- Email: [email protected]
Management of gastric lymphoma
original article
P. Balfe S. O’Brian P. Daly J.V. Reynolds Department of Surgery, Pathology and Medical Oncology, St James’s Hospital and Trinity College Dublin Correspondence to: Professor John V Reynolds, University Department of Surgery, Trinity Centre for Health Sciences, St James’s Hospital, Dublin 8, Ireland Tel: +353 01 4537479 Fax: +353 01 4546534 email: [email protected]
MANAGEMENT OF GASTRIC LYMPHOMA Introduction: The management of gastric lymphoma is controversial and a wide variety of unimodality or multimodality approaches have been used. The aim of this report is to highlight the variety of treatment regimens deployed, the outcomes achieved and to present a modern management approach for this enigmatic tumour. Results: 42 cases of primary gastric lymphoma managed at one centre over a 15year period were reviewed. Weight loss (52%), pain (41%) and anorexia (33%) were the most common presenting symptoms. Most patients (86%) had high-grade lymphoma. Primary treatment modalities included surgery (36%), chemotherapy (40%), supportive care only (22%) and Hpylori eradication (2%). Adjuvant therapies included chemotherapy (17%), radiotherapy (7%) and combined chemoradiotherapy (5%). The overall median survival was 53 months, with a ve year survival of 46%. In the curative group, the median survival was 75 months and ve year survival 58%. Curative surgery or chemotherapy +/- radiotherapy were similarly effective for stage IE and IIE disease. Conclusions: The prognosis for gastric lymphoma is grade- and stage-dependent. With equivalent outcomes for cure in localised gastric lymphoma for surgery and chemotherapy, the latter is preferred in this unit because of gastric preservation, with surgery being reserved for failed medical management or presentations with haemorrhage, perforation or obstruction refractive to steroid therapy. keywords: gastric, lymphoma Surgeon, 1 October 2008, pp.262-5
INTRODUCTION Malignant lymphoma of the gastrointestinal tract is uncommon, constituting 10% to 15% of all primary lymphomas. The stomach is by far the most common gastrointestinal site, and gastric lymphoma accounts for 3% to 6% of all gastric malignancies.1-3 The pattern of presentation and clinical, endoscopic and radiological findings mimic gastric adenocarcinoma.4 Ten to fifteen years ago, management of gastric lymphoma was predominantly with surgery, but excellent response rates and good functional outcomes with systemic chemotherapy question the need for surgery as primary therapy. The vast majority of primary gastric lymphomas are phenotypically non-Hodgkin’s, B-cell tumours. They infiltrate diffusely both radially and transmurally and may lead to ulceration, bleeding and perforation. The antrum/pylorus is the most common site with the frequency of occurrence diminishing in the body, fundus and cardia. A greater understanding exists of aetiological factors, particularly the role of Helicobacter pylori.5 The concept of mucosa associated lymphoid tissue (MALT) was advanced to differentiate extra-nodal from nodal lymphoid tissue. MALT is naturally associated in the gastrointestinal tract with Peyer’s patches and constitutes an integral defence mechanism against intra-luminal antigens. However, in normal circumstances, the stomach is devoid of lymphoid tissue. A ‘MALTOMA’ represents the aggregation of activated B cells in response to the antigenic stimulation of a T cell clone. Therefore, when, for example, the gastric mucosa is colonised 262
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the royal colleges of surgeons of edinburgh and ireland
by Hpylori, it induces an antigenic response leading to the proliferation of a monoclonal B cell population.6-8 The B cell clone may, if chronically activated, undergo malignant transformation into a MALT lymphoma.9 Where the chronic stimulus is infection with Hpylori, the associated lymphoma, in its low grade state, may completely regress macroscopically and histologically with eradication of the infection.10,11 The classification of lymphoma (nodal and extranodal) has rapidly evolved in line with advances in the understanding of the molecular, immunological and cytogenetic features of the disease. Various classification systems have been used including that of Rappaport, Lukes Collins, Kiel and the ‘Working Formulation’.12-15 The REAL (Revised EuropeanAmerican Classification of Lymphoid Neoplasms) subsequently updated by and integrated with the WHO classification is now widely used (Table 1).16,17 The International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) have, in formulating the TNM classification of malignant tumours, considered it impractical to propose a TNM classification for lymphoma and instead use the modified Ann Arbor staging system.18 In this, Stage IE denotes tumour confined to the stomach, Stage IIE denotes involved regional nodes plus other nodes on the same side of the diaphragm, Stage IIIE represents nodal involvement on both sides of the diaphragm, and Stage IV denotes systemic metastases. © 2008 Surgeon 6; 5: 262-5
Table 1. LOW GRADE MALT (extranodal marginal zone B cell lymphoma) Non-MALT HIGH GRADE Diffuse large B-cell lymphoma (with low grade MALT) Diffuse large B-cell lymphoma (without low grade MALT) OTHER Mantle cell (lymphomatous polyposis), Burkitt’s, Burkitt-like variants, T-cell lymphoma Time trends and practices have evolved in the management of gastric lymphoma over the last 10-15 years. This is highlighted in this report of a 15-year experience with the management of gastric lymphoma in this centre, and the rationale for a current algorithm and protocol is discussed.
MATERIALS AND METHODS The case records of 42 cases of primary gastric lymphoma managed at St. James’s Hospital, Dublin between 1990 and 2005 were reviewed. These were sourced from histoptathology records and from a prospective upper gastrointestinal cancer database (established in 1996). All the pathology was re-reviewed by a consultant pathologist (SOB) in line with modern classification. The entry-point of patients was either through the specialist oesophagogastric unit, or directly to a medical oncologist with a special interest in lymphoma. Since 2002, the majority of patients are discussed at a Multidisciplinary Team Meeting; this was sporadically but not consistently done in the early period of the study. Standard staging since 1996 has involved CT imaging, endoscopy, laparoscopy and bone marrow analysis.
RESULTS The male:female ratio was 1.33:1 with a mean age at presentation of 66 years (32-84). Weight loss (52%), epigastric pain (41%) and anorexia (33%) were the most common presenting symptoms. Only one patient was asymptomatic. The mean interval between onset and presentation was 26 weeks (2-104). Table 2. Histological Grade/Classication of Gastric Lymphoma Low grade
No. of patients
MALT (extranodal marginal zone B-cell lymphoma)
6
Non-MALT
0
High grade Diffuse large B-cell lymphoma (with MALT)
10
Diffuse large B-cell lymphoma (without MALT)
25
Other Mantle cell (small cell lymphoma) © 2008 Surgeon 6; 5: 262-5
1
The disease grade and tumour classification of the 42 patients in this series is shown in Table 2. Twenty-seven (64%) patients were Stage IE or IIE, and 15(36%) were Stage IIIE or IV at presentation. Twentynine (70%) patients were treated with curative intent; 13 (30%) were treated with palliative approaches due to either systemic disease or lack of fitness for curative therapy. The primary treatment modality was surgery in 15 (36%) cases, chemotherapy in 17 (40%), supportive care only in 9 (22%) and Hpylori eradication alone in one patient. Adjuvant therapies included chemotherapy (17%), radiotherapy (7%) and combined chemo-radiotherapy (5%). Of the 29 patients treated with curative intent, 6 (21%) had surgery alone, 7 (24%) had surgery and adjuvant chemotherapy, 13 (34%) had chemotherapy alone, 2 (7%) had a combination of chemotherapy and radiotherapy and one (3%) had Hpylori eradication therapy alone. At a median follow-up of 48 months, the median survival overall was 53 months, with a 1-, 3- and 5-year survival rate of 72%, 63% and 46% respectively. The median survival for the 29 patients treated with curative intent was 75 months, with 79% alive at one year and a 59% five year surival (Figure 1). Thirteen patients were treated with palliative intent; the median survival was 20 months, and the 1- 3- and 5-year survival was 54%, 46% and 15% respectively.
DISCUSSION Gastric lymphoma is a rare and enigmatic disease. As a clinicopathological entity, it does not behave like nodal lymphoma in that the patient is usually older at presentation, the disease is frequently localised and long-term cure and disease free survival are not uncommon. Histological classification has proved challenging but has evolved over the past 15 years, leading to the WHO/REAL classification which is now widely used and accepted internationally. There is, as yet, no established consensus as to the optimal management of primary gastric lymphoma. This is in part due to its relative rarity making it difficult to conduct large-scale prospective randomised trials. The approach in this centre up to recently reflected a bias depending on whether the patient presented through the oesophagogastric service or lymphoma service. This is consistent with a report from De Jong of treatment at 19 different centres where both primary and adjuvant treatment depended in large measure on the preference of the centres and units rather than on any well established set of defined evidence-based protocols with, for example, ‘haematology-oriented’ groups opting in the main for a non-surgical approach involving eradication therapy combined with chemotherapy +/- radiotherapy and ‘gastroenterology-oriented’ groups preferring surgery +/- adjuvant chemotherapy or radiotherapy.19 Brands also reported a wide variation in management when analysing 100 papers involving the treatment of over 3000 patients between 1974 and 1995.20 For example, with Stage IE disease, the recommended treatment was surgery alone in 30% of studies, surgery and radiotherapy in 32%, surgery and chemotherapy in 15% and chemotherapy and radiotherapy in 8%. The outcomes with surgery as the primary treatment modality for Stages IE and IIE disease are variable, with five-year survival rates ranging from 50% to 95% depending on the series.21-22 The best results are for Stage IE and low-grade lymphoma, and the 52% five-year survival in this series may reflect a higher proportion of Stage IIE patients and of patients with high-grade lymphoma. Gastrectomy carries an approximate 5% risk of mortality in specialist centers, and an approximate 30% risk of complications.23
the royal colleges of surgeons of edinburgh and ireland | 263
Curative Palliative
29 13
23 7
20 6
17 2
Fig 1. Overall survival for patients treated with curative and palliative intent. The numbers in the table represent patients at risk at time 0 and at 1, 3 and 5 years Table 3. Study
Study type
Treatment
No. patients
Five year survival (%)
Aviles24
Prospective randomised
Surgery + C/T C/T
24 28
75 75
Taal25
Retrospective
Surgery + DXT DXT
73 46
82 71
Brincker26
Retrospective
Surg +/- DXT +/- C/T DXT +/- C/T
67 36
67 67
Ferreri27
Retrospective
Surg +/- C/T +/-DXT C/T +/- DXT
62 21
NR 82
Koch4
Prospective non-randomised
Surg + DXT +/- C/T DXT +/- C/T
79 106
82 84.4
Balfe
Retrospective
Surg +/- C/T +/- DXT C/T +/- DXT
13 16
52 52
In part because of the risks of gastric resection, and in part due to improving cure rates of lymphoma with chemotherapy, there is an emerging trend to treat gastric lymphoma with chemotherapy, with or without radiotherapy, and results at least equivalent to surgery in terms of disease-free and five year survival have been reported.4,24-27 These modalities are also not without risk of complications, but they permit gastric preservation. A traditional concern with primary chemotherapy is the risk of haemorrhage or perforation, but this appears to be rare, approximately two per cent. A number of series showing equivalence of non-operative approaches with radical surgery are shown in Table 3. Numerous recent reports of high cure rates with CHOP-like regimens, as well as combinations with the monoclonal antibody rituximab, question the primary role of surgery and indeed radiation therapy in a modern approach to gastric lymphoma.28-30
In 2007 we believe that the standard of care is that all patients with a histologically confirmed gastric lymphoma should be discussed at a multidisciplinary conference. True MALTOMA has been uncommon in our experience, and hence H. pylori eradication therapy alone is rarely a primary treatment modality. High-grade tumours were the most common, and the rationale for multi-agent chemotherapy is based on equivalent outcomes to multimodality regimens, with gastric preservation good function and rare treatment related mortality the principal factors determining this preference. Although this cannot be supported by Level I evidence, surgery for high-grade lymphoma is now reserved for failed primary therapy or presentations with haemorrhage, perforation, or refractory obstruction. We believe this approach is consistent with other recent reports that highlight the diminishing role of surgery.31,32
Copyright © 30 October 2007
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© 2008 Surgeon 6; 5: 262-5
REFERENCES 1. D’Amore F, Brincker H, Gronbaek K et al. NonHodgkin’s lymphoma of the gastrointestinal tract: a population-based analysis of incidence, geographic distribution, clinicopathologic presentation features and prognosis. Danish Lymphoma Study Group. J Clin Oncol 2001;19: 3874-83 2. Gurney K, Cartwright R, Gilman E. Descriptive epidemiology of gastrointestinal Non-Hodgkin’s lymphoma in a population-based registry. Br J Cancer 1999;79:1929-34 3. Arenas R. gastric lymphoma. In: Posner M, Vokes E, Weichselbaum R eds. Cancer of the Upper Gastrointestinal Tract. London: BC Decker, Inc;2002: 322-35 4. Koch P, del Valle F, Bardel W, et al. Primary gastrointestinal non-Hodgkin’s lymphoma: II. Combined surgical and conservative or conservative management only in localised gastric lymphoma – results of the prospective German Multicenter Study GIT NHL 01/92 J Clin Oncol 2001;19: 3874-83 5. Parsonnet J, Hansen S, Rodriguez L et al. Helicobacter pylori infection and gastric lymphoma. N Engl J Med 1994;330: 1267-71 6. Hussell T, Isaacson P, Crabtree J et al. The response of cells from low grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue to Helicobacter pylori. Lancet 1993; 342:571-4 7.I Isaacson P, Wright D. Malignant lymphoma of mucosa associated lymphoid tissue. A distinctive type of B-cell lymphoma. Cancer 1983; 52:1410 8. Isaacson P, Wright D. Extranodal malignant lymphoma arising from mucosa associated lymphoid tissue. Cancer 1984; 53: 2515 9. Isaacson P. Gastric MALT lymphoma: from concept to cure. Ann Oncol 1999;10: 637-45 10. Neubauer A, Thiede C, Morgner A 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;89:1350-5 11. Weston A, Banerjee S, Horvat R et al. Prospective long-term endoscopic and histologic follow-up of gastric lymphoproliferative disease of early stage IE low-grade B-cell mucosa-associated lymphoid tissue type following Helicobacter pylori eradication treatment. Int J Oncol 1999;15: 899-907 12. Rappaport H. Tumors of the hematopoietic system. In:Atlas of Tumor Pathology, section 3, fascicle 8. US Armed Forces Institute of Pathology, Washington DC 1966 13. Lukes R, Collins R. New approaches to the classication of the lymphomas. Br J Cancer 1975; 31 (Suppl II):1 14. Lennert K, Mohri N, Stein H et al. Malignant lymphomas other than Hodgkin’s disease. Springer, Berlin, Heidelberg, New York 1978 15. National Cancer Institute sponsored study of classications of non-Hodgkin’s lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin’s Lymphoma Pathologic Classication Project. Cancer 1983; 52: 1410 16. Harris NL, Jaffe ES, Stein H et al. A Revised European-American classication of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84: 1361–92
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17. Harris N, Jaffe E, Diebold J et al. World Health Organisation classication of neoplastic diseases of the hematopoietic and lymphoid tissues. J Clin Oncol 1999;17:3835 18. Crump M, Gospodarowicz M, Shepherd F. Lymphoma of the gastrointestinal tract. Semin Oncol 1999; 26: 324-37 19. De Jong D, Aleman B, Taal B et al. Controversies and consensus in the diagnosis, workup and treatment of gastric lymphoma; an international survey. Ann Oncol 1999;10: 275-80 20. Brands F, Monig S, Raab M. Treatment and prognosis of gastric lymphoma. Eur J Surg. 1997;163: 803-13 21. Bartlett D, Karpeh M, Filippa D et al. Long-term follow-up after curative surgery for early gastric lymphoma. Ann Surg 1996; 223: 53-63 22. Kodera Y, Yamamura Y, Nakamura S et al. The role of radical gastrectomy with systematic lymphadenectomy for the diagnosis and treatment of primary gastric lymphoma. Ann Surg 1998; 227: 45-50 23. McCulloch P, Ward J, Tekkis P. Mortality and morbidity in gastro-oesophageal cancer surgery: initial results of ASCOT multicentre prospective study. BMJ 2003; 327: 1192-97 24. Aviles A, Diaz-Maqueo J, de la Torre A et al. Is surgery necessary in the treatment of primary gastric non-Hodgkin lymphoma. Leuk Lymphoma. 1991;5: 365-69 25. Taal B, Burgers J, van Heerde P et al. The clinical spectrum and treatment of primary non-Hodgkin’s lymphoma of the stomach. Ann Oncol 1993;4: 839-46 26. Brincker H, D’Amore F. A retrospective analysis of treatment outcome in 106 cases of localized gastric non-Hodgkin lymphomas. Danish Lymphoma Study Group, LYFO. Leuk Lymphoma 1995; 18: 281-88 27. Ferreri A, Cordio S, Paro S et al. Therapeutic management of stage I-II high-grade primary gastric lymphomas. Oncology 1999; 56: 274-82 28. Kochi M, Fujii M, Kanamori N, Kaiga T et al. Complete remission by chemotherapy in stage IE-IIE primary gastric lymphoma. Hepatogastroenterology 2007; 54; 1285-8 29. Pfeunschuh M, Trumper L, Osterborg A, Pettengell R, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large –B-cell lymphoma: a randomized controlled trial by the MabThera International Trial (MinT) Group. Lancet Oncol 2006; 7: 379-91 30. Raderer M, Chott A, Drach J, Montalban C, et al. Chemotherapy for management of localized highgrade gastric B-cell lymphoma: how much is necessary? Ann Oncol 2002; 13: 1094-98 31. Ferruci PF, Zucca E. Primary gastric lymphoma pathogenesis and treatment: what has changed over the past 10 years. Br J Haematol 2007; 136: 521-38 32. Yoon SS, Coit DG, Portlock CS, Karpeh MS. The diminishing role of surgery in the treatment of gastric lymphoma. Ann Surg 2004; 240: 28-37
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P. Balfe S. O’Brian P. Daly J.V. Reynolds Department of Surgery, Pathology and Medical Oncology, St James’s Hospital and Trinity College Dublin Correspondence to: Professor John V Reynolds, University Department of Surgery, Trinity Centre for Health Sciences, St James’s Hospital, Dublin 8, Ireland Tel: +353 01 4537479 Fax: +353 01 4546534 email: [email protected]
MANAGEMENT OF GASTRIC LYMPHOMA Introduction: The management of gastric lymphoma is controversial and a wide variety of unimodality or multimodality approaches have been used. The aim of this report is to highlight the variety of treatment regimens deployed, the outcomes achieved and to present a modern management approach for this enigmatic tumour. Results: 42 cases of primary gastric lymphoma managed at one centre over a 15year period were reviewed. Weight loss (52%), pain (41%) and anorexia (33%) were the most common presenting symptoms. Most patients (86%) had high-grade lymphoma. Primary treatment modalities included surgery (36%), chemotherapy (40%), supportive care only (22%) and Hpylori eradication (2%). Adjuvant therapies included chemotherapy (17%), radiotherapy (7%) and combined chemoradiotherapy (5%). The overall median survival was 53 months, with a ve year survival of 46%. In the curative group, the median survival was 75 months and ve year survival 58%. Curative surgery or chemotherapy +/- radiotherapy were similarly effective for stage IE and IIE disease. Conclusions: The prognosis for gastric lymphoma is grade- and stage-dependent. With equivalent outcomes for cure in localised gastric lymphoma for surgery and chemotherapy, the latter is preferred in this unit because of gastric preservation, with surgery being reserved for failed medical management or presentations with haemorrhage, perforation or obstruction refractive to steroid therapy. keywords: gastric, lymphoma Surgeon, 1 October 2008, pp.262-5
INTRODUCTION Malignant lymphoma of the gastrointestinal tract is uncommon, constituting 10% to 15% of all primary lymphomas. The stomach is by far the most common gastrointestinal site, and gastric lymphoma accounts for 3% to 6% of all gastric malignancies.1-3 The pattern of presentation and clinical, endoscopic and radiological findings mimic gastric adenocarcinoma.4 Ten to fifteen years ago, management of gastric lymphoma was predominantly with surgery, but excellent response rates and good functional outcomes with systemic chemotherapy question the need for surgery as primary therapy. The vast majority of primary gastric lymphomas are phenotypically non-Hodgkin’s, B-cell tumours. They infiltrate diffusely both radially and transmurally and may lead to ulceration, bleeding and perforation. The antrum/pylorus is the most common site with the frequency of occurrence diminishing in the body, fundus and cardia. A greater understanding exists of aetiological factors, particularly the role of Helicobacter pylori.5 The concept of mucosa associated lymphoid tissue (MALT) was advanced to differentiate extra-nodal from nodal lymphoid tissue. MALT is naturally associated in the gastrointestinal tract with Peyer’s patches and constitutes an integral defence mechanism against intra-luminal antigens. However, in normal circumstances, the stomach is devoid of lymphoid tissue. A ‘MALTOMA’ represents the aggregation of activated B cells in response to the antigenic stimulation of a T cell clone. Therefore, when, for example, the gastric mucosa is colonised 262
|
the royal colleges of surgeons of edinburgh and ireland
by Hpylori, it induces an antigenic response leading to the proliferation of a monoclonal B cell population.6-8 The B cell clone may, if chronically activated, undergo malignant transformation into a MALT lymphoma.9 Where the chronic stimulus is infection with Hpylori, the associated lymphoma, in its low grade state, may completely regress macroscopically and histologically with eradication of the infection.10,11 The classification of lymphoma (nodal and extranodal) has rapidly evolved in line with advances in the understanding of the molecular, immunological and cytogenetic features of the disease. Various classification systems have been used including that of Rappaport, Lukes Collins, Kiel and the ‘Working Formulation’.12-15 The REAL (Revised EuropeanAmerican Classification of Lymphoid Neoplasms) subsequently updated by and integrated with the WHO classification is now widely used (Table 1).16,17 The International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) have, in formulating the TNM classification of malignant tumours, considered it impractical to propose a TNM classification for lymphoma and instead use the modified Ann Arbor staging system.18 In this, Stage IE denotes tumour confined to the stomach, Stage IIE denotes involved regional nodes plus other nodes on the same side of the diaphragm, Stage IIIE represents nodal involvement on both sides of the diaphragm, and Stage IV denotes systemic metastases. © 2008 Surgeon 6; 5: 262-5
Table 1. LOW GRADE MALT (extranodal marginal zone B cell lymphoma) Non-MALT HIGH GRADE Diffuse large B-cell lymphoma (with low grade MALT) Diffuse large B-cell lymphoma (without low grade MALT) OTHER Mantle cell (lymphomatous polyposis), Burkitt’s, Burkitt-like variants, T-cell lymphoma Time trends and practices have evolved in the management of gastric lymphoma over the last 10-15 years. This is highlighted in this report of a 15-year experience with the management of gastric lymphoma in this centre, and the rationale for a current algorithm and protocol is discussed.
MATERIALS AND METHODS The case records of 42 cases of primary gastric lymphoma managed at St. James’s Hospital, Dublin between 1990 and 2005 were reviewed. These were sourced from histoptathology records and from a prospective upper gastrointestinal cancer database (established in 1996). All the pathology was re-reviewed by a consultant pathologist (SOB) in line with modern classification. The entry-point of patients was either through the specialist oesophagogastric unit, or directly to a medical oncologist with a special interest in lymphoma. Since 2002, the majority of patients are discussed at a Multidisciplinary Team Meeting; this was sporadically but not consistently done in the early period of the study. Standard staging since 1996 has involved CT imaging, endoscopy, laparoscopy and bone marrow analysis.
RESULTS The male:female ratio was 1.33:1 with a mean age at presentation of 66 years (32-84). Weight loss (52%), epigastric pain (41%) and anorexia (33%) were the most common presenting symptoms. Only one patient was asymptomatic. The mean interval between onset and presentation was 26 weeks (2-104). Table 2. Histological Grade/Classication of Gastric Lymphoma Low grade
No. of patients
MALT (extranodal marginal zone B-cell lymphoma)
6
Non-MALT
0
High grade Diffuse large B-cell lymphoma (with MALT)
10
Diffuse large B-cell lymphoma (without MALT)
25
Other Mantle cell (small cell lymphoma) © 2008 Surgeon 6; 5: 262-5
1
The disease grade and tumour classification of the 42 patients in this series is shown in Table 2. Twenty-seven (64%) patients were Stage IE or IIE, and 15(36%) were Stage IIIE or IV at presentation. Twentynine (70%) patients were treated with curative intent; 13 (30%) were treated with palliative approaches due to either systemic disease or lack of fitness for curative therapy. The primary treatment modality was surgery in 15 (36%) cases, chemotherapy in 17 (40%), supportive care only in 9 (22%) and Hpylori eradication alone in one patient. Adjuvant therapies included chemotherapy (17%), radiotherapy (7%) and combined chemo-radiotherapy (5%). Of the 29 patients treated with curative intent, 6 (21%) had surgery alone, 7 (24%) had surgery and adjuvant chemotherapy, 13 (34%) had chemotherapy alone, 2 (7%) had a combination of chemotherapy and radiotherapy and one (3%) had Hpylori eradication therapy alone. At a median follow-up of 48 months, the median survival overall was 53 months, with a 1-, 3- and 5-year survival rate of 72%, 63% and 46% respectively. The median survival for the 29 patients treated with curative intent was 75 months, with 79% alive at one year and a 59% five year surival (Figure 1). Thirteen patients were treated with palliative intent; the median survival was 20 months, and the 1- 3- and 5-year survival was 54%, 46% and 15% respectively.
DISCUSSION Gastric lymphoma is a rare and enigmatic disease. As a clinicopathological entity, it does not behave like nodal lymphoma in that the patient is usually older at presentation, the disease is frequently localised and long-term cure and disease free survival are not uncommon. Histological classification has proved challenging but has evolved over the past 15 years, leading to the WHO/REAL classification which is now widely used and accepted internationally. There is, as yet, no established consensus as to the optimal management of primary gastric lymphoma. This is in part due to its relative rarity making it difficult to conduct large-scale prospective randomised trials. The approach in this centre up to recently reflected a bias depending on whether the patient presented through the oesophagogastric service or lymphoma service. This is consistent with a report from De Jong of treatment at 19 different centres where both primary and adjuvant treatment depended in large measure on the preference of the centres and units rather than on any well established set of defined evidence-based protocols with, for example, ‘haematology-oriented’ groups opting in the main for a non-surgical approach involving eradication therapy combined with chemotherapy +/- radiotherapy and ‘gastroenterology-oriented’ groups preferring surgery +/- adjuvant chemotherapy or radiotherapy.19 Brands also reported a wide variation in management when analysing 100 papers involving the treatment of over 3000 patients between 1974 and 1995.20 For example, with Stage IE disease, the recommended treatment was surgery alone in 30% of studies, surgery and radiotherapy in 32%, surgery and chemotherapy in 15% and chemotherapy and radiotherapy in 8%. The outcomes with surgery as the primary treatment modality for Stages IE and IIE disease are variable, with five-year survival rates ranging from 50% to 95% depending on the series.21-22 The best results are for Stage IE and low-grade lymphoma, and the 52% five-year survival in this series may reflect a higher proportion of Stage IIE patients and of patients with high-grade lymphoma. Gastrectomy carries an approximate 5% risk of mortality in specialist centers, and an approximate 30% risk of complications.23
the royal colleges of surgeons of edinburgh and ireland | 263
Curative Palliative
29 13
23 7
20 6
17 2
Fig 1. Overall survival for patients treated with curative and palliative intent. The numbers in the table represent patients at risk at time 0 and at 1, 3 and 5 years Table 3. Study
Study type
Treatment
No. patients
Five year survival (%)
Aviles24
Prospective randomised
Surgery + C/T C/T
24 28
75 75
Taal25
Retrospective
Surgery + DXT DXT
73 46
82 71
Brincker26
Retrospective
Surg +/- DXT +/- C/T DXT +/- C/T
67 36
67 67
Ferreri27
Retrospective
Surg +/- C/T +/-DXT C/T +/- DXT
62 21
NR 82
Koch4
Prospective non-randomised
Surg + DXT +/- C/T DXT +/- C/T
79 106
82 84.4
Balfe
Retrospective
Surg +/- C/T +/- DXT C/T +/- DXT
13 16
52 52
In part because of the risks of gastric resection, and in part due to improving cure rates of lymphoma with chemotherapy, there is an emerging trend to treat gastric lymphoma with chemotherapy, with or without radiotherapy, and results at least equivalent to surgery in terms of disease-free and five year survival have been reported.4,24-27 These modalities are also not without risk of complications, but they permit gastric preservation. A traditional concern with primary chemotherapy is the risk of haemorrhage or perforation, but this appears to be rare, approximately two per cent. A number of series showing equivalence of non-operative approaches with radical surgery are shown in Table 3. Numerous recent reports of high cure rates with CHOP-like regimens, as well as combinations with the monoclonal antibody rituximab, question the primary role of surgery and indeed radiation therapy in a modern approach to gastric lymphoma.28-30
In 2007 we believe that the standard of care is that all patients with a histologically confirmed gastric lymphoma should be discussed at a multidisciplinary conference. True MALTOMA has been uncommon in our experience, and hence H. pylori eradication therapy alone is rarely a primary treatment modality. High-grade tumours were the most common, and the rationale for multi-agent chemotherapy is based on equivalent outcomes to multimodality regimens, with gastric preservation good function and rare treatment related mortality the principal factors determining this preference. Although this cannot be supported by Level I evidence, surgery for high-grade lymphoma is now reserved for failed primary therapy or presentations with haemorrhage, perforation, or refractory obstruction. We believe this approach is consistent with other recent reports that highlight the diminishing role of surgery.31,32
Copyright © 30 October 2007
264
|
the royal colleges of surgeons of edinburgh and ireland
© 2008 Surgeon 6; 5: 262-5
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