Best Practice & Research Clinical Gastroenterology 28 (2014) 1069e1077
Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
10
Gastric MALT lymphoma e Update on diagnosis and treatment Prof. Dr. med. Wolfgang Fischbach, M.D., Ph.D. * Medizinische Klinik II und Klinik für Palliativmedizin, Klinikum Aschaffenburg, Academic Teaching Hospital of the University of Würzburg, Am Hasenkopf, D-63739 Aschaffenburg, Germany
a b s t r a c t Keywords: Gastric MALT lymphoma Pathogenesis Diagnosis Staging Treatment Follow-up management
Gastrointestinal lymphoma represent a heterogenous group with differences in pathogenesis, treatment and prognosis. Gastric MALT lymphoma is the most common entity. Helicobacter pylori has been identified as its decisive pathogenetic factor. Once a definitive diagnosis has been established a staging procedure is obligatory for defining the stage of disease. H. pylori eradication is the treatment of choice in all MALT lymphoma patients being infected by the bacterium. In some 70e80% of patients with stages I/II complete regression of the lymphoma will develop after successful eradication of H. pylori. Another 20% of patients will reveal minimal histological residuals after eradication. They can be successfully managed by a watch-and-wait strategy if initial endoscopic abnormalities disappear. At present, it is unclear if this strategy can be also offered to patients with persisting minimal endoscopic abnormalities. Why eradication therapy is effective in some patients with negative H. pylori status is highly speculative at present. Non-responders to H. pylori therapy are transferrred to radiotherapy in stages I/II or to immuno-chemotherapy in stages III/IV. © 2014 Published by Elsevier Ltd.
Gastrointestinal lymphoma represent a heterogeneous group. The various subtypes are characterized by histological, immunohistochemical and molecular genetic properties. Aetiology, pathogenesis, biological behaviour, prognosis and treatment strategies vary widely between the different lymphoma
* Tel.: þ49 6021 323010; fax: þ49 6021 323031. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.bpg.2014.09.006 1521-6918/© 2014 Published by Elsevier Ltd.
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W. Fischbach / Best Practice & Research Clinical Gastroenterology 28 (2014) 1069e1077
types. Therefore, definitive diagnosis and subtyping of the lymphoma is of utmost importance for any further decision making. Classification Table 1 represents the WHO classification as established in 2002 and updated in 2008 [1]. In terms of numbers, extranodal marginal zone B-cell lymphoma of MALT (mucosa-associated-lymphoid tissue) are highly predominant under the gastric lymphoma (gastric MALT lymphoma). The second most common gastric lymphoma are diffuse large B-cell lymphoma (DLBCL) with or without MALT components. In this article, I exclusively focus on gastric MALT lymphoma. Pathogenesis Intensive basic and clinical research during the last three decades has substantially enriched our understanding of the development and progression of gastric MALT lymphoma. In short, mucosaassociated-lymphoid tissue (MALT) is acquired in a secondary process against Helicobacter pylori (H. pylori). The bacterium is the cause of chronic gastritis and leads to the formation of intramucosal lymph follicles [2,3]. There are convincing data from histomorphological, molecular biological, epidemiological and experimental studies that H. pylori is the decisive pathogenetic factor for the development of gastric MALT lymphoma. Up to 98% of patients with gastric MALT lymphoma are H. pylori positive when tested by serology [4]. However, only a small minority of all H. pylori infected individuals develops gastric MALT lymphoma. Virulence factors of the bacterium do obviously not determine this risk. There is, however, growing evidence that genetic host factors may play an important role in this context [5,6]. If any further evidence were needed for the pathogenetic significance of H. pylori for the development of gastric MALT lymphoma, it has been provided by experience with eradication treatment. In a first series of six patients with gastric MALT lymphoma of stage I successful eradication of H. pylori lead to a complete and lasting regression of the lymphoma [7]. The authors concluded that H. pylori eradication should be the first choice of treatment. This was a quite audacious statement at that time considering the small number of patients treated in this way. However, it turned out to be right. Clinical features The clinical features of gastric MALT lymphoma are nonspecific. It is characterized by abdominal symptoms, pain, vomiting, diarrhoea, weight loss, and manifest or occult bleeding [8]. However, gastric MALT lymphoma are also often only an incidental finding at endoscopy. Complications such as obstruction, perforation, or bleeding are very rarely observed. Prognostic factors In the early 1990ies based on two large retrospective series, Cogliatti et al [9] and Radaszkiewicz and co-workers [10] described grade of malignancy (gastric MALT lymphoma versus DLBCL with/
Table 1 WHO classification of gastrointestinal lymphoma [1]]. B-cell-lymphoma
T-cell-lymphoma
Extranodal marginal zone B-cell-lymphoma (MZBCL) of MALT Follicular lymphoma (grade I-III) Mantle cell lymphoma (lymphomatous polyposis) Diffuse large B-cell-lymphoma (DLBCL) with/without MALT components Burkitt lymphoma Immundeficiency associated lymphoma
Enteropathy-associated T-cell-lymphoma (EATCL) Peripheral T-cell-lymphoma (previously: non-EATCL)
W. Fischbach / Best Practice & Research Clinical Gastroenterology 28 (2014) 1069e1077
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without MALT components) and stage of the disease as the two major prognostic factors. Since then, they represent the two therapeutic determinants as several prospective have confirmed these findings [11e16]. It implies a very thorough endoscopic biopsy protocol ('gastric mapping') and clinical staging procedures as outlined below. Translocation t(11; 18) is the most common genetic aberration in gastric MALT lymphoma. It is found in 25% of cases, more frequent in cases at stage II or above than in stage I. T(11; 18) has also been proven to be of prognostic value as it strongly predicts the response of gastric MALT lymphoma to H. pylori eradication [17,18]. Nevertheless, routine testing for t(11; 18) within the staging process is not mandatory as H. pylori eradication is recommended as the initial treatment irrespective of the bacterial status [19,20]. Diagnosis In view of the nonspecific appearance of gastric MALT lymphoma [8] and the need for an exact diagnosis and typing of the lymphoma, a sufficient number of biopsies from both macroscopic lesions and normal appearing mucosa is necessary. This procedure named gastric mapping (Fig. 1) is recommended by the German S3 guideline (grade C, evidence lever 5; 19) as well as in the European EGILs Consensus Report of 2011 [20]. The minimal number of biopsy samples that should be taken from visible lesions is ten. The number of biopsies to be taken from macroscopically normal mucosa is not specified. However, four biopsies from the antrum and body, respectively, and two additional biopsies from the fundus seem reasonable. In general, such a biotic protocol is not performed during a routine diagnostic endoscopy. Therefore, a diagnostic algorithm as outlined in Fig. 2 seems appropriate. Lymphoepithelial lesions represent the histomorphological characteristic of gastric MALT lymphoma. There is a widely accepted consensus that the diagnosis of gastric MALT lymphoma is based on histomorphological criteria according to the WHO classification [19,20]. Additional molecular genetic findings such as clonality analysis of the rearranged immunoglobulin genes may be helpful in the individual case but are not recommended for clinical routine. Staging Once the diagnosis of gastric MALT lymphoma is established, a staging procedure to assess the dissemination of the lymphoma is obligatory. Clinical stage should be based on the Ann Arbor classification system with its modifications by Musshoff [21] and Radaszkiewicz [10] (Table 2). The Paris staging system is an alternative based on the well-known TNM classification system [22]. However, the latter has not been validated by prospective studies yet. Table 3 summarizes the various examinations which must be done [20]. Endoscopic ultrasound and bone marrow puncture are strongly recommended while ileocolonoscopy should be considered.
• 1 biopsy from corpus and antrum, resp. for urease test Fundus IX + X Korpus V-VIII Antrum I-IV
• 4 biopsies from normal mucosa in antrum and corpus, resp., and 2 biopsies from the fundus
> 10 biopsies from macroscopic visible lesions Fig. 1. Gastric mapping.
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W. Fischbach / Best Practice & Research Clinical Gastroenterology 28 (2014) 1069e1077
(Suspected) gastric MALT lymphoma
Second endoscopy with gastric mapping biopsies
confirmation by reference pathology
Staging: (see table 2)
Diagnosis and stage of gastric MALT lymphoma
therapy
Fig. 2. Recommended diagnostic procedure in gastric MALT lymphoma.
Therapy In general, therapy of gastric MALT lymphoma always has a curative intent. In a recent large prospective study from Japan, an excellent outcome of patients revealing ten-years overall survival of 95% and disease-free survival of 86%, respectively, was demonstrated [23]. The treatment strategies used in this study were very similar to those outlined in Fig. 3 which represent the recommendations of the German S3 guideline [19] and the European EGILs consensus report of 2011 [20]. H. pylori eradication For stages I and II, H. pylori eradication is the initial treatment of choice with a curative aim (19: evidence Ia; 20). According to a recent meta-analysis, 77.5% of patients with gastric MALT lymphoma achieve complete regression after successful eradication of H. pylori [24]. Complete regression of lymphoma was more often observed in stage I than in stage II (78% versus 56%). A relapse occurred in 7.2% (2.2% per year). High-grade transformation into aggressive lymphoma was an extreme rare event (0.05%). A necessary precondition for lymphoma regression is the success of eradication therapy for H. pylori. In a pooled data analysis, Zullo and co-workers reported on a success rate of first-line eradication therapy in 91% [25]. Including second-to fifth-line treatment protocols a definite eradication rate of 98.3% was achieved. Although there is no evidence from the literature that H. pylori eradication may also cure the few patients (
Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
10
Gastric MALT lymphoma e Update on diagnosis and treatment Prof. Dr. med. Wolfgang Fischbach, M.D., Ph.D. * Medizinische Klinik II und Klinik für Palliativmedizin, Klinikum Aschaffenburg, Academic Teaching Hospital of the University of Würzburg, Am Hasenkopf, D-63739 Aschaffenburg, Germany
a b s t r a c t Keywords: Gastric MALT lymphoma Pathogenesis Diagnosis Staging Treatment Follow-up management
Gastrointestinal lymphoma represent a heterogenous group with differences in pathogenesis, treatment and prognosis. Gastric MALT lymphoma is the most common entity. Helicobacter pylori has been identified as its decisive pathogenetic factor. Once a definitive diagnosis has been established a staging procedure is obligatory for defining the stage of disease. H. pylori eradication is the treatment of choice in all MALT lymphoma patients being infected by the bacterium. In some 70e80% of patients with stages I/II complete regression of the lymphoma will develop after successful eradication of H. pylori. Another 20% of patients will reveal minimal histological residuals after eradication. They can be successfully managed by a watch-and-wait strategy if initial endoscopic abnormalities disappear. At present, it is unclear if this strategy can be also offered to patients with persisting minimal endoscopic abnormalities. Why eradication therapy is effective in some patients with negative H. pylori status is highly speculative at present. Non-responders to H. pylori therapy are transferrred to radiotherapy in stages I/II or to immuno-chemotherapy in stages III/IV. © 2014 Published by Elsevier Ltd.
Gastrointestinal lymphoma represent a heterogeneous group. The various subtypes are characterized by histological, immunohistochemical and molecular genetic properties. Aetiology, pathogenesis, biological behaviour, prognosis and treatment strategies vary widely between the different lymphoma
* Tel.: þ49 6021 323010; fax: þ49 6021 323031. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.bpg.2014.09.006 1521-6918/© 2014 Published by Elsevier Ltd.
1070
W. Fischbach / Best Practice & Research Clinical Gastroenterology 28 (2014) 1069e1077
types. Therefore, definitive diagnosis and subtyping of the lymphoma is of utmost importance for any further decision making. Classification Table 1 represents the WHO classification as established in 2002 and updated in 2008 [1]. In terms of numbers, extranodal marginal zone B-cell lymphoma of MALT (mucosa-associated-lymphoid tissue) are highly predominant under the gastric lymphoma (gastric MALT lymphoma). The second most common gastric lymphoma are diffuse large B-cell lymphoma (DLBCL) with or without MALT components. In this article, I exclusively focus on gastric MALT lymphoma. Pathogenesis Intensive basic and clinical research during the last three decades has substantially enriched our understanding of the development and progression of gastric MALT lymphoma. In short, mucosaassociated-lymphoid tissue (MALT) is acquired in a secondary process against Helicobacter pylori (H. pylori). The bacterium is the cause of chronic gastritis and leads to the formation of intramucosal lymph follicles [2,3]. There are convincing data from histomorphological, molecular biological, epidemiological and experimental studies that H. pylori is the decisive pathogenetic factor for the development of gastric MALT lymphoma. Up to 98% of patients with gastric MALT lymphoma are H. pylori positive when tested by serology [4]. However, only a small minority of all H. pylori infected individuals develops gastric MALT lymphoma. Virulence factors of the bacterium do obviously not determine this risk. There is, however, growing evidence that genetic host factors may play an important role in this context [5,6]. If any further evidence were needed for the pathogenetic significance of H. pylori for the development of gastric MALT lymphoma, it has been provided by experience with eradication treatment. In a first series of six patients with gastric MALT lymphoma of stage I successful eradication of H. pylori lead to a complete and lasting regression of the lymphoma [7]. The authors concluded that H. pylori eradication should be the first choice of treatment. This was a quite audacious statement at that time considering the small number of patients treated in this way. However, it turned out to be right. Clinical features The clinical features of gastric MALT lymphoma are nonspecific. It is characterized by abdominal symptoms, pain, vomiting, diarrhoea, weight loss, and manifest or occult bleeding [8]. However, gastric MALT lymphoma are also often only an incidental finding at endoscopy. Complications such as obstruction, perforation, or bleeding are very rarely observed. Prognostic factors In the early 1990ies based on two large retrospective series, Cogliatti et al [9] and Radaszkiewicz and co-workers [10] described grade of malignancy (gastric MALT lymphoma versus DLBCL with/
Table 1 WHO classification of gastrointestinal lymphoma [1]]. B-cell-lymphoma
T-cell-lymphoma
Extranodal marginal zone B-cell-lymphoma (MZBCL) of MALT Follicular lymphoma (grade I-III) Mantle cell lymphoma (lymphomatous polyposis) Diffuse large B-cell-lymphoma (DLBCL) with/without MALT components Burkitt lymphoma Immundeficiency associated lymphoma
Enteropathy-associated T-cell-lymphoma (EATCL) Peripheral T-cell-lymphoma (previously: non-EATCL)
W. Fischbach / Best Practice & Research Clinical Gastroenterology 28 (2014) 1069e1077
1071
without MALT components) and stage of the disease as the two major prognostic factors. Since then, they represent the two therapeutic determinants as several prospective have confirmed these findings [11e16]. It implies a very thorough endoscopic biopsy protocol ('gastric mapping') and clinical staging procedures as outlined below. Translocation t(11; 18) is the most common genetic aberration in gastric MALT lymphoma. It is found in 25% of cases, more frequent in cases at stage II or above than in stage I. T(11; 18) has also been proven to be of prognostic value as it strongly predicts the response of gastric MALT lymphoma to H. pylori eradication [17,18]. Nevertheless, routine testing for t(11; 18) within the staging process is not mandatory as H. pylori eradication is recommended as the initial treatment irrespective of the bacterial status [19,20]. Diagnosis In view of the nonspecific appearance of gastric MALT lymphoma [8] and the need for an exact diagnosis and typing of the lymphoma, a sufficient number of biopsies from both macroscopic lesions and normal appearing mucosa is necessary. This procedure named gastric mapping (Fig. 1) is recommended by the German S3 guideline (grade C, evidence lever 5; 19) as well as in the European EGILs Consensus Report of 2011 [20]. The minimal number of biopsy samples that should be taken from visible lesions is ten. The number of biopsies to be taken from macroscopically normal mucosa is not specified. However, four biopsies from the antrum and body, respectively, and two additional biopsies from the fundus seem reasonable. In general, such a biotic protocol is not performed during a routine diagnostic endoscopy. Therefore, a diagnostic algorithm as outlined in Fig. 2 seems appropriate. Lymphoepithelial lesions represent the histomorphological characteristic of gastric MALT lymphoma. There is a widely accepted consensus that the diagnosis of gastric MALT lymphoma is based on histomorphological criteria according to the WHO classification [19,20]. Additional molecular genetic findings such as clonality analysis of the rearranged immunoglobulin genes may be helpful in the individual case but are not recommended for clinical routine. Staging Once the diagnosis of gastric MALT lymphoma is established, a staging procedure to assess the dissemination of the lymphoma is obligatory. Clinical stage should be based on the Ann Arbor classification system with its modifications by Musshoff [21] and Radaszkiewicz [10] (Table 2). The Paris staging system is an alternative based on the well-known TNM classification system [22]. However, the latter has not been validated by prospective studies yet. Table 3 summarizes the various examinations which must be done [20]. Endoscopic ultrasound and bone marrow puncture are strongly recommended while ileocolonoscopy should be considered.
• 1 biopsy from corpus and antrum, resp. for urease test Fundus IX + X Korpus V-VIII Antrum I-IV
• 4 biopsies from normal mucosa in antrum and corpus, resp., and 2 biopsies from the fundus
> 10 biopsies from macroscopic visible lesions Fig. 1. Gastric mapping.
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W. Fischbach / Best Practice & Research Clinical Gastroenterology 28 (2014) 1069e1077
(Suspected) gastric MALT lymphoma
Second endoscopy with gastric mapping biopsies
confirmation by reference pathology
Staging: (see table 2)
Diagnosis and stage of gastric MALT lymphoma
therapy
Fig. 2. Recommended diagnostic procedure in gastric MALT lymphoma.
Therapy In general, therapy of gastric MALT lymphoma always has a curative intent. In a recent large prospective study from Japan, an excellent outcome of patients revealing ten-years overall survival of 95% and disease-free survival of 86%, respectively, was demonstrated [23]. The treatment strategies used in this study were very similar to those outlined in Fig. 3 which represent the recommendations of the German S3 guideline [19] and the European EGILs consensus report of 2011 [20]. H. pylori eradication For stages I and II, H. pylori eradication is the initial treatment of choice with a curative aim (19: evidence Ia; 20). According to a recent meta-analysis, 77.5% of patients with gastric MALT lymphoma achieve complete regression after successful eradication of H. pylori [24]. Complete regression of lymphoma was more often observed in stage I than in stage II (78% versus 56%). A relapse occurred in 7.2% (2.2% per year). High-grade transformation into aggressive lymphoma was an extreme rare event (0.05%). A necessary precondition for lymphoma regression is the success of eradication therapy for H. pylori. In a pooled data analysis, Zullo and co-workers reported on a success rate of first-line eradication therapy in 91% [25]. Including second-to fifth-line treatment protocols a definite eradication rate of 98.3% was achieved. Although there is no evidence from the literature that H. pylori eradication may also cure the few patients (
