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Gastric Irradiation for Low-grade MALT Lymphoma of the Stomach: Report of Two Cases and Review of the Literature
Clinical Oncology (2002) 14: 464–467 doi:10.1053/clon.2001.0009, available online at http://www.idealibrary.com on
Case Report Gastric Irradiation for Low-grade MALT Lymphoma of the Stomach: Report of Two Cases and Review of the Literature A. El-Modir, J. Glaholm The Cancer Centre at The Queen Elizabeth Hospital, Birmingham, U.K. ABSTRACT: We report the case history of two patients treated with primary gastric irradiation for localized low-grade mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach that failed to respond to anti-Helicobacter pylori antibiotics. One patient refused gastrectomy and the other was considered unfit for surgery. Both patients obtained a biopsy–confirmed complete response and are well and disease free after a median follow-up time of 28 months. A review of the literature on the treatment options for this condition has been undertaken. Gastric irradiation is an effective and safe alternative to gastrectomy in the treatment of low-grade MALT lymphoma of the stomach with the added advantage of organ preservation. El-Modir, A. et al. (2002). Clinical Radiology 14, 464–467 2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved. Key words: MALT, gastrectomy, gastric lymphoma, radiotherapy
Introduction
Gastric lymphoma accounts for only 3% of all gastric neoplasms, the majority of these are high-grade lymphomas. Low-grade mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach constitute a distinct clinico-pathological entity. Helicobacter pylori has been implicated as an aetiological factor [1]. Other potential pathogens in the development of MALT lymphoma include the Epstein–Barr virus and the human T-cell leukaemia/lymphoma virus [2]. MALT lymphoma has also been reported to develop in the thyroid, thymus, urinary bladder, salivary glands and conjunctiva. Unlike diffuse large B-cell lymphoma of the stomach, low-grade lymphoma rarely spreads beyond regional lymph nodes, making it amenable to local therapy. Recent advances in radiology, endoscopy, endoscopic ultrasound (EUS), immunology and genetics have reduced the prior dependence on surgery for diagnosis and staging. Case Report 1
A 54-year-old man presented in 1997 with persistent upper gastrointestinal symptoms. On endoscopy he was found to have a tumour on the lesser curvature of the stomach. Gastric biopsy showed a low-grade B-cell MALT lymphoma arising in a background of chronic gastritis. CLO test for H. pylori bacteria was strongly positive. Staging investigations showed this to be a stage I lymphoma. He failed to respond to two courses of triple therapy (Omeprazole 20 mg twice daily, Clarithro0936–6555/02/060464+04 $35.00/0
mycin 500 mg twice daily, amoxicillin 1 g twice daily for 1 week). Repeat biopsies confirmed persistence of lymphoma although there was less lymphoid infiltration suggesting a partial response to antibiotics. He is otherwise well with no significant past medical history. The patient refused to have surgery and was referred for radical radiotherapy. He received a total radiation dose of 30 Gy in 15 fractions over 21 days to the stomach and perigastric lymph nodes, treating in two phases: phase 1, 14 Gy mid-plane dose in seven fractions over 9 days using opposed anterior and posterior fields with the appropriate shielding (Fig. 1); phase 2, 16 Gy to the isocentre in eight fractions over 10 days using a threefield plan (Fig. 2). The patient was treated supine on an empty stomach, with 8 MV photons. We used oral contrast and computed tomography (CT) scan films to aid in localization of the stomach, and intravenous urogram to aid localization of the kidneys. With the use of the prophylactic Maxolon 20 mg and Omepazole 20 mg prior to radiotherapy, he tolerated the treatment well, experiencing minimal nausea and no vomiting. He remains well and asymptomatic with no evidence of recurrence of his lymphoma 32 months after the completion of his treatment. Case Report 2
A 79-year-old man presented in 1998 with a few months history of dyspepsia, epigastric pain and weight loss, despite regular ranitidine. He suffered from diabetes
2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved.
-
465
junction. There was also evidence of antral gastritis but no evidence of H. pylori infection. In view of his past medical history he was given a course of triple therapy. The patient was symptomatically better but a repeat endoscopy 6 months later showed slight progression of the tumour. Staging investigations were normal apart from two enlarged perigastric lymph nodes, making this a stage II gastric lymphoma. He was referred for radical radiotherapy. He received a 30 Gy mid-plane dose in 15 fractions over 3 weeks using opposed anterior and posterior fields to the stomach and perigastric lymph nodes with 8 MV photons. He tolerated the treatment very well. Repeat biopsy 4 months after treatment showed complete remission of the lymphoma. The patient remains well with no evidence of recurrence of his lymphoma 24 months after the completion of treatment.
Discussion
Fig. 1 – AP simulator film with barium meal showing the target volume and shielding use in phase 1.
mellitus, ischaemic heart disease and has suffered a previous myocardial infarction. He also had a past history of transient ischaemic attacks. Endoscopy and gastric biopsy showed a low-grade MALT lymphoma just distal to the gastro-oesophageal
Gastric MALT lymphoma has been treated with different modalities including antibiotic therapy, surgery, radiotherapy, chemotherapy and various combinations of these options. There is increasing evidence that antibiotic therapy against H. pylori leads to lymphoma remission in 50–80% of patients [3]. When triple therapy fails or in the absence of H. pylori, other treatment options need to be considered. Furthermore, the longterm efficacy of antibiotic therapy is still of concern. Thiede et al. reported that most patients (70%) have remained monoclonal by PCR even after they have
Fig. 2 – Three-field treatment plan for phase 2.
466
achieved a histological remission [4]. The persistence of monoclonality in post treatment biopsies without histological evidence of MALT lymphoma suggests that eradication of H. pylori suppresses but does not eradicate the neoplastic clone in all cases. The experience of treating low-grade MALT lymphoma of the stomach with primary chemotherapy is limited. Montalban and colleagues have reported a 5-year survival of 100% for gastric MALT lymphoma treated with surgery alone, 34% for those treated with chemotherapy alone and 100% for those treated with surgery plus chemotherapy [5]. Pinotti et al. reported a 43% 5-year event-free survival in stage I patients treated with chemotherapy alone [6]. These results suggest that chemotherapy alone may not be the optimal treatment for stage I gastric MALT lymphoma. Local therapy either with surgery and/or radiotherapy is the definitive therapy for localized gastric MALT lymphoma in patients who fail antibiotic therapy or in the absence of H. pylori infection. Recently, Fung et al. reported a 100% 10-year cancer-free survival rate for patients with stage IE low-grade MALT lymphoma of the stomach treated with local therapy alone (gastrectomy and/or radiotherapy) [7]. The 10-year relapse free survival was 93%. Pinotti et al reported a 100% complete remission rate using local treatment only in stage I disease but did not report the relapse rate or the overall survival [6]. Traditionally, the primary definitive local therapy for localized gastric lymphoma is gastrectomy, either partial or total. With advances in radiology, endoscopy, immunology and the advent of EUS, dependency on surgery for diagnosis and staging has reduced dramatically. Meanwhile, a number of studies using primary radiotherapy reported similar results to surgery with acceptable toxicity. What is the optimal local therapy for gastric MALT lymphoma when antibiotics have failed or are inappropriate? Both surgery and radiotherapy have advantages and disadvantages. It is well known that 20–30% of gastric MALT lymphomas are multifocal [7] and a partial gastrectomy may be inadequate. Total gastrectomy is associated with significant mortality and morbidity such as anaemia, malnutrition, diarrhoea and dumping syndrome. In Montalban’s review [5], the postoperative mortality was 4.8%. Incomplete resections would still need postoperative radiotherapy and/or chemotherapy. Primary gastric irradiation is an attractive alternative to surgery. The sensitivity of gastric lymphoma to radiotherapy has been known for decades but unsubstantiated fears of toxicity, in particular the risk of perforation and bleeding, has limited its use in the past. A review of the literature suggests that primary gastric irradiation may be the optimal local treatment for localized gastric MALT lymphoma. Surgery would still be the main treatment for emergency situations such as gastric perforation or severe haemorrhage. Schechter and colleagues [8] from Memorial Sloan Kettering Cancer Centre reported on 17 patients with stages I and
II low-grade B-cell gastric MALT lymphoma without evidence of H. pylori or with persistent lymphoma after antibiotics, treated with radiotherapy to the stomach and perigastric lymph nodes. The median age was 69 years (range 39–84 years). The median total radiation dose was 30 Gy (range 28.5 to 43.5 Gy) delivered in 1.5 Gy fractions. All 17 patients obtained a biopsy confirmed complete response. At a median follow-up time of 27 months (range 11–68 months) event-free survival was 100%. The treatment was well tolerated and none of the 17 patients developed gastrointestinal bleeding or gastric perforation during or after radiotherapy. In a retrospective analysis of 16 patients with stage IE gastric MALT lymphoma, Fung et al concluded that radiation therapy is well tolerated, effective and may well be the optimal non-antibiotic treatment for patients with localized MALT lymphoma of the stomach [7]. The reported incidence of radiation-induced perforation or haemorrhage is 0–4%. Other potential side-effects if gastric irradiation include diarrhoea, renal toxicity and induction of second malignancies. The risk of clinically significant hypertension or radiation nephritis is very small [9]. Patients with gastric lymphoma have an increased risk of gastric adenocarcinoma, irrespective of the treatment modality.
Conclusion
Low-grade gastric MALT lymphoma is a relatively new pathological entity which is often associated with the presence of H. phylori bacteria. Eradication of H. pylori leads to lymphoma remission in 50–80% of patients. Chemotherapy alone has not been proven as a successful treatment for these tumours. Both surgery and radiotherapy are effective local treatments. Our two cases agree with the published studies which suggest that primary gastric irradiation for these lymphomas is a safe and effective alternative to gastrectomy with the significant advantage of gastric organ preservation and may be less morbidity. We currently prescribe a dose of 30 Gy in 15 fractions to the stomach and perigastric lymph nodes. Future studies may well address the use of lower doses.
References 1 Eidt S, Stolte M, Fischer R. Helicobacter pylori gastritis and primary gastric non-Hodgkin’s lymphomas. J Clin Pathol 1994;47:436–439. 2 Ben Rejeb A, Kchir NJ, et al. Detection of Epstein–Barr virus in MALT type gastric malignant lymphoma using in situ hybridization. Clin Exp Pathol 1999;47:101–105. 3 Wotherspoon A, Doglioni C, Diss T, et al. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet 1993;342:575. 4 Thiede C, Alpen B, Morgner A, et al. Monoclonal PCR after histological remission in gastric low-grade MALT B-cell
- lymphoma – a common phenomenon. Blood 1997;90:391a (abstract 1740). 5 Montalban C, Castrillo JM, Abraira V, et al. Gastric B-cell mucosaassociated lymphoid tissue (MALT) lymphoma: clinicopathological study and evaluation of the prognostic factors in 143 patients. Ann Oncol 1995;6:355–362. 6 Pinotti G, Zucca E, Roggero E, et al. Clinical features, treatment and outcome in a series of 93 patients with low-grade gastric MALT lymphoma. Leuk Lymphoma 1997;26:527–537.
467
7 Fung C, Grossbard M, Linggood R, et al. Mucosa-associated lymphoid tissue lymphoma of the stomach: long-term outcome after local treatment. Cancer 1999;85:9–17. 8 Schechter N, Portlock C, Yahalom J. Treatment of mucosaassociated lymphoid tissue lymphoma of the stomach with radiation alone. J Clin Oncol 1998;16:1916–1921. 9 Maor M, Morth L, Cabanillas F, et al. Outcomes of high-dose unilateral kidney irradiation in patients with gastric lymphoma. Int J Radiat Oncol Biol Phys 1998;41:647–650.
Case Report Gastric Irradiation for Low-grade MALT Lymphoma of the Stomach: Report of Two Cases and Review of the Literature A. El-Modir, J. Glaholm The Cancer Centre at The Queen Elizabeth Hospital, Birmingham, U.K. ABSTRACT: We report the case history of two patients treated with primary gastric irradiation for localized low-grade mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach that failed to respond to anti-Helicobacter pylori antibiotics. One patient refused gastrectomy and the other was considered unfit for surgery. Both patients obtained a biopsy–confirmed complete response and are well and disease free after a median follow-up time of 28 months. A review of the literature on the treatment options for this condition has been undertaken. Gastric irradiation is an effective and safe alternative to gastrectomy in the treatment of low-grade MALT lymphoma of the stomach with the added advantage of organ preservation. El-Modir, A. et al. (2002). Clinical Radiology 14, 464–467 2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved. Key words: MALT, gastrectomy, gastric lymphoma, radiotherapy
Introduction
Gastric lymphoma accounts for only 3% of all gastric neoplasms, the majority of these are high-grade lymphomas. Low-grade mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach constitute a distinct clinico-pathological entity. Helicobacter pylori has been implicated as an aetiological factor [1]. Other potential pathogens in the development of MALT lymphoma include the Epstein–Barr virus and the human T-cell leukaemia/lymphoma virus [2]. MALT lymphoma has also been reported to develop in the thyroid, thymus, urinary bladder, salivary glands and conjunctiva. Unlike diffuse large B-cell lymphoma of the stomach, low-grade lymphoma rarely spreads beyond regional lymph nodes, making it amenable to local therapy. Recent advances in radiology, endoscopy, endoscopic ultrasound (EUS), immunology and genetics have reduced the prior dependence on surgery for diagnosis and staging. Case Report 1
A 54-year-old man presented in 1997 with persistent upper gastrointestinal symptoms. On endoscopy he was found to have a tumour on the lesser curvature of the stomach. Gastric biopsy showed a low-grade B-cell MALT lymphoma arising in a background of chronic gastritis. CLO test for H. pylori bacteria was strongly positive. Staging investigations showed this to be a stage I lymphoma. He failed to respond to two courses of triple therapy (Omeprazole 20 mg twice daily, Clarithro0936–6555/02/060464+04 $35.00/0
mycin 500 mg twice daily, amoxicillin 1 g twice daily for 1 week). Repeat biopsies confirmed persistence of lymphoma although there was less lymphoid infiltration suggesting a partial response to antibiotics. He is otherwise well with no significant past medical history. The patient refused to have surgery and was referred for radical radiotherapy. He received a total radiation dose of 30 Gy in 15 fractions over 21 days to the stomach and perigastric lymph nodes, treating in two phases: phase 1, 14 Gy mid-plane dose in seven fractions over 9 days using opposed anterior and posterior fields with the appropriate shielding (Fig. 1); phase 2, 16 Gy to the isocentre in eight fractions over 10 days using a threefield plan (Fig. 2). The patient was treated supine on an empty stomach, with 8 MV photons. We used oral contrast and computed tomography (CT) scan films to aid in localization of the stomach, and intravenous urogram to aid localization of the kidneys. With the use of the prophylactic Maxolon 20 mg and Omepazole 20 mg prior to radiotherapy, he tolerated the treatment well, experiencing minimal nausea and no vomiting. He remains well and asymptomatic with no evidence of recurrence of his lymphoma 32 months after the completion of his treatment. Case Report 2
A 79-year-old man presented in 1998 with a few months history of dyspepsia, epigastric pain and weight loss, despite regular ranitidine. He suffered from diabetes
2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved.
-
465
junction. There was also evidence of antral gastritis but no evidence of H. pylori infection. In view of his past medical history he was given a course of triple therapy. The patient was symptomatically better but a repeat endoscopy 6 months later showed slight progression of the tumour. Staging investigations were normal apart from two enlarged perigastric lymph nodes, making this a stage II gastric lymphoma. He was referred for radical radiotherapy. He received a 30 Gy mid-plane dose in 15 fractions over 3 weeks using opposed anterior and posterior fields to the stomach and perigastric lymph nodes with 8 MV photons. He tolerated the treatment very well. Repeat biopsy 4 months after treatment showed complete remission of the lymphoma. The patient remains well with no evidence of recurrence of his lymphoma 24 months after the completion of treatment.
Discussion
Fig. 1 – AP simulator film with barium meal showing the target volume and shielding use in phase 1.
mellitus, ischaemic heart disease and has suffered a previous myocardial infarction. He also had a past history of transient ischaemic attacks. Endoscopy and gastric biopsy showed a low-grade MALT lymphoma just distal to the gastro-oesophageal
Gastric MALT lymphoma has been treated with different modalities including antibiotic therapy, surgery, radiotherapy, chemotherapy and various combinations of these options. There is increasing evidence that antibiotic therapy against H. pylori leads to lymphoma remission in 50–80% of patients [3]. When triple therapy fails or in the absence of H. pylori, other treatment options need to be considered. Furthermore, the longterm efficacy of antibiotic therapy is still of concern. Thiede et al. reported that most patients (70%) have remained monoclonal by PCR even after they have
Fig. 2 – Three-field treatment plan for phase 2.
466
achieved a histological remission [4]. The persistence of monoclonality in post treatment biopsies without histological evidence of MALT lymphoma suggests that eradication of H. pylori suppresses but does not eradicate the neoplastic clone in all cases. The experience of treating low-grade MALT lymphoma of the stomach with primary chemotherapy is limited. Montalban and colleagues have reported a 5-year survival of 100% for gastric MALT lymphoma treated with surgery alone, 34% for those treated with chemotherapy alone and 100% for those treated with surgery plus chemotherapy [5]. Pinotti et al. reported a 43% 5-year event-free survival in stage I patients treated with chemotherapy alone [6]. These results suggest that chemotherapy alone may not be the optimal treatment for stage I gastric MALT lymphoma. Local therapy either with surgery and/or radiotherapy is the definitive therapy for localized gastric MALT lymphoma in patients who fail antibiotic therapy or in the absence of H. pylori infection. Recently, Fung et al. reported a 100% 10-year cancer-free survival rate for patients with stage IE low-grade MALT lymphoma of the stomach treated with local therapy alone (gastrectomy and/or radiotherapy) [7]. The 10-year relapse free survival was 93%. Pinotti et al reported a 100% complete remission rate using local treatment only in stage I disease but did not report the relapse rate or the overall survival [6]. Traditionally, the primary definitive local therapy for localized gastric lymphoma is gastrectomy, either partial or total. With advances in radiology, endoscopy, immunology and the advent of EUS, dependency on surgery for diagnosis and staging has reduced dramatically. Meanwhile, a number of studies using primary radiotherapy reported similar results to surgery with acceptable toxicity. What is the optimal local therapy for gastric MALT lymphoma when antibiotics have failed or are inappropriate? Both surgery and radiotherapy have advantages and disadvantages. It is well known that 20–30% of gastric MALT lymphomas are multifocal [7] and a partial gastrectomy may be inadequate. Total gastrectomy is associated with significant mortality and morbidity such as anaemia, malnutrition, diarrhoea and dumping syndrome. In Montalban’s review [5], the postoperative mortality was 4.8%. Incomplete resections would still need postoperative radiotherapy and/or chemotherapy. Primary gastric irradiation is an attractive alternative to surgery. The sensitivity of gastric lymphoma to radiotherapy has been known for decades but unsubstantiated fears of toxicity, in particular the risk of perforation and bleeding, has limited its use in the past. A review of the literature suggests that primary gastric irradiation may be the optimal local treatment for localized gastric MALT lymphoma. Surgery would still be the main treatment for emergency situations such as gastric perforation or severe haemorrhage. Schechter and colleagues [8] from Memorial Sloan Kettering Cancer Centre reported on 17 patients with stages I and
II low-grade B-cell gastric MALT lymphoma without evidence of H. pylori or with persistent lymphoma after antibiotics, treated with radiotherapy to the stomach and perigastric lymph nodes. The median age was 69 years (range 39–84 years). The median total radiation dose was 30 Gy (range 28.5 to 43.5 Gy) delivered in 1.5 Gy fractions. All 17 patients obtained a biopsy confirmed complete response. At a median follow-up time of 27 months (range 11–68 months) event-free survival was 100%. The treatment was well tolerated and none of the 17 patients developed gastrointestinal bleeding or gastric perforation during or after radiotherapy. In a retrospective analysis of 16 patients with stage IE gastric MALT lymphoma, Fung et al concluded that radiation therapy is well tolerated, effective and may well be the optimal non-antibiotic treatment for patients with localized MALT lymphoma of the stomach [7]. The reported incidence of radiation-induced perforation or haemorrhage is 0–4%. Other potential side-effects if gastric irradiation include diarrhoea, renal toxicity and induction of second malignancies. The risk of clinically significant hypertension or radiation nephritis is very small [9]. Patients with gastric lymphoma have an increased risk of gastric adenocarcinoma, irrespective of the treatment modality.
Conclusion
Low-grade gastric MALT lymphoma is a relatively new pathological entity which is often associated with the presence of H. phylori bacteria. Eradication of H. pylori leads to lymphoma remission in 50–80% of patients. Chemotherapy alone has not been proven as a successful treatment for these tumours. Both surgery and radiotherapy are effective local treatments. Our two cases agree with the published studies which suggest that primary gastric irradiation for these lymphomas is a safe and effective alternative to gastrectomy with the significant advantage of gastric organ preservation and may be less morbidity. We currently prescribe a dose of 30 Gy in 15 fractions to the stomach and perigastric lymph nodes. Future studies may well address the use of lower doses.
References 1 Eidt S, Stolte M, Fischer R. Helicobacter pylori gastritis and primary gastric non-Hodgkin’s lymphomas. J Clin Pathol 1994;47:436–439. 2 Ben Rejeb A, Kchir NJ, et al. Detection of Epstein–Barr virus in MALT type gastric malignant lymphoma using in situ hybridization. Clin Exp Pathol 1999;47:101–105. 3 Wotherspoon A, Doglioni C, Diss T, et al. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet 1993;342:575. 4 Thiede C, Alpen B, Morgner A, et al. Monoclonal PCR after histological remission in gastric low-grade MALT B-cell
- lymphoma – a common phenomenon. Blood 1997;90:391a (abstract 1740). 5 Montalban C, Castrillo JM, Abraira V, et al. Gastric B-cell mucosaassociated lymphoid tissue (MALT) lymphoma: clinicopathological study and evaluation of the prognostic factors in 143 patients. Ann Oncol 1995;6:355–362. 6 Pinotti G, Zucca E, Roggero E, et al. Clinical features, treatment and outcome in a series of 93 patients with low-grade gastric MALT lymphoma. Leuk Lymphoma 1997;26:527–537.
467
7 Fung C, Grossbard M, Linggood R, et al. Mucosa-associated lymphoid tissue lymphoma of the stomach: long-term outcome after local treatment. Cancer 1999;85:9–17. 8 Schechter N, Portlock C, Yahalom J. Treatment of mucosaassociated lymphoid tissue lymphoma of the stomach with radiation alone. J Clin Oncol 1998;16:1916–1921. 9 Maor M, Morth L, Cabanillas F, et al. Outcomes of high-dose unilateral kidney irradiation in patients with gastric lymphoma. Int J Radiat Oncol Biol Phys 1998;41:647–650.