 2003;98(5):975–86. 12. Tsai HK, Li S, Ng AK, Silver B, Stevenson MA, Mauch PM. Role of radiation therapy in the treatment of stage I/II mucosa-associated lymphoid tissue lymphoma. Ann Oncol. 2007;18(4):672–8. 13. Zucca E, Conconi A, Pedrinis E, Cortelazzo S, Motta T, Gospodarowicz MK, et al. Nongastric marginal zone B-cell lymphoma of mucosaassociated lymphoid tissue. Blood. 2003;101(7):2489–95. 14. Martinelli G, Laszlo D, Ferreri AJ, Pruneri G, Ponzoni M, Conconi A, et al. Clinical activity of rituximab in gastric marginal zone nonHodgkin’s lymphoma resistant to or not eligible for anti-Helicobacter pylori therapy. J Clin Oncol: Off J Am Soc Clin Oncol. 2005;23(9): 1979–83.
15. Oh SY, Kim WS, Kim JS, Kim SJ, Kwon HC, Lee DH, et al. Pulmonary marginal zone B-cell lymphoma of MALT type—what is a prognostic factor and which is the optimal treatment, operation, or chemotherapy?: Consortium for Improving Survival of Lymphoma (CISL) study. Ann Hematol. 2010;89(6):563–8. 16. Hammel P, Haioun C, Chaumette MT, Gaulard P, Divine M, Reyes F, et al. Efficacy of single-agent chemotherapy in low-grade B-cell mucosa-associated lymphoid tissue lymphoma with prominent gastric expression. J Clin Oncol: Off J Am Soc Clin Oncol. 1995;13(10): 2524–9. 17. Wohrer S, Drach J, Hejna M, Scheithauer W, Dirisamer A, Puspok A, et al. Treatment of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) with mitoxantrone, chlorambucil and prednisone (MCP). Ann Oncol. 2003;14(12):1758–61. 18. Conconi A, Martinelli G, Thieblemont C, Ferreri AJ, Devizzi L, Peccatori F, et al. Clinical activity of rituximab in extranodal marginal zone B-cell lymphoma of MALT type. Blood. 2003;102(8):2741–5. 19. Zucca E, Conconi A, Laszlo D, Lopez-Guillermo A, Bouabdallah R, Coiffier B, et al. Addition of rituximab to chlorambucil produces superior event-free survival in the treatment of patients with extranodal marginal-zone B-cell lymphoma: 5-year analysis of the IELSG-19 Randomized Study. J Clin Oncol: Off J Am Soc Clin Oncol. 2013;31(5):565–72. 20. Colovic N, Jurisic V, Terzic T, Atkinson HD, Colovic M. Immunochemotherapy for Bcl-2 and MUM-negative aggressive primary cutaneous B-cell non-Hodgkin’s lymphoma. Arch Dermatol Res. 2009;301(9):689–92. 21. Olszewski AJ, Castillo JJ. Survival of patients with marginal zone lymphoma: analysis of the Surveillance, Epidemiology, and End Results database. Cancer. 2013;119(3):629–38. 22. Thieblemont C, Bastion Y, Berger F, Rieux C, Salles G, Dumontet C, et al. Mucosa-associated lymphoid tissue gastrointestinal and nongastrointestinal lymphoma behavior: analysis of 108 patients. J Clin Oncol: Off J Am Soc Clin Oncol. 1997;15(4):1624–30. 23. Thieblemont C, Berger F, Dumontet C, Moullet I, Bouafia F, Felman P, et al. Mucosa-associated lymphoid tissue lymphoma is a disseminated disease in one third of 158 patients analyzed. Blood. 2000;95(3):802–6.
