Gastric marginal zone lymphoma of MALT type: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
2013; Elsevier BV; Volume: 24; Linguagem: Inglês
10.1093/annonc/mdt343
ISSN1569-8041
AutoresEmanuele Zucca, Christiane Copie‐Bergman, Umberto Ricardi, Catherine Thiéblemont, Markus Raderer, Marco Ladetto,
Tópico(s)Colorectal Cancer Treatments and Studies
ResumoincidenceExtranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT) type represent ∼7% of all non-Hodgkin's lymphomas in the western world and can arise at any extranodal site. At least one-third of them present as a primary gastric lymphoma, which in approximately two-thirds of cases is associated with a chronic Helicobacter pylori infection [1.Bertoni F. Coiffier B. Salles G. et al.MALT Lymphomas: pathogenesis can drive treatment.Oncology. 2011; 25 (1147): 1134-1142Google Scholar].diagnosisThe most common presenting symptoms of a gastric MALT lymphoma are non-specific upper gastrointestinal complaints that often lead to an endoscopy usually revealing non-specific gastritis or peptic ulcer with mass lesions being unusual [2.Bertoni F. Zucca E. State-of-the-art therapeutics: marginal-zone lymphoma.J Clin Oncol. 2005; 23: 6415-6420Crossref PubMed Scopus (99) Google Scholar, 3.Thieblemont C. Clinical presentation and management of marginal zone lymphomas.Hematol Am Soc Hematol Educ Program. 2005; : 307-313Crossref PubMed Scopus (101) Google Scholar].Diagnosis is based on the histopathological evaluation of the gastric biopsies [III, A]. The diagnosis should be in accordance with the current World Health Organisation (WHO) classification and accurate assessment of a potential associated large B-cell lymphoma is essential [4.Isaacson P.G. Chott A. Nakamura S. Swerdlow S.H. Campo E. Harris N.L. et al.Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma).in: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th edition. IARC Press, Lyon, France2008: 214-217Google Scholar]. The diagnosis should, therefore, be confirmed by an expert haematopathologist [5.Dreyling M. Thieblemont C. Gallamini A. et al.ESMO Consensus conferences: guidelines on malignant lymphoma. part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma.Ann Oncol. 2013; 24: 857-877Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar]. It should be noted that the term 'high grade MALT lymphomas' is no longer accepted in the current WHO classification, hence cases with solid or sheet-like proliferation of transformed large cells have to be diagnosed as diffuse large B-cell lymphoma [4.Isaacson P.G. Chott A. Nakamura S. Swerdlow S.H. Campo E. Harris N.L. et al.Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma).in: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th edition. IARC Press, Lyon, France2008: 214-217Google Scholar]. Differentiation from other indolent lymphomas is not always straightforward and a minimum immunohistochemistry panel should include CD20, CD10, CD5 and cyclin D1 [IV, B]. It is noteworthy that lymphoepithelial lesions, despite being very typical of MALT lymphoma, are neither essential for the diagnosis nor pathognomonic, as they can be seen under some reactive conditions as well as in other lymphoma subtypes.If the presence of active H. pylori infection is not demonstrated by histochemistry, it must be ruled out by serology, urea breath test and/or stool antigen test [5.Dreyling M. Thieblemont C. Gallamini A. et al.ESMO Consensus conferences: guidelines on malignant lymphoma. part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma.Ann Oncol. 2013; 24: 857-877Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 6.Ruskone-Fourmestraux A. Fischbach W. Aleman B.M. et al.EGILS Consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT.Gut. 2011; 60: 747-758Crossref PubMed Scopus (247) Google Scholar].In addition to routine histology and immunohistochemistry, fluorescence in situ hybridisation studies for detection of t(11;18) (p21;p21) may be useful for identifying patients who are unlikely to respond to antibiotic therapy [III, B] [5.Dreyling M. Thieblemont C. Gallamini A. et al.ESMO Consensus conferences: guidelines on malignant lymphoma. part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma.Ann Oncol. 2013; 24: 857-877Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 6.Ruskone-Fourmestraux A. Fischbach W. Aleman B.M. et al.EGILS Consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT.Gut. 2011; 60: 747-758Crossref PubMed Scopus (247) Google Scholar].staging and risk assessmentThe question of which is the best system for the staging of gastric MALT lymphoma is controversial [2.Bertoni F. Zucca E. State-of-the-art therapeutics: marginal-zone lymphoma.J Clin Oncol. 2005; 23: 6415-6420Crossref PubMed Scopus (99) Google Scholar, 6.Ruskone-Fourmestraux A. Fischbach W. Aleman B.M. et al.EGILS Consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT.Gut. 2011; 60: 747-758Crossref PubMed Scopus (247) Google Scholar]. The 'Lugano staging system' has been widely used in the past two decades, but more modern systems have been proposed, such as the 'Paris staging system', which describes more accurately the depth of gastric wall involvement, a parameter that may predict the lymphoma response to H. pylori eradication (Table 1) [7.Rohatiner A. d'Amore F. Coiffier B. et al.Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma.Ann Oncol. 1994; 5: 397-400Abstract Full Text PDF PubMed Scopus (489) Google Scholar, 8.Ruskone-Fourmestraux A. Dragosics B. Morgner A. et al.Paris staging system for primary gastrointestinal lymphomas.Gut. 2003; 52: 912-913Crossref PubMed Scopus (95) Google Scholar].Table 1Comparison of the Lugano and Paris staging systems for gastrointestinal tract lymphomaLugano staging system [7.Rohatiner A. d'Amore F. Coiffier B. et al.Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma.Ann Oncol. 1994; 5: 397-400Abstract Full Text PDF PubMed Scopus (489) Google Scholar]Paris staging system [8.Ruskone-Fourmestraux A. Dragosics B. Morgner A. et al.Paris staging system for primary gastrointestinal lymphomas.Gut. 2003; 52: 912-913Crossref PubMed Scopus (95) Google Scholar]Tumour extensionStage I = confined to the GI tract (single primary or multiple, non-contiguous)T1m N0 M0T1sm N0 M0T2 N0 M0T3 N0 M0MucosaSubmucosaMuscularis propriaSerosaStage II = extending into abdomen II1 = local nodal involvement II2 = distant nodal involvementT1-3 N1 M0T1-3 N2 M0Perigastric lymph nodesMore distant regional nodesStage IIE = penetration of serosa to involve adjacent organs or tissuesT4 N0-2 M0Invasion of adjacent structures with or withoutabdominal lymph nodesStage IV = disseminated extranodal involvement or concomitant supra-diaphragmatic nodal involvementT1-4 N3 M0T1-4 N0-3 M1T1-4 N0-3 M2T1-4 N0-3 M0-2 BXT1-4 N0-3 M0-2 B0T1-4 N0-3 M2 B1Extra-abdominal lymph nodesAnd/or additional distant (non-continuous) gastrointestinal sitesOr non-gastrointestinal sitesBone marrow not assessedBone marrow not involvedBone marrow involvementGI, gastrointestinal; T describes the gastric wall infiltration; N describes the regional lymph node involvement; M describes distant dissemination; B describes the bone marrow assessment. Reproduced from: Rohatiner A et al. [7.Rohatiner A. d'Amore F. Coiffier B. et al.Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma.Ann Oncol. 1994; 5: 397-400Abstract Full Text PDF PubMed Scopus (489) Google Scholar] With permission of Oxford University Press. Ruskone-Fourmestrauxet al. [8.Ruskone-Fourmestraux A. Dragosics B. Morgner A. et al.Paris staging system for primary gastrointestinal lymphomas.Gut. 2003; 52: 912-913Crossref PubMed Scopus (95) Google Scholar]. With permission from BMJ Publishing Group Ltd. Open table in a new tab The initial staging procedures must include an esophagogastroduodenoscopy with multiple biopsies taken from each region of the stomach, duodenum and gastroesophageal junction and from any site with an abnormal appearance. Endoscopic ultrasound is recommended to evaluate the regional lymph nodes and gastric wall infiltration [III, A] [2.Bertoni F. Zucca E. State-of-the-art therapeutics: marginal-zone lymphoma.J Clin Oncol. 2005; 23: 6415-6420Crossref PubMed Scopus (99) Google Scholar, 3.Thieblemont C. Clinical presentation and management of marginal zone lymphomas.Hematol Am Soc Hematol Educ Program. 2005; : 307-313Crossref PubMed Scopus (101) Google Scholar, 5.Dreyling M. Thieblemont C. Gallamini A. et al.ESMO Consensus conferences: guidelines on malignant lymphoma. part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma.Ann Oncol. 2013; 24: 857-877Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 6.Ruskone-Fourmestraux A. Fischbach W. Aleman B.M. et al.EGILS Consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT.Gut. 2011; 60: 747-758Crossref PubMed Scopus (247) Google Scholar, 9.Raderer M. Wöhrer S. Streubel B. et al.Assessment of disease dissemination in gastric compared with extragastric mucosa-associated lymphoid tissue lymphoma using extensive staging: a single-center experience.J Clin Oncol. 2006; 24: 3136-3141Crossref PubMed Scopus (157) Google Scholar]. Work-up studies should include history and physical examination, including lymph node regions, eye and ear, nose and throat areas, liver and spleen evaluation; complete blood counts, basic biochemical studies, which may include evaluation of renal and liver function, lactate dehydrogenase and β2-microglobulin, serum protein immunofixation, human immunodeficiency virus, hepatitis C virus and hepatitis B virus serology, computed tomography scan of the chest, abdomen and pelvis [IV, B] [2.Bertoni F. Zucca E. State-of-the-art therapeutics: marginal-zone lymphoma.J Clin Oncol. 2005; 23: 6415-6420Crossref PubMed Scopus (99) Google Scholar, 3.Thieblemont C. Clinical presentation and management of marginal zone lymphomas.Hematol Am Soc Hematol Educ Program. 2005; : 307-313Crossref PubMed Scopus (101) Google Scholar, 5.Dreyling M. Thieblemont C. Gallamini A. et al.ESMO Consensus conferences: guidelines on malignant lymphoma. part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma.Ann Oncol. 2013; 24: 857-877Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 6.Ruskone-Fourmestraux A. Fischbach W. Aleman B.M. et al.EGILS Consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT.Gut. 2011; 60: 747-758Crossref PubMed Scopus (247) Google Scholar, 9.Raderer M. Wöhrer S. Streubel B. et al.Assessment of disease dissemination in gastric compared with extragastric mucosa-associated lymphoid tissue lymphoma using extensive staging: a single-center experience.J Clin Oncol. 2006; 24: 3136-3141Crossref PubMed Scopus (157) Google Scholar]. A bone marrow aspirate and biopsy is recommended [IV, B] [5.Dreyling M. Thieblemont C. Gallamini A. et al.ESMO Consensus conferences: guidelines on malignant lymphoma. part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma.Ann Oncol. 2013; 24: 857-877Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar]. The value of a positron emission tomography scan is controversial and has little clinical utility [IV, D] [5.Dreyling M. Thieblemont C. Gallamini A. et al.ESMO Consensus conferences: guidelines on malignant lymphoma. part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma.Ann Oncol. 2013; 24: 857-877Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar].treatment planHelicobacter pylori eradication therapy must be given to all gastric MALT lymphomas, independently of stage [5.Dreyling M. Thieblemont C. Gallamini A. et al.ESMO Consensus conferences: guidelines on malignant lymphoma. part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma.Ann Oncol. 2013; 24: 857-877Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar]. Anti-helicobacter regimens combining proton-pump inhibitor (PPI) plus clarithromycin-based triple therapy with either amoxicillin or metronidazole for 10–14 days are usually highly effective [10.Fuccio L. Laterza L. Zagari R.M. et al.Treatment of Helicobacter pylori infection.BMJ. 2008; 337: a1454Crossref PubMed Scopus (41) Google Scholar]. The outcome of the eradication therapy should be checked by a urea breath test (or by a monoclonal stool antigen test) at least 6 weeks after eradication therapy and at least 2 weeks after PPI withdrawal. In case of unsuccessful H. pylori eradication, a second-line therapy should be attempted with alternative triple- or quadruple-therapy regimens of PPI plus antibiotics [1.Bertoni F. Coiffier B. Salles G. et al.MALT Lymphomas: pathogenesis can drive treatment.Oncology. 2011; 25 (1147): 1134-1142Google Scholar, 6.Ruskone-Fourmestraux A. Fischbach W. Aleman B.M. et al.EGILS Consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT.Gut. 2011; 60: 747-758Crossref PubMed Scopus (247) Google Scholar].Eradication of H. pylori with antibiotics should be the sole initial therapy for a localised H. pylori-positive gastric MALT lymphoma, where this treatment can induce lymphoma regression and long-term clinical disease control in most patients [II, A]. The length of time necessary to obtain a remission can span from very few months to >12 months. It is reasonable to wait for at least 12 months before starting another treatment in patients who achieve a clinical and endoscopic remission together with eradication of H. pylori, albeit having persistent (residual) lymphoma at the histological level [III, B] [6.Ruskone-Fourmestraux A. Fischbach W. Aleman B.M. et al.EGILS Consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT.Gut. 2011; 60: 747-758Crossref PubMed Scopus (247) Google Scholar]. Several studies of post-antibiotic molecular follow-up have shown the frequent persistence of monoclonal B-cells after histological regression of the lymphoma [1.Bertoni F. Coiffier B. Salles G. et al.MALT Lymphomas: pathogenesis can drive treatment.Oncology. 2011; 25 (1147): 1134-1142Google Scholar, 6.Ruskone-Fourmestraux A. Fischbach W. Aleman B.M. et al.EGILS Consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT.Gut. 2011; 60: 747-758Crossref PubMed Scopus (247) Google Scholar].In H. pylori-negative cases, a regression of the lymphoma after antibiotic treatment is unlikely and the immediate start of oncological treatments (see below) should be considered, but the administration of an anti-helicobacter regimen may be worthwhile since occasional lymphoma responses have been reported (possibly due to a false-negative test or to infection by other Helicobacter species) [6.Ruskone-Fourmestraux A. Fischbach W. Aleman B.M. et al.EGILS Consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT.Gut. 2011; 60: 747-758Crossref PubMed Scopus (247) Google Scholar]. In these H. pylori-negative patients, an oncological treatment (usually radiotherapy as described below) should, however, be considered if no signs of lymphoma regression are seen at a repeat endoscopy assessment 2 to 3 months after antibiotics administration [6.Ruskone-Fourmestraux A. Fischbach W. Aleman B.M. et al.EGILS Consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT.Gut. 2011; 60: 747-758Crossref PubMed Scopus (247) Google Scholar].In patients who do not achieve a lymphoma regression following antibiotic therapy, irradiation and systemic oncological therapies should be applied depending on the stage of disease. Radiotherapy might be the preferred option for localised stage. Excellent disease control using radiation therapy alone has been reported by several institutions supporting the use of moderate-dose involved-field radiotherapy (24–30 Gy radiation to the stomach and perigastric nodes given in 3 to 4 weeks) [III, B] [11.Tsang R.W. Gospodarowicz M.K. Radiation therapy for localized low-grade non-Hodgkin's lymphomas.Hematol Oncol. 2005; 23: 10-17Crossref PubMed Scopus (67) Google Scholar, 12.Wirth A. Gospodarowicz M. Aleman B.M. et al.Long-term outcome for gastric marginal zone lymphoma treated with radiotherapy: a retrospective, multi-centre, International Extranodal Lymphoma Study Group Study.Ann Oncol. 2013; 24: 1344-1351Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar].Chemotherapy and/or immunotherapy are effective in patients with MALT lymphoma of all stages. Chemoimmunotherapy should be preferred in case of histological transformation, contraindications to radiotherapy, and vice versa. However, there is no definitive evidence to guide the choice between radiotherapy and systemic treatment in localised gastric MALT lymphoma, which depends very much on the local expertise of the attending physicians [1.Bertoni F. Coiffier B. Salles G. et al.MALT Lymphomas: pathogenesis can drive treatment.Oncology. 2011; 25 (1147): 1134-1142Google Scholar, 5.Dreyling M. Thieblemont C. Gallamini A. et al.ESMO Consensus conferences: guidelines on malignant lymphoma. part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma.Ann Oncol. 2013; 24: 857-877Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar]. Patients with t(11;18) will most probably be unresponsive to alkylating agents as a sole treatment [1.Bertoni F. Coiffier B. Salles G. et al.MALT Lymphomas: pathogenesis can drive treatment.Oncology. 2011; 25 (1147): 1134-1142Google Scholar, 6.Ruskone-Fourmestraux A. Fischbach W. Aleman B.M. et al.EGILS Consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT.Gut. 2011; 60: 747-758Crossref PubMed Scopus (247) Google Scholar]. Surgery has not been shown to achieve superior results in comparison with more conservative approaches in various trials. It may impair the quality of life and no longer has a role in the initial treatment [13.Koch P. Probst A. Berdel W.E. et al.Treatment results in localized primary gastric lymphoma: data of patients registered within the German multicenter study (GIT `NHL 02/96).J Clin Oncol. 2005; 23: 7050-7059Crossref PubMed Scopus (210) Google Scholar].Patients with symptomatic systemic disease should be considered for systemic treatment [III, A]. As in other disseminated low-grade lymphomas, rituximab plus chemotherapy would then be the most appropriate choice when treatment is needed.Only a few compounds and regimens have been tested specifically in MALT lymphomas. Oral alkylating agents (either cyclophosphamide or chlorambucil) or purine nucleoside analogues (fludarabine, cladribine) and the combination of rituximab and bendamustine have shown a high rate of disease control in non-randomised studies. The activity of rituximab has also been demonstrated in phase II studies [14.Martinelli G. Laszlo D. Ferreri A.J. et al.Clinical activity of rituximab in gastric marginal zone non-Hodgkin's lymphoma resistant to or not eligible for anti-Helicobacter pylori therapy.J Clin Oncol. 2005; 23: 1979-1983Crossref PubMed Scopus (220) Google Scholar] and its efficacy in combination with chlorambucil has been proven in a randomised study [II, A] [15.Zucca E. Conconi A. Laszlo D. et al.Addition of rituximab to chlorambucil produces superior event-free survival in the treatment of patients with extranodal marginal-zone B-cell lymphoma: 5-year analysis of the IELSG-19 randomized study.J Clin Oncol. 2013; 31: 565-572Crossref PubMed Scopus (176) Google Scholar]. This combination was very well-tolerated but no overall survival benefit has been shown [15.Zucca E. Conconi A. Laszlo D. et al.Addition of rituximab to chlorambucil produces superior event-free survival in the treatment of patients with extranodal marginal-zone B-cell lymphoma: 5-year analysis of the IELSG-19 randomized study.J Clin Oncol. 2013; 31: 565-572Crossref PubMed Scopus (176) Google Scholar] and there is not yet an accepted standard chemotherapy to be recommended. It should, however, be mentioned that treatment with purine analogues might be associated with an increased risk of secondary myelodysplasia. There are no data supporting a rituximab maintenance strategy. Aggressive anthracycline-containing regimens are not usually necessary and should be reserved for the few patients with a very aggressive clinical course or histological transformation [3.Thieblemont C. Clinical presentation and management of marginal zone lymphomas.Hematol Am Soc Hematol Educ Program. 2005; : 307-313Crossref PubMed Scopus (101) Google Scholar]. Treatment algorithms summarising the above discussed management strategies for either localised or advanced gastric MALT lymphoma are shown in Figure 1.personalised medicineAbsence of H. pylori, deep invasion of the gastric wall (beyond the sub-mucosa), regional lymph node involvement, the presence of chromosomal translocations that result in deregulation of MALT1 or Bcl-10 and other genetic features (such as overexpression of miR-142-5p and miR-155) can be associated with a reduced probability of lymphoma regression after antibiotics [1.Bertoni F. Coiffier B. Salles G. et al.MALT Lymphomas: pathogenesis can drive treatment.Oncology. 2011; 25 (1147): 1134-1142Google Scholar, 2.Bertoni F. Zucca E. State-of-the-art therapeutics: marginal-zone lymphoma.J Clin Oncol. 2005; 23: 6415-6420Crossref PubMed Scopus (99) Google Scholar, 3.Thieblemont C. Clinical presentation and management of marginal zone lymphomas.Hematol Am Soc Hematol Educ Program. 2005; : 307-313Crossref PubMed Scopus (101) Google Scholar, 16.Nakamura S. Sugiyama T. Matsumoto T. et al.Long-term clinical outcome of gastric MALT lymphoma after eradication of Helicobacter pylori: a multicentre cohort follow-up study of 420 patients in Japan.Gut. 2012; 61: 507-513Crossref PubMed Scopus (198) Google Scholar, 17.Zullo A. Hassan C. Cristofari F. et al.Effects of Helicobacter pylori eradication on early stage gastric mucosa-associated lymphoid tissue lymphoma.Clin Gastroenterol Hepatol. 2010; 8: 105-110Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar, 18.Saito Y. Suzuki H. Tsugawa H. et al.Overexpression of miR-142-5p and miR-155 in gastric mucosa-associated lymphoid tissue (MALT) lymphoma resistant to Helicobacter pylori eradication.PLoS One. 2012; 7: e47396Crossref PubMed Scopus (98) Google Scholar]. As discussed above, detection of t(11;18) may also help to distinguish patients who may not respond to alkylating agents alone. Nevertheless, in this disease setting, more research is needed to identify molecular markers which could lead to advances in personalised medicine.response evaluation and follow-upHistological evaluation of repeat biopsies remains an essential follow-up procedure to exclude either the possibility of persistent significant disease or, particularly in patients with persistent H. pylori infection, the appearance of early epithelial changes, which may be related to gastric carcinoma. Unfortunately, the interpretation of lymphoid infiltrate in post-treatment gastric biopsies can be very difficult and there are no uniform criteria for the definition of histological remission. Comparison with previous biopsies should be carried out to assess response, and we recommend the GELA (Group d'Etude des Lymphomes de l'Adult) scoring system (Table 2) as a reproducible method [IV, B] [19.Copie-Bergman C. Wotherspoon A.C. Capella C. et al.Gela histological scoring system for post-treatment biopsies of patients with gastric MALT lymphoma is feasible and reliable in routine practice.Br J Haematol. 2013; 160: 47-52Crossref PubMed Scopus (61) Google Scholar].Table 2GELA grading system proposed to define the histological response of gastric MALT lymphoma after H. pylori eradication [17.Zullo A. Hassan C. Cristofari F. et al.Effects of Helicobacter pylori eradication on early stage gastric mucosa-associated lymphoid tissue lymphoma.Clin Gastroenterol Hepatol. 2010; 8: 105-110Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar]Response (score)DescriptionHistological Characteristics CRComplete histological remissionNormal or empty LP and/or fibrosis with absent or scattered plasma cells and small lymphoid cells in the LP, no LEL pMRDProbable minimal residual diseaseEmpty LP and/or fibrosis with aggregates of lymphoid cells or lymphoid nodules in the LP/MM and/or SM, no LEL rRDResponding residual diseaseFocal empty LP and/or fibrosis with dense, diffuse or nodular lymphoid infiltrate, extending around glands in the LP, focal LEL or absent NCNo changeDense, diffuse or nodular lymphoid infiltrate, LEL usually presentLEL, lymphoepithelial lesions; LP, lamina propria; MM, muscularis mucosa; SM, submucosa.Copie-Bergman C et al. [18.Saito Y. Suzuki H. Tsugawa H. et al.Overexpression of miR-142-5p and miR-155 in gastric mucosa-associated lymphoid tissue (MALT) lymphoma resistant to Helicobacter pylori eradication.PLoS One. 2012; 7: e47396Crossref PubMed Scopus (98) Google Scholar]. Reprinted with permission. ©2012 Blackwell Publishing Ltd. Open table in a new tab Following the documentation of the achieved H. pylori eradication, a strict endoscopic follow-up is recommended, with multiple biopsies taken 2 to 3 months after treatment to rule out tumour progression, and subsequently (twice per year for 2 years) to monitor the histological regression of the lymphoma.Gastric MALT lymphomas have a limited tendency to distant spreading and to histological transformation. Transient, apparent histological relapses are occasionally observed in endoscopic follow-up biopsies, but they have to be sustained and progressive in order to be considered a relapse, as they tend to be self-limiting, especially in the absence of H. pylori reinfection. Hence, in the case of persistent but stable residual disease or histological relapse (without distant dissemination and/or gross endoscopic tumour), a watch-and-wait policy appears to be safe [IV, C] [16.Nakamura S. Sugiyama T. Matsumoto T. et al.Long-term clinical outcome of gastric MALT lymphoma after eradication of Helicobacter pylori: a multicentre cohort follow-up study of 420 patients in Japan.Gut. 2012; 61: 507-513Crossref PubMed Scopus (198) Google Scholar, 20.Stathis A. Chini C. Bertoni F. et al.Long-term outcome following Helicobacter pylori eradication in a retrospective study of 105 patients with localized gastric marginal zone B-cell lymphoma of MALT type.Ann Oncol. 2009; 20: 1086-1093Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 21.Fischbach W. Goebeler M.E. Ruskone-Fourmestraux A. et al.Most patients with minimal histological residuals of gastric MALT lymphoma after successful eradication of Helicobacter pylori can be managed safely by a watch and wait strategy: experience from a large international series.Gut. 2007; 56: 1685-1687Crossref PubMed Scopus (130) Google Scholar, 22.Wündisch T. Thiede C. Morgner A. et al.Long-term follow-up of gastric MALT lymphoma after Helicobacter pylori eradication.J Clin Oncol. 2005; 23: 8018-8024Crossref PubMed Scopus (246) Google Scholar]. Nevertheless, a long-term careful endoscopic and systemic follow-up (clinical examination, blood counts and minimal adequate radiological or ultrasound examinations every 12–18 months) is recommended for all patients. Indeed, the risk of gastric adenocarcinoma among patients diagnosed with gastric MALT lymphomas has been reported to be sixfold higher than in the general population [23.Capelle L.G. de Vries A.C. Looman C.W. et al.Gastric MALT lymphoma: epidemiology and high adenocarcinoma risk in a nation-wide study.Eur J Cancer. 2008; 44: 2470-2476Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar] and also the risk of other non-Hodgkin's lymphomas may be increased [24.Wündisch T. Dieckhoff P. Greene B. et al.Second cancers and residual disease in patients treated for gastric mucosa-associated lymphoid tissue lymphoma by Helicobacter pylori eradication and followed for 10 years.Gastroenterology. 2012; 143: 936-942Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar].noteLevels of evidence and grades of recommendation have been applied using the system shown in Table 3. Statements without grading were considered justified standard clinical practice by the experts and the ESMO faculty.Table 3Levels of evidence and grades of recommendation (adapted from the Infectious Diseases Society of America-United States Public Health Service Grading SystemaDykewicz CA. Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Clin Infect Dis 2001; 33: 139–144. By permission of the Infectious Diseases Society of America.)Levels of evidence IEvidence from at least one large randomised, controlled trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomised trials without heterogeneity IISmall randomised trials or large randomised trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneity IIIProspective cohort studies IVRetrospective cohort studies or case–control studies VStudies without control group, case reports, experts opinionsGrades of recommendation AStrong evidence for efficacy with a substantial clinical benefit, strongly recommended BStrong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended CInsufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, …), optional DModerate evidence against efficacy or for adverse outcome, generally not recommended EStrong evidence against efficacy or for adverse outcome, never recommendeda Dykewicz
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