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Annals of Oncology 19: 1992–1999, 2008 doi:10.1093/annonc/mdn525 Published online 22 July 2008 review Primary extranodal lymphomas of stomach: clinical presentation, diagnostic pitfalls and management A. Psyrri1,2, S. Papageorgiou1* & T. Economopoulos1 1Second Department of Internal Medicine Propaedeutic, Athens University Medical School, University General Hospital ‘Attikon’, Haidari, Greece; 2Department of Internal Medicine, Yale University School of Medicine, New Haven, USA Received 25 January 2008; revised 17 June 2008; accepted 20 June 2008 Gastrointestinal lymphoma is the most common form of extranodal lymphoma, accounting for 30%–40% of cases. The most commonly involved site is the stomach (60%–75% of cases), followed by the small bowel, ileum, cecum, colon and rectum. The most common histological subtypes are diffuse large B-cell lymphoma (DLBCL) and marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT). Helicobacter pylori infection has been implicated in the pathogenesis of MALT gastric lymphoma, but its role in gastric diffuse large B-cell non-Hodgkin’s lymphoma (NHL) is controversial. The therapeutic approach for patients with gastric NHL has been revised over the last 10 years. Conservative treatment with anthracycline-based chemotherapy alone or in combination with involved-field radiotherapy has replaced gastrectomy as standard therapy in cases with DLBCL. Additionally, MALT lymphomas are mainly treated with antibiotics alone, which can induce lasting remissions in those cases associated with H. pylori infection. Nevertheless, various therapeutic aspects for primary gastric lymphomas are still controversial and several questions remain unanswered. Among others, the role of rituximab, consolidation radiotherapy as well as H. pylori eradication in histological aggressive subtypes warrants better clarification. Key words: diffuse large B-cell lymphomas, extranodal lymphomas, Helicobacter pylori infection, mucosa- associated lymphoid tissue, primary gastric lymphomas introduction The term primary extranodal non-Hodgkin’s lymphoma (PE- NHL) refers to lymphomas which present with disease at any organ or tissue other than lymph nodes or spleen; the symptoms at initial presentation are caused mainly from extranodal involvement and after routine staging procedures, the extranodal involvement remains the clinically dominant site of the disease. PE-NHL comprise �25%–40% of non- Hodgkin’s lymphoma (NHL) and may occur at any organ [1, 2]. Primary non-Hodgkin’s lymphoma of the gastrointestinal tract is the most commonly involved extranodal site and represents 10%–15% of all NHL cases and 30%–40% of all extranodal sites [3]. The most commonly involved site is the stomach (60%–75% of cases), followed by the small bowel, ileum, cecum, colon and rectum [4, 5]. All histological categories of nodal lymphomas may also arise in the gastrointestinal (GI), but the main two histological subtypes (>90% of cases) are mucosa-associated lymphoid tissue (MALT) NHL and diffuse large B-cell (DLBC) NHL (Table 1). Primary gastric non-Hodgkin’s lymphoma (PG-NHL) is localized in the stomach, with or without perigastric and/or abdominal lymph node involvement, and constitutes 20%–30% of all PE-NHL. PG-NHL shows an incidence of 1 per 100 000 of the population in Western countries, but the incidence is progressively increasing. Any histological subtype can arise in the stomach, but the main two histological subtypes (>90% of cases) are MALT NHL and DLBC NHL. Helicobacter pylori infection has been implicated in the pathogenesis of MALT PG- NHL [6, 7], but its role in gastric DLBC NHL is controversial [8]. The present review summarizes the clinical presentation, diagnostic work-up and management of patients with primary gastric lymphomas. diagnosis and staging Clinical presentation of PG-NHL is not specific and varied, with abdominal pain being the most common symptom followed by dyspepsia, vomiting nausea and anorexia. Weight loss is common, but it is mainly associated with the localization of the disease. Gastric bleeding as presenting symptom occurs in 20%–30% of patients, while gastric occlusion and perforation are less common [4]. Bone marrow involvement, elevated lactate dehydrogenase (LDH) and B symptoms are less re v ie w *Correspondence to: Dr S. Papageorgiou, Second Department of Internal Medicine Propaedeutic, Atttikon General Hospital, 1 Rimini street, 124 62 Haidari, Greece. Tel: +30-210-58-31-663; Fax: +30-210-53-26-454; E-mail: sotirispapageorgiou@hotmail.com ª The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org common in gastric compared with nodal lymphomas. Endoscopy usually reveals nonspecific gastritis or peptic ulcer with mass lesions being unusual [9]. Occasionally, PG-NHL can present as a multifocal stomach disease with numerous clonally identical foci in macroscopically unaffected tissue [10]. Therefore, gastric mapping of unaffected mucosa is crucially recommended in order to establish diagnosis. Gastric MALT lymphoma is characterized by the presence of lymphoepithelial lesions that are formed by invasion of single glands by aggregates of neoplastic cells with centrocyte morphology [11], in contrast to aggressive lymphoma where lymphoma- infiltrating cells show a centroblastic morphology [12]. Staging work-up for PG-NHL include complete hematological biochemical examinations (including LDH and b2-microglobulin), computerized tomography (CT) of chest, abdomen and pelvis and bone marrow aspiration and biopsy. Upper GI endoscopy and multiple biopsies from stomach, duodenum, gastroesophageal junction and from abnormal- appearing lesions are required. An endoscopic ultrasound should be carried out to determine the depth of invasion and the presence of perigastric nodes. Examination of the pharynx by an otorhinolaryngologist should be carried out to exclude infiltration of Waldeyer ring that is occasionally associated with PG-NHL [13, 14]. In addition to routine histology and immunohistochemistry, cytogenetic studies should be carried out. FISH for the detection of three specific MALT-related translocations is recommended. The pertinent genotypic evaluations should be carried out at the time of diagnosis to guide treatment decisions. Histochemistry (Genta stain or Warthin–Starry stain) and breath test should be carried out to determine the presence of an active H. pylori infection. If histology is negative, serology should be undertaken to identify truly negative H. pylori gastric MALT NHL which is �10% of the cases. Positron emission tomography (PET) scan bears a documented diagnostic value only for DLBCLs but is controversial for MALT lymphomas, which are frequently reported as PET negative due to their indolent behavior and small tumor volume of disease [15, 16]. The Ann-Arbor classification system [17] is not easily applied to GI tract lymphomas and although alternative staging systems have been proposed, the problem of ‘staging’ a PG-NHL is controversial even today. The use of different staging systems combined with the variability in staging procedures hamper meaningful comparisons of published series. However, factors that have consistently been associated with poor prognosis in these series are involvement of paraortic (versus local) lymph nodes, serosal penetration and intestinal (versus gastric) origin. An International Workshop in 1994, during the fifth International Conference on Malignant Lymphoma, proposed a modification to Blackledge’s system, known as ‘Lugano staging’ which examines separately local spreading to neighboring anatomic sites [18]. More recently, in 2003, a modified tumor–node–metastasis classification system—the Paris staging system—was proposed in order to describe more efficiently (i) the depth of tumor infiltration, (ii) extent of nodal involvement and (iii) extent of local tissue infiltration by lymphoma [19] (Table 2). PG MALT lymphomas Isaacson and Wright [20] first observed in 1983 that primary low-grade gastric B-cell lymphoma and immunoproliferative small intestinal disease share histological characteristics more similar to MALT than those of peripheral lymph nodes. Gastric MALT lymphomas represent the vast majority of the three different types of marginal zone B-cell lymphomas (MZBCLs) according to the Revised European-American Lymphoma (REAL) classification [21]. MALT lymphomas comprise 50% of PG-NHL and are often multifocal. They occur predominantly in individuals >50 years, with a peak in the seventh decade, but cases have been reported in younger patients (third decade or even earlier). In �90% of cases, a strong association between chronic H. pylori infection and MALT gastric lymphoma has been found [22]. It is accepted that gastric MALT lymphomas arise from MALT acquired as a consequence of H. pylori infection and the bacterial infection plays a crucial role in the genesis and development of this tumor [23]. H. pylori can be demonstrated in the gastric mucosa of most cases with gastric MALT lymphomas [6]. In addition, epidemiological studies have demonstrated the association between H. pylori infection and development of gastric lymphoma [24, 25]. Nevertheless, host immune responses play a less well-defined role in MALT lymphoma formation as indicated by the fact that only a minority of H. pylori-infected patients will eventually develop lymphoma. As with other MZBCL, the cells of PG MALT are typically CD20 positive and express surface and, to a lesser extent, cytoplasmic immunoglobulin (Ig) showing light chain restriction. Most cases express IgM and a few IgA or IgG, but IgD expression is rare. In �50% of cases, they aberrantly express CD43. In addition, MALT lymphomas contain moderately high concentrations of CD3+ and CD5+ T cells, but in the majority of cases the lymphoma cells themselves are CD5 negative. Three translocations, t(11;18)(q21;q21), t(1;14)(p22;q32) and t(14;18)(q32;q21), are specifically associated with MALT lymphomas and the genes involved have been characterized. Although these three translocations involve different genes, they all converge on the activation of the same nuclear factor Table 1. Distribution of the main histological types (according to the REAL classification) in the Greek and German study for gastrointestinal non-Hodgkin’s lymphoma [4, 5] Histological type Greek study (128 patients) frequency (%) German study (371 patients) frequency (%) Diffuse large B-cell lymphoma 45 59 With MALT component 9 14 Without MALT component 36 45 MALT lymphoma of the marginal zone 48 38 Follicular lymphoma 2 0.5 Mantle cell lymphoma 1 1 Peripheral T-cell lymphoma 4 1.5 REAL, Revised European-American Lymphoma; MALT, mucosa-associated lymphoid tissue. Annals of Oncology review Volume 19 | No. 12 | December 2008 doi:10.1093/annonc/mdn525 | 1993 kB (NF-kB) oncogenic pathway [23]. Translocation t(11;18), very common in gastric MALT lymphomas as well as MALT lymphomas at other anatomic sites (30% of MALT lymphomas) [26], results in a chimeric fusion between AP12 and MALT1 genes [27, 28]. This translocation is not seen in H. pylori gastritis and its presence is associated with extension of the disease outside the stomach (regional lymph nodes and/or distal sites) [29]. The t(11;18)(q21;q21) translocation as well as the t(1;14)(p22;q32) can identify cases that will not respond to H. Pylori eradication [30]. In H. Pylori-associated gastritis and at the early stages of MALT lymphoma, development antigens expressed by H. pylori in conjunction with antigen-specific T cells activate the antigen receptor of polyclonal B cells and lead to the interaction of BCL10 and MALT1 proteins and consequently the activation of NF-kB pathway. During the long course of a chronic infection and persistent antigenic stimulation, a subclone may acquire one of the MALT lymphoma-specific translocations and develop a growth advantage. As a result, constitutive activation of NF-kB pathway occurs independently of H. pylori infection and the eradication of the bacterium does not reverse the disease process [23]. The scoring system proposed by Wotherspoon et al. [22] reflects this spectrum of proliferation from polyclonal to monoclonal state. High-grade MALT lymphomas are equivalent to DLBCL in the REAL classification [21] and they have probably transformed from low-grade MALT lymphomas as they share common clone-specific Ig heavy chain gene rearrangements with low-grade lesions [31]. treatment of early stage gastric MALT lymphomas antibiotic therapy More than 20 studies have shown a high rate of complete remission (CR) of low-grade MALT lymphomas confined to the stomach following eradication of H. pylori with antibiotics [32–36]. Therefore, antibiotic treatment is a reasonable initial treatment in low-grade gastric MALT lymphoma provided thorough hematological and endoscopic follow-up takes place. Thorough endoscopic follow-up is recommended because initial diagnostic gastric biopsies do not exclude the coexistence of aggressive lymphoma which requires cytotoxic chemotherapy. Breath test 2 months after treatment to confirm H. pylori eradication and repeat endoscopies with biopsies every 6 months for 2 years and then annually to document remission of the lymphoma are recommended. Despite the fact that eradication of H. pylori may take place within 1 month of completion of drug therapy, disappearance of lymphoma may take several months and histologic CR may be delayed up to 18 months. When remission occurs, it appears to be stable. If relapse occurs, it is usually associated with H. pylori reinfection. Indications also exist that stage I patients with minimal histological lymphoma residuals after H. pylori eradication show a favorable course when treated only by regular follow-up with endoscopies and multiple biopsies without administration of oncological therapy, suggesting the potential role of watch and wait strategy in these patients [37, 38]. In patients with histological CR, lymphoma clone can be detected by PCR analysis of the rearranged Ig gene on postremission gastric Table 2. Comparison of ‘Lugano’ and ‘Paris’ staging system for primary GI lymphomas Lougano staging system [18] TNM Paris system [19] Lymphoma extension Stage I T1–3 N0 M0 Lymphoma confined to GI tract. Single primary site or noncontiguous lesions. Stage I1 T1m N0 M0 Confined to mucosa Stage I2: infiltrating the gastric wall up to the serosa T1sm N0 M0 Lymphoma infiltrates the submucosa T2 N0 M0 Lymphoma infiltrates muscularis propria or subserosa T3 N0 M0 Lymphoma penetrates serosa Stage II T1–3 N1–2 M0 Lymphoma extending to abdominal lymph nodes Stage II1 T1–3 N1 M0 Involvement of local (paragastric) lymph nodes Stage II2 T1–3 N2 M0 Involvement of distant (mesenteric, para-aortic, paracaval, pelvic, inguinal) lymph nodes Stage IIE T4 N0–2 M0 Infiltration of adjacent organs or tissues by direct infiltration Stage IV: extranodal involvement or concomitant supradiaphragmatic nodal involvement T1–4 N3 M0 Spread to extraabdominal lymph nodes T1–4 N0–3 M1 Noncontinuous involvement of separate site in GI tract (e.g. stomach and rectum) T1–4 N0–3 M2 Noncontinuous involvement of other organs (e.g. tonsils, parotid gland, ocular adnexa, liver and spleen) or tissues (e.g. peritoneum and pleura) T1–4 N0–3 M0–2 B0 Bone marrow not involved T1–4 N0–3 M0–2 B1 Lymphomas infiltrates bone marrow A Presence of systemic symptoms (fever, night sweats and weight loss >10% BW) B Absence of systemic symptoms X Bulky mass (lesion of 10 cm or more in the longest diameter) GI, gastrointestinal; TNM, tumor–node–metastasis; BM, body weight. review Annals of Oncology 1994 | Psyrri et al. Volume 19 | No. 12 | December 2008 biopsies in 50% of the cases. This group should be observed closely, whereas long-term negative PCR may indicate cure of the disease [39]. therapy of cases refractory to antibiotics or H. Pylori negative There are no treatment guidelines for the management of patients who show unresponsiveness to antibiotics or for the subset of H. pylori-negative cases. This latter group of patients usually does not respond to antibiotics. A choice can be made between conventional therapeutic approaches. Radiation therapy (RT) alone is a reasonable treatment option in patients with early-stage (stages I and II) gastric MALT lymphomas refractory to antibiotics. Two small prospective series have shown a 100% complete response rate following RT with a median dose of 30 Gy. The first study by Yahalom [40] from Memorial Sloan-Kettering Cancer Center demonstrated only one treatment failure at a median follow-up of 18 months, whereas the one from Schechter et al. [41] showed no treatment failure at a median follow-up of 27 months. Additionally, Tsang et al. [42] reported on 85 patients with MALT lymphoma (17 patients with gastric MALT NHL) receiving RT alone that up to 90% of patients attained a CR with excellent 5-year progression free and overall survival (OS) rates of 98% and 77%, respectively. With the recent evolvement of CT radiotherapy planning, advanced techniques such as three-dimensional conformal radiotherapy and intensity modulated radiotherapy have facilitated the determination of the clinical target volume, thereby reducing the toxicity that is related to the irradiation of normal gastric mucosa and of nearby organs (especially the left kidney). However, side-effects of RT are encountered, most frequently anorexia, nausea and vomiting. Although with the standard dose (30–35 Gy), no delayed toxicity (such as peptic ulcers or GI haemorrhaging) has been reported; the long-term effects of RT on the structure and function of the gastric mucosa remain to be clarified. There is no consensus regarding the role of adjuvant chemotherapy after antibiotic treatment. The role of chemotherapeutic agents such as alkylating agents, nucleoside analogues or combination chemotherapy for gastric MALT lymphomas refractory to antibiotics has been tested, but only limited data especially on untreated patients with localized disease exist to date. Recently, Nakamura et al. [43] reported CR rates of 89% after oral monotherapy with cyclophosphamide 100 mg/day on patients with gastric MALT NHL, refractory to antibiotic therapy. In this study, the results were comparable to the results achieved after RT; hence, oral monotherapy with cyclophosphamide might also be a suitable second-line therapeutic option after failure of H. pylori eradication therapy. The role of the translocation t(11;18) for the prediction of response to chemotherapy is yet under investigation. Recent data support that for oral alkylating agents such as chlorambucil or cyclophhosphamide, the presence of this translocation in gastric MALT NHL is predictive of resistance [44]. CR rates after 1 and 8 years were 42% and 8% for t(11;18)-positive and 89% for t(11;18)- negative patients, respectively (P = 0.0003, 8 years). Hence, oral alkylating agents might only be administered in patients without the translocation t(11;18). Nucleoside analogue named cladribine or 2-chlorodeoxyadenosine has been tested in a phase II study in patients with gastric (n = 19) and no-gastric MALT NHL at any stage [45]. Patients had to be chemotherapy naive, not responding to H. pylori eradication therapy in case of gastric NHL or suffering from relapse after RT. 2- Chlorodeoxyadenosine was administered at a dose of 0.12 mg/ kg body weight by i.v. infusion over 2 h on days 1–5 and was repeated every 4 weeks. All patients responded to treatment after a median number of four cycles, and 84% achieved CR including all patients with gastric NHL. Three patients with gastric NHL have relapsed locally after 13, 18 and 22 months and were salvaged with RT. Gr