- Open Access
Surgical treatment of primitive gastro-intestinal lymphomas: a systematic review
- Roberto Cirocchi†1Email author,
- Eriberto Farinella†2,
- Stefano Trastulli†1,
- Davide Cavaliere†3,
- Piero Covarelli†1,
- Chiara Listorti†1,
- Jacopo Desiderio†1,
- Francesco Barberini†1,
- Nicola Avenia†1,
- Antonio Rulli†1,
- Giorgio Maria Verdecchia†3,
- Giuseppe Noya†1 and
- Carlo Boselli†1
© Cirocchi et al; licensee BioMed Central Ltd. 2011
- Received: 5 July 2011
- Accepted: 7 November 2011
- Published: 7 November 2011
Primitive Gastrointestinal Lymphomas (PGIL) are uncommon tumours, although time-trend analyses have demonstrated an increase. The role of surgery in the management of lymphoproliferative diseases has changed over the past 40 years. Nowadays their management is centred on systemic treatments as chemo-/radio- therapy. Surgery is restricted to very selected indications, always discussed in a multidisciplinary setting. The aim of this systematic review is to evaluate the actual role of surgery in the treatment of PGIL.
A systematic review of literature was conducted according to the recommendations of The Cochrane Collaboration. Main outcomes analysed were overall survival (OS) and disease free survival (DFS).
There are currently 1 RCT and 4 non-randomised prospective controlled studies comparing surgical versus medical treatment for PGIL. Seven hundred and one patients were analysed, divided into two groups: 318 who underwent to surgery alone or associated with chemotherapy and/or radiotherapy (surgical group) versus 383 who were treated with chemotherapy and/or radiotherapy (medical group).
Despite the OS at 10 years between surgical and medical groups did not show relevant differences, the DFS was significantly better in the medical group (P = 0.00001). Accordingly a trend was noticed in the recurrence rate, which was lower in the medical group (6.06 vs. 8.57%); and an higher mortality was revealed in the surgical group (4.51% vs. 1.50%).
The chemotherapy confirms its primary role in the management of PGIL as part of systemic treatment in the medical group. Surgery remains the treatment of choice in case of PGIL acutely complicated, although there is no evidence in literature regarding the utility of preventive surgery.
- Overall Survival
- Disease Free Survival
- National Comprehensive Cancer Network
- Medical Group
- Malt Lymphoma
Primitive Gastrointestinal Lymphomas (PGIL) are uncommon tumours, although time-trend analyses have demonstrated an increase of 2.7% per annum in incidence for gastric (6.3%) and small bowel diseases (5.9%) .
PGIL could be localised in any site of the gastrointestinal tract [1–7]. The most frequent site is the stomach (44-75%). Other locations might be the jejunum or the ileo-cecal region, while duodenum, colon and rectum are rare. Multiple gastrointestinal lesions are very infrequent.
The treatment of patient with PGIL is quite undefined. In fact, although the efficacy of chemotherapy (CT) is well recognised and all treatment strategies for PGIL include CT, with or without radiotherapy (RT); whether or not CT should be performed as unique medical treatment or as part of a combined treatment, which includes the surgical resection of the primary lymphoma, is still discussed. Moreover, surgery is sometime necessary to manage acute complications, such as haemorrhage, abscess, gastrointestinal occlusion or perforation during systemic therapies or suggested for prevention of such emergencies.
The aim of this systematic review is to evaluate the actual role of surgery in the treatment of PGIL, analysing overall and disease free survival as main outcomes.
We conducted the review according to the recommendations of The Cochrane Collaboration and performed the statistical analysis using Review Manager 5 (RevMan) software.
Research methods for identification of studies
We searched for all published and unpublished randomised controlled trials (RCT) and controlled clinical trials (CCT) using the following electronic databases: Cochrane Central Register of Controlled Trials, MEDLINE, Science Citation Index, ISI Proceedings, Current Controlled Trials metaRegister, Zetoc, CINAHL and EMBASE. The following medical search headings (MeSH) and free text words were used: ''surgery''; "chemotherapy"; "radiotherapy"; "gastric lymphoma"; ''gastrointestinal lymphoma", "colonic lymphoma". We checked the reference lists of all relevant studies obtained from our search and from previously published systematic reviews in order to identify other possible articles. The latest date for this search was February 25th 2010.
Three authors (RC and ST) assessed titles or abstracts of all the studies identified by the initial search and excluded clearly non-relevant studies. They obtained the full text of all potentially relevant studies and also those with unclear methodology. These studies were assessed by the authors as to whether they met the inclusion criteria for this review. Disagreements on inclusion were resolved by discussing and, if necessary, by involving an independent third author (EF).
To be included in the analysis, the studies had to compare surgery alone or associated with chemotherapy and/or radiotherapy (surgical group) versus chemotherapy and/or radiotherapy (medical group) in the treatment of gastrointestinal lymphoma tumours.
Studies were excluded from the meta-analysis if the outcomes of interest were not reported for both groups, or solid tumours were considered, or there was a considerable overlap between authors, centres or patient cohorts evaluated.
Outcomes of Interest
Primary outcomes analysed were: overall survival (OS) and disease free survival (DFS). Secondary outcomes measured were: recurrence rate and mortality.
Measures of treatment effect
Statistical analysis for categorical variables was performed by using the odds ratio (OR). This ratio represents the odds of an adverse event occurring in the surgical treatment group compared with the medical treatment group. The Mantel-Haenszel method was used to combine the ORs for the outcomes of interest. Intention-to-treat analyses were performed extracting the number of patients originally allocated to each treatment group irrespective of compliance. Results were presented on a forest plot graphs.
Assessment of heterogeneity
Heterogeneity was first tested using Chi-squared test. A Chi-squared test with a P value < 0.100 representing statistical significance. However, since tests of heterogeneity had a relative low power when there were few study we further explored heterogeneity derived from another statistical method named "inconsistency" or I2 metric, which is independent of the number of combined studies. If I2 is equal 0%, there is no heterogeneity. If I2 > 50% heterogeneity is indicated.
Characteristics of the included studies
Types of study
N° of total evaluated patients
Surgical treatment +/- medical theraphy
Medical theraphy alone
Avilés et al. 
Patients with low-grade gastric MALT lymphoma age < 70 yr old, no gender difference, ECOG status ≤2, immunodeficiency virus test negative,
tumor mass > 5, previously untreated, stage I or IIE (according to the Lugano Conference criteria)
80 patients received surgery alone
78 patients received only radiotherapy
83 patients received only chemotherapy
7, 5 years
(range 4.8-11.6 yr)
80% S group
75% R group
85% C group
52% S group
52% R group
87% C group
Gobbi et al. 
Patients who fulfilled Lewin's criteria for diagnosing PGL (stomach and intestinal). Low-grade MALT lymphomas were excluded from this study
106 patients received
chemotherapy plus surgery
48 patients received chemotherapy
Radiotherapy was optionally given only when residual
tumor masses seemed to persist at restaging after primary
therapy or when bulky masses were present at onset.
Popescu et al. 
Patients with a histological diagnosis of intermediate or high-grade NHL according to the Working Formulation (WF) involving the stomach were included. Patients who received radiotherapy but no chemotherapy treatment were not included.
Patients in whom lymphoma diagnosis predated demonstration of gastric involvement or where the bulk of the disease and its manifestations was extra-abdominal, nodal, hepatic or splenic were considered to have secondary involvement of the stomach were excluded.
13 Surgery and chemotherapy
5 total gastrectomy
8 partial gastrectomy
24 patients received chemotherapy alone
60% in S+C group
67% in medical therapy group
85 > % % in S+C group
62% in medical therapy group
Binn et al. 
Patients with diffuse large B-cell
primary gastric lymphoma with stage IE and IIE according to the Ann Arbor staging system. Mediterranean lymphoma, human immunodeficiency virus-related lymphoma and post-transplantation
lymphoma were not included.
40 patients received surgery plus chemotherapy
21 total gastrectomy
19 partial gastrectomy
44 patients received chemotherapy alone
7 patients received additional radiotherapy
90, 5% in S+C group
91, 1% in medical therapy group
85, 5% in S+C group
91, 6% in medical terapy group
Koch et al. 
Patients with all histological tips of gastric low and high grade lymphoma but only in stage I E and II E 1- 2.
Patients who were older than 75 years and/or presented with second malignancies,
had missing confirmation of histologic subtype by central review, or had comorbidity prohibiting therapy were excluded from study
79 patients received
complete or partial resection
in combination with
radio- and/or chemotherapy
106 patients received only radio- and/or chemotherapy
(range 0-92 months)
84, 2% in medical therapy group
Combined surgical treatment
78.7% in medical therapy group
Combined surgical treatment
Results of Meta-analysis
Based on the assumption that PGIL is a localised disease, the surgical treatment was traditionally considered the cornerstone of the therapeutical strategy showing impressive results in terms of long DFS and OS [3, 12–16].
Nowadays this approach has been extensively revised and the management of PGIL is centred on systemic treatments such as chemo- and radiotherapy.
The current National Comprehensive Cancer Network (NCCN) guidelines [17, 18] suggests for the gastric MALT lymphoma chemotherapy mainly and Helicobacter pylori eradication therapy in the early stage. Surgery is restricted to the treatment of complications, such as occlusion, bleeding or perforation. Preventive surgery is sometime advocated in bulky tumours, when rapid tumour necrosis secondary to chemo-/radiotherapy may be associated with a high risk of life threatening complications. Surgery is also required for removal of residual disease after medical debulking . Total gastrectomy is the most frequent procedure performed for gastric MALT lymphomas, given the evidence that they are multicentric; a D2 lymphadenectomy is recommended .
The majority of small bowel lymphomas are represented by B-large cell lymphomas. The NCCN guidelines proposes surgery or radiotherapy as equally effective in the early stage of MALT lymphomas, while chemotherapy for B-large cell lymphomas and advanced stage of MALT lymphomas. In locally advanced lymphomas of the small bowel, surgical resection is indicated during laparotomy/laparoscopy for tumours of undefined histology or complicated by intestinal occlusion, bleeding, and perforation. Surgery may be advocated before chemotherapy in bulky lesions in order to prevent bowel perforation. A segmental intestinal resection with the own mesentery containing at least 12 lymph nodes is recommended.
In the colon-rectum localization, the MALT lymphomas are more common. The NCCN proposed for the colon the same protocols as for the small intestine. In this cases the surgical approach is represented by the segmental resection of the colon, or a local excision for rectal tumours.
Given the actual dominant role of chemotherapy in the treatment of PGIL, in our literature research most of outcomes resulted from combined therapy. We could identify only one trial  analysing surgery, radiotherapy and chemotherapy separately. In this trial, Aviles et al included only patients with diagnosis of low-grade gastric MALT lymphoma, who were randomised to be treated with primary surgical resection (total gastrectomy and D2 limphadenectomy), radiotherapy or chemotherapy. At 4 weeks complete response was achieved in all patients, but relapse in another abdominal site were more frequent in patients treated with surgery or radiotherapy. At 10 years DFS and OS were statistical significantly higher in the chemotherapy group (p = 0.01 and p = 0.04).
Surgery lost its leading role, becoming the treatment of choice only in acute complicated cases or in the prevention of chemotherapy and/or radiotherapy related complications secondary to rapid tumour necrosis . The aim of preventive surgery is to reduce the high incidence of severe morbidity and mortality due to an emergency laparotomy in highly compromised patients . In the past this risk was overestimated and a surgical management was more frequently advocated; actually it stands at 5% : surgery has more than 5% of procedure related morbidity  and similarly, from our meta-analysis resulted a higher mortality (P = 0, 29). Therefore surgery must be reserved to very selected patients.
One of the main limitations of our study is the retrospective nature of the majority of studies included in the systematic review. These studies are heterogeneous, combining different types of malignant lymphoma, using different histology classifications and staging systems. Moreover, the aim of this review was the comparison of surgery versus medical therapies but only one study confronted these two approaches. In the others studies, surgery was part of a multimodal treatment, associated to chemo with or without radiotherapy. Besides, case history considers different type of lymphomas, in different stages, with different prognosis, without stratification. Therefore, the application of selective methods and statistical analysis, even if apparently they are in line with what is the generally accepted, they cannot bring to evidence based conclusions.
It would be interesting to analyze only studies including surgery during not surgical treatments in order to evaluate if, when and why surgery was used. From this type of analysis prognostic factors for development of acute complications could be evident and could help selecting high risk patients that are preemptively candidate for surgery.
Although from our meta-analysis there was not any significant difference in terms of OS between surgical and medical groups, DFS was significantly better in the medical group. Accordingly a lower recurrence rate was reported in the medical group. Moreover, our meta-analysis showed an higher mortality in the surgical group. This confirms the widely recognized primary role of the chemotherapy, as part of systemic treatment in the medical group. Surgery remains the treatment of choice in case of PGIL acutely complicated, although there is no evidence in literature regarding the utility of preventive surgery.
Despite the absence in literature of high quality studies (RCT) demonstrating the effectiveness of chemotherapy without local surgical resection in patient with PGIL, the evidence present in literature and analyzed in our review well support a systemic approach for PGIL patients.
- Gurney KA, Cartwright RA, Gilman EA: Descriptive epidemiology of gastrointestinal non-Hodgkin's lymphoma in a population-based registry. Br J Cancer. 1999, 79 (11-12): 1929-34.PubMed CentralView ArticlePubMedGoogle Scholar
- Freeman C, Berg JW, Cutler SJ: Occurrence and prognosis of extranodal lymphomas. Cancer. 1972, 29 (1): 252-60. 10.1002/1097-0142(197201)29:1<252::AID-CNCR2820290138>3.0.CO;2-#.View ArticlePubMedGoogle Scholar
- Radaszkiewicz T, Dragosics B, Bauer P: Gastrointestinal malignant lymphomas of the mucosa-associated lymphoid tissue: factors relevant to prognosis. Gastroenterology. 1992, 102 (5): 1628-38.PubMedGoogle Scholar
- d'Amore F, Brincker H, Gronbaek K, Thorling K, Pedersen M, Jensen MK, Mortensen LS: Non-Hodgkin'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. 1994, 12 (8): 1673-84.PubMedGoogle Scholar
- Liang R, Todd D, Chan TK, Chiu E, Lie A, Kwong YL, Choy D, Ho FC: Prognostic factors for primary gastrointestinal lymphoma. Hematol Oncol. 1995, 13 (3): 153-63. 10.1002/hon.2900130305.View ArticlePubMedGoogle Scholar
- Koch P, del Valle F, Berdel WE, Willich NA, Reers B, Hiddemann W, Grothaus-Pinke B, Reinartz G, Brockmann J, Temmesfeld A, Schmitz R, Rübe C, Probst A, Jaenke G, Bodenstein H, Junker A, Pott C, Schultze J, Heinecke A, Parwaresch R, Tiemann M: Primary gastrointestinal non-Hodgkin's lymphoma: II: Combined surgical and conservative or conservative management only in localized gastric lymphoma--results of the prospective German Multicenter Study GIT NHL 01/92. J Clin Oncol. 2001, 19 (18): 3874-83.PubMedGoogle Scholar
- Nakamura S, Matsumoto T, Iida M, Yao T, Tsuneyoshi M: Primary gastrointestinal lymphoma in Japan: a clinicopathologic analysis of 455 patients with special reference to its time trends. Cancer. 2003, 97 (10): 2462-73. 10.1002/cncr.11415.View ArticlePubMedGoogle Scholar
- Aviles A, Nambo MJ, Neri N, Talavera A, Cleto S: Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach: results of a controlled clinical trial. Med Oncol. 2005, 22 (1): 57-62. 10.1385/MO:22:1:057.View ArticlePubMedGoogle Scholar
- Popescu RA, Wotherspoon AC, Cunningham D, Norman A, Prendiville J, Hill ME: Surgery plus chemotherapy or chemotherapy alone for primary intermediate- and high-grade gastric non-Hodgkin's lymphoma: the Royal Marsden Hospital experience. Eur J Cancer. 1999, 35 (6): 928-34. 10.1016/S0959-8049(99)00069-6.View ArticlePubMedGoogle Scholar
- Gobbi PG, Ghirardelli ML, Cavalli C, Baldini L, Broglia C, Clo V, Bertè R, Ilariucci F, Carotenuto M, Piccinini L, Stelitano C, Attardo-Parrinello G, Ascari E: The role of surgery in the treatment of gastrointestinal lymphomas other than low-grade MALT lymphomas. Haematologica. 2000, 85 (4): 372-80.PubMedGoogle Scholar
- Binn M, Ruskone-Fourmestraux A, Lepage E, Haioun C, Delmer A, Aegerter P, Lavergne A, Guettier C, Delchier JC: Surgical resection plus chemotherapy versus chemotherapy alone: comparison of two strategies to treat diffuse large B-cell gastric lymphoma. Ann Oncol. 2003, 14 (12): 1751-7. 10.1093/annonc/mdg495.View ArticlePubMedGoogle Scholar
- Cogliatti SB, Schmid U, Schumacher U, Eckert F, Hansmann ML, Hedderich J, Takahashi H, Lennert K: Primary B-cell gastric lymphoma: a clinicopathological study of 145 patients. Gastroenterology. 1991, 101 (5): 1159-70.PubMedGoogle Scholar
- Seifert E, Schulte F, Stolte M: Long-term results of treatment of malignant non-Hodgkin's lymphoma of the stomach. Z Gastroenterol. 1992, 30 (8): 505-8.PubMedGoogle Scholar
- Montalban C, Castrillo JM, Abraira V, Serrano M, Bellas C, Piris MA: Gastric B-cell mucosa-associated lymphoid tissue (MALT) lymphoma. Clinicopathological study and evaluation of the prognostic factors in 143 patients. Ann Oncol. 1995, 6 (4): 355-62.PubMedGoogle Scholar
- Pasini F, Ambrosetti A, Sabbioni R, Todeschini G, Santo A, Meneghini V, Perona G, Cetto GL: Postoperative chemotherapy increases the disease-free survival rate in primary gastric lymphomas stage IE and IIE. Eur J Cancer. 1994, 30A (1): 33-6.View ArticlePubMedGoogle Scholar
- Bartlett DL, Karpeh MS, Filippa DA, Brennan MF: Long-term follow-up after curative surgery for early gastric lymphoma. Ann Surg. 1996, 223 (1): 53-62. 10.1097/00000658-199601000-00008.PubMed CentralView ArticlePubMedGoogle Scholar
- National Comprehensive Cancer Network. http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf
- Zucca E, Cavalli F: Gut lymphomas. Baillieres Clin Haematol. 1996, 9 (4): 727-41. 10.1016/S0950-3536(96)80051-5.View ArticlePubMedGoogle Scholar
- Yoon SS, Coit DG, Portlock CS, Karpeh MS: The diminishing role of surgery in the treatment of gastric lymphoma. Ann Surg. 2004, 240 (1): 28-37. 10.1097/01.sla.0000129356.81281.0c.PubMed CentralView ArticlePubMedGoogle Scholar
- Kodera Y, Yamamura Y, Nakamura S, Shimizu Y, Torii A, Hirai T, Yasui K, Morimoto T, Kato T, Kito T: The role of radical gastrectomy with systematic lymphadenectomy for the diagnosis and treatment of primary gastric lymphoma. Ann Surg. 1998, 227 (1): 45-50. 10.1097/00000658-199801000-00007.PubMed CentralView ArticlePubMedGoogle Scholar
- Day D, Jass J, Price A, Shepherd N, JM S: Non-epithelial tumours of the stomach. 2003, Malden (USA): Blackwell Publishing Inc.View ArticleGoogle Scholar
- Aviles A, Nambo MJ, Neri N, Huerta-Guzman J, Cuadra I, Alvarado I, Castañeda C, Fernández R, González M: The role of surgery in primary gastric lymphoma: results of a controlled clinical trial. Ann Surg. 2004, 240 (1): 44-50. 10.1097/01.sla.0000129354.31318.f1.PubMed CentralView ArticlePubMedGoogle Scholar
- Al-Refaie W, Abdalla E, Ahmad S, Mansfield P: Gastric cancer. 2006, Houston (USA) Lippincott Williams & WilkinsGoogle Scholar
- Mercer DW, Robinson EK, editors: Gastric neoplasia. 2007, PhiladelphiaGoogle Scholar
- Friedberg J, Mauch P, Rimsza L, Fisher R, editors: 2008, Non-Hodgkin's Lymphomas: Lippincott Williams & WilkinsGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.