6 Gut lymphomas

6 Gut lymphomas EMANUELE ZUCCA F R A N C O CAVALLI

Gastrointestinal (GI) tract non-Hodgkin's lymphoma (NHL) has been and still remains the subject of much debate and controversy with respect to pathological classification, clinical staging and treatment. Conflicting results with regard to optimal treatment and long-term outcome have emerged from the enormous amount of published studies. This is mainly due to the fact that most studies reported retrospective non-randomized evaluations of small series, often undertaken before the widespread use of modem invasive and non-invasive staging procedures, and lacked uniformity in histopathological classification, patients' characteristics and type of treatment. Moreover, most of the historical series were published before the recognition of mucosa-associated lymphoid tissue (MALT) as the origin of most GI lymphomas (Isaacson and Spencer, 1987; Harris et al, 1994; Isaacson and Norton, 1994). Therefore, with very few recent exceptions (Cogliatti et al, 1991; Morton et al, 1993; Montalban et al, 1995), primary gastric lymphomas have usually been classified in the literature similarly to nodal lymphoma, without consideration for the fact that their origin can be different. Different therapeutic strategies cannot be properly compared without uniformity in definition of the disease, histological classification, selection of patients and staging criteria. Therefore, the debate on optimal management of GI lymphomas seems far from its completion. THE PROBLEM OF DEFINITION

Dawson originally defined primary GI lymphomas using strict criteria: a predominant GI tract lesion, with or without spread to its contiguous lymph node group, and no involvement of peripheral or mediastinal lymph nodes. This definition precludes bone marrow, liver or spleen involvement; the white blood cell count and differential cell count are also required to be normal (Dawson et al, 1961). Using this very restrictive criterion all GI lymphomas will, by definition, be at a favourable stage and this can lead to misunderstanding regarding their biological behaviour. Subsequently, the definition was extended to all cases involving the GI tract and mesenteric Baillidre's Clinical Haematotogy-727 Vol. 9, No. 4, December 1996 ISBN 0-7020--2253-5 0950-3536/96/040727 + 15 $12.00/00

Copyright © 1996, by Bailli~re Tindall All rights of reproduction in any form reserved

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lymph nodes and presenting with GI symptoms (Lewin et al, 1978). With the advent of modern staging procedures more operational definitions of extranodal lymphoma have emerged (D'Amore et al, 1991) that can be applied to GI lymphomas to describe a wider spectrum of presentation and to allow inclusion of cases presenting with symptoms of a GI disease in which the GI tract is the most probable site of origin. In the presence of both nodal and GI disease the following definition can be proposed: the lymphoma is considered 'primary extranodal' when, after routine staging procedures, there is no or only 'minor' nodal involvement along with a clinically 'dominant' extranodal component. Minor nodal or dominant extranodal components are defined as <25% or >75% of the total tumour volume (D'Amore et al, 1991). EPIDEMIOLOGY AND INCIDENCE The GI tract is the most frequently involved extranodal localization in NHL (Freeman et al, 1972; Otter et al, 1989a,b). In hospital- and populationbased series published thus far, GI-NHL accounts for 4 to 20% (on average 12 to 13%) of all NHL and 30 to 40% of all extranodal cases (D'Amore et al, 1994; Herrmann et al, 1980). In the Western world, the most common locations are stomach (approximately 50 to 60%), small intestine (approximately 30%) and large intestine (approximately 10%). Localized oesophageal lymphoma is extremely rare. In the small intestine, ileocaecal presentations are the most common (approximately 60%), followed by jejunal (approximately 30%) and duodenal sites (approximately 10%). Colorectal lymphomas most commonly occur in the caecum. These proportions can differ geographically, with small intestinal lymphomas being more common than gastric lymphomas in the Middle East. This special type of extranodal lymphoma will not be discussed in detail in this chapter. NHL represents 3 to 10% of all gastric tumours (Hockey et al, 1987), and is thus the most common malignancy of the stomach after adenocarcinoma. NHL accounts for about 1/5 of small intestine cancers (WiUiamson et al, 1983), but less than 1% of all large bowel malignancies. It has been suggested that the incidence of gastric and intestinal lymphoma may have increased over the past two decades (Hayes and Dunn, 1989; Severson and Davis, 1990; DeVesa and Fears, 1992). Whether this is due to an actual increase or to more efficient case registration is as yet unclear. Recent data from a Danish population-based registry involving almost 2500 NHL cases collected over a 9-year period (1983-1991) did not demonstrate an increase in the incidence of gastric or intestinal lymphomas (D'Amore et al, 1994). A recent analysis performed in demographically comparable communities of the UK and Italy revealed a much higher incidence of gastric NHL in northeastern Italy than in the corresponding UK communities (13.2x 105/year versus 1 x l@/year), suggesting the existence of geographical variations in the incidence of gastric NHL (Doglioni et al, 1992). Infection by Helicobacter pylori has been cited as an environmental factor

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of possible aetiological relevance in those cases of gastric NHL deriving from the so-called mucosa-associated lymphoid tissue (MALT) (Wotherspoon et al, 1991; Parsonnet et al, 1994). There is less epidemiological information available on intestinal NHL than on gastric NHL. Patients with coeliac disease have a 200-fold increased risk of developing intestinal lymphoma, the so-called enteropathy-associated T-cell lymphoma (EATCL) and some authors even favour the hypothesis that adult-onset coeliac disease is itself a form of low-grade lymphoma (Wright et al, 1991). DIAGNOSIS, CLASSIFICATION AND STAGING Presenting symptoms are generally due to the local lesion (pain, obstruction, haemorrhage). Fever and night sweats are uncommon and if they do occur are more often associated with a T-cell phenotype and/or intestinal localization (D'Amore et al, 1994). Weight loss, however, is common, although this is more often a consequence of the localization of the primary lymphoma rather than a constitutional symptom of the disease. Radiological appearances are often suggestive of the presence of a GINHL. Within the stomach, lymphoma is most common at the pylori antrum, followed by the body, and then the cardia. Computed tomography is useful for evaluating the size of regional lymph nodes and might also reveal wall thickening. The intraluminal component is, however, not readily imaged (Sutcliffe et al, 1992). In the past, surgery was regarded as an essential component of the diagnostic work-up on the grounds that it provided large biopsy specimens for diagnosis. Its current role as a treatment option, mainly for gastric lymphomas, will be dealt with later. From a purely diagnostic viewpoint, however, improved endoscopy and imaging techniques are sufficiently advanced that its role, at least in gastric lymphomas, must be questioned (Rossi et al, 1993). In fact, sufficient material for diagnosis is currently obtained in more than 90% of cases by endoscopic biopsy although this approach does not permit a distinction to be made between stages I and II (as defined in Musshoff, 1977); a distinction that may, in fact, have no therapeutic relevance. Furthermore, the introduction of endoscopic ultrasonography has helped to assess the degree of involvement of the stomach wall and to identify patients at high risk of bleeding and/or perforation (Taal et al, 1989). Endoscopic ultrasound might also have a useful role in the diagnosis of MALT lymphomas, and in assessing responses to lymphoma therapy (Stolte and Eidt, 1993; Pavlick et al, 1996). It is not always possible to establish whether lymphomas are of gastric origin. Recently (Rohatiner, 1994), cases in which the stomach is most probably the site of origin have generally been accepted as primary gastric lymphomas, irrespective of the extent of dissemination within the abdominal cavity. Gastrointestinal tract lymphomas comprise a number of distinct clinicopathological entities which have been variously defined according to the histological classification in vogue at the time; in the Working Formulation,

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most are of intermediate- or high-grade malignancy, with low-grade lymphomas representing only 15 to 20% (Herrmann et al, 1980; D'Amore et al, 1994). Intestinal lesions more often tend to be of a high-grade than do gastric lymphomas (Herrmann et al, 1980; Rohatiner, 1994). Despite the enormous amount of historical and recently published studies on GI-NHL the optimal management remains controversial, mostly because of the lack of prospective randomized trials, and is a matter of active debate. Moreover, variability exists among studies. Some authors (Weingrad et al, 1982; Brooks and Enterline, 1983; Shimm et al, 1983; Maor et al, 1984; Brincker and D'Amore, 1995; Durr et al, 1995) include in their studies only patients with primary tumours confined to the GI tract and adjacent nodes, others (Rosenfelt and Rosenberg, 1980; Economopulos et al, 1985; List et al, 1988; Mentzer et al, 1988; Bellesi et al, 1989) include patients with advanced stage disease at presentation. The best staging system is also controversial. In view of the current lack of consensus concerning classification and staging of GI-NHL, a workshop was organized at the fifth International Conference on Malignant Lymphoma in Lugano (June, 1993), to consider the problems of evaluating patients with GI tract lymphoma (Rohatiner, 1994). The attendees concurred that there is a compelling need for a new classification for primary GI tract lymphomas because of their unique histology, special features and origin in mucosal tissue. Adoption was recommended of the histological classification presented in Table 1, which follows the general principles of the Kiel Classification (Lennert and Feller, 1992) and is based on a proposal by Isaacson et al (1988), with revision of the name of centrocytic lymphoma according to the recent definition of mantle cell lymphoma (MCL) (Banks et al, 1992; Harris et al, 1994). This classification includes the MALT lymphomas as a particular disease entity. Indeed, most low-grade gastric lymphomas arise from MALT. However, the identification of high-grade MALT lymphomas is often problematical; residual foci of low-grade MALT lymphoma can be identified in a significant proportion of high-grade GI lymphomas, and vice versa foci of high-grade lymphoma can be seen in low-grade MALT lymphoma, suggesting transformation from one Table 1. Histological classification of primary gastrointestinal lymphomas. B-cell Mucosa-associated lymphoid tissue (MALT) type: Low-grade MALT lymphoma High-grade MALT lymphoma (with or without a low-grade component) Immunoproliferative small intestinal disease Low-grade High-grade (with or without a low-grade component) Mantle cell (lymphomatous polyposis) Burkitt's and Burkitt's-like Other types (low- or high-grade) corresponding to lymph node equivalents T-cell Enteropathy associated T-cell lymphoma Other types not associated with enteropathy Reproduced from Isaacson and Norton (1994, Extranodal Lymphomas. Edinburgh: Churchill Livingstone) with permission,

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to the other as occurs in other low-grade lymphomas. There is, therefore, a problem in the concept of high-grade MALT lymphoma which relates to the amount of transformed (high-grade) cells: thus far no agreed definition exists. A second problem is posed by the high-grade lymphomas in which no low-grade MALT component can be identified. These must be considered as primary high-grade lymphomas de novo. Whether this latter group should be categorized as MALT lymphoma remains controversial, but some of these lymphomas are almost certainly transformed low-grade MALT lymphoma (Isaacson and Norton, 1994). The applicability of the Ann Arbor staging system to GI tract lymphoma has often been questioned. In view of the features specific to the GI localization, alternative staging systems were proposed (Musshoff, 1977; Blackledge et al, 1979). Moreover, the modifications proposed by Musshoff (1977) have been of value in identifying subsets of patients with different prognoses. At the Lugano workshop, a revised version of the Blackledge staging system (Table 2) was recommended for future general use (Rohatiner, 1994). Regardless of the type of treatment, several prognostic factors have been associated with a poor prognosis. In addition to the factors commonly reported to affect the prognosis of nodal lymphomas negatively (i.e. advanced age, advanced stage, poor performance status, elevated lactic acid dehydrogenase (LDH) and ~2-microglobulin, number of extranodal sites, large tumour size, high-grade histology) other prognostic factors can be identified that are specifically related to the GI localization, namely: involvement of para-aortic versus local (paragastric or paraintestinal) lymph nodes, penetration of serosa to involve adjacent organs or tissues, intestinal versus gastric origin (Dawson et al, 1961; Loehr et al, 1969; Herrmann et al, 1980; Weingrad et al, 1982; Gospodarowicz et al, 1983, 1990; Dragosics et al, 1985; Shiu et al, 1986; Tondini et al, 1993). In terms of histological subtypes, low-grade MALT lymphoma usually has a very good prognosis, whilst MCL-type and EATCL have a very poor outcome (Cogliatti et al, 1991; Domizio et al, 1993; Morton et al, 1993). The International Prognostic Index, initially proposed for patients with diffuse large cell lymphoma (The International Non-Hodgkin's Lymphoma Table 2. Modified Blackledge staging system for primary gastrointestinal lymphomas. Stage I: Stage H: Stage liE:

Stage IV:

Tumour confined to gastrointestinal (GI) tract Single primary site or multiple, non-contiguous lesions Tumour extending into abdomen from primary GI site Stage 1I~ = local nodal involvement (paragastric or paraintestinal) Stage ll~ = distant nodal involvement (mesenteric, retroperitoneal, pelvic, inguinal) Penetration of serosa to involve adjacent organs or tissues (Enumerate actual sites of involvement, e.g. li E (pancreas), II~ (post-abdominal wall)) Where there is both nodal involvement and penetration to involve adjacent organs, stage should be denoted using both a subscript (~ or 2) and E, for example II,e (pancreas) Disseminated extranodal involvement or concomitant supradiaphragmatic nodal involvement

Reproduced from Rohatiner (1994, Anals of Oncology 5: 397-400) with permission.

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Prognostic Factors Project, 1993), also seems useful for predicting outcome in patients with high-grade GI lymphoma (Rohatiner, 1994). TREATMENT

Locally advanced and disseminated lymphoma with aggressive histology It is now evident, in our opinion, that combination chemotherapy is the treatment of choice for patients with advanced local involvement (stage II~), with multiple node involvement (stage IIE with residual disease) or with disseminated disease. In a recent prospective study of intensive chemotherapy including more than 700 patients with aggressive lymphomas, about 15% of the patients were believed to have primary GI lymphoma (Salles et al, 1991). In that study, no difference in therapy outcome was observed between patients with an advanced aggressive nodal lymphoma and the subset in which the lymphoma was deemed to have arisen in the GI tract. Advanced GI-NHL thus appear to behave in the same manner as other advanced lymphomas, with comparable histology and prognostic factors (Tondini et al, 1993; Rohatiner, 1994). The outcome of patients who present with more advanced disease in the abdomen is characterized by a long-term success rate of approximately 40% (Tondini et al, 1993). These results are indirectly supported by data (to be discussed later) derived from a series in which patients with more localized GI-NHL were treated with chemotherapy alone. Analogous to events in other chemosensitive neoplasms (e.g. testicular tumours), the effectiveness of combination chemotherapy in advanced cases of GI-NHL has engendered a reconsideration of the role of primary surgery in less advanced cases, where surgery has, historically, been the initial procedure of choice. This is particularly true for gastric lymphomas. For primary intestinal lymphoma, however, there are as yet no studies which clearly demonstrate that surgery is unnecessary (Rossi et al, 1993). Even though there is a dearth of randomized studies comparing surgery alone with the addition of adjuvant chemotherapy, combined modality treatment is nowadays considered the procedure of choice for patients with primary intestinal lymphoma (Sutcliffe and Gospodarowicz, 1992; Rossi et al, 1993; Tondini, 1993). In a large series from the Istituto Nazionale dei Tumori (National Cancer Institute) in Milan (Tondini, 1993), it is noteworthy that with such an approach, primary gastric and intestinal lymphomas appear to have similar outcomes if they have a comparable histology and prognostic index; in the past, the prognosis for intestinal localization was considered to be generally worse (Rossi et al, 1993; D'Amore et al, 1994).

Localized lymphomas with aggressive histology Much more controversial nowadays is the situation with cases of gastric lymphoma in which there is limited involvement (stage IE). Traditionally,

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surgery has played a major role in the treatment of localized gastric lymphoma by simultaneously solving diagnostic and therapeutic problems. Since endoscopy and computed tomography have become generally available, the necessity of surgery for biopsy and staging has, as previously stated, almost entirely disappeared (Otter et al, 1989a; Rossi et al, 1993). The possible advantage of debulking as well as the lessening of the risk of bleeding and perforation were other reasons for advocating surgery as a primary treatment. The role of debulking has never been properly defined in this situation. Moreover, the presence of a bulky mass is sometimes itself an obstacle to surgical intervention, and surgery does not necessarily prevent these complications, as episodes of bleeding or perforation have also been reported to occur despite surgical resection (Weingrad et al, 1982). Nevertheless, the risk does exist; in fact, a review of 17 series including about 600 patients with unresected gastric lymphoma treated with radiation therapy showed a 4% incidence of gastric perforation at initial presentation (Mittal et al, 1983). However, other series have revealed that gastric lymphoma can be treated with chemotherapy or radiotherapy alone without perforation or bleeding (Herrmann et al, 1980; Mittal et al, 1983). It seems therefore, that the risk of bleeding or perforation during chemotherapy has been generally overestimated, as was well demonstrated by recent series (Economopulos et al, 1990; Gobbi et al, 1990; Maor et al, 1990; Salles et al, 1991). On the other hand, surgical resection of the stomach has an intrinsic mortality (about 5 to 10%) which is comparable, if not superior, to the risk of bleeding (Lira et al, 1977; Weingrad et al, 1982; Mittal et al, 1983; Shiu et al, 1986; Hockey et al, 1987; Rosen et al, 1987; Gobbi et al, 1990; Talamonti et al, 1990). Finally, post-surgical complications can delay subsequent chemotherapy or radiotherapy and can also adversely affect the performance status. In view of these facts, new approaches have been advocated. In a recently published retrospective study of 119 patients with localized gastric NHL treated with either radiotherapy alone (after clinical staging) or with surgery followed by adjuvant radiotherapy, the survivals at 5 years were 70% and 37%, respectively, for patients with stage I and II disease, with no difference between the results for patients receiving radiotherapy alone, or radiotherapy after surgical resection (Taal et al, 1989). The study was not randomized, but no obvious bias in the selection of the treatment procedure was detected. It was therefore proposed that radiotherapy is the treatment of choice for non-bulky lesions in stage I or II disease. For larger tumours, results are less satisfactory and these authors advocate the addition of combination chemotherapy. It is also possible that improved results in patients with stage I and II disease would be achieved by including chemotherapy in the treatment regimen. It has been suggested by the results of at least four series (Gobbi et al, 1990; Maor et al, 1990; Avilrs et al, 1991; Salles et al, 1991) that chemotherapy, sometimes combined with radiotherapy (Maor et al, 1990), is as effective as surgery and that gastrectomy is thus redundant. In another study (Brinker and D'Amore, 1995), 106 cases of localized gastric lymphoma reported to a populationbased Danish registry were analysed. Of these, 67 had surgical resection,

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51 chemotherapy, and 55 radiotherapy, or combinations thereof. None of the treatment modalities showed any relative superiority with respect to survival (P = 0.13); the overall 5-year survival was 67%. By Cox regression analysis the pre-therapeutic presence of fever or LDH elevation bad a far more significant influence on survival than did any of the treatments or treatment combinations. Of note is the fact that in these series, surgical resection was associated with a significantly higher risk of late complications than was radiotherapy. Interesting data also comes from a recent interim analysis of an ongoing European prospective cooperative randomized trial for the treatment of localized GI lymphomas with aggressive histology (Bron et al, 1996). This study compares radiotherapy (40 Grays) with three cycles of chemotherapy in pathological stage I patients. Patients with pathological or clinical stage II are treated with six cycles of the same chemotherapy and complete responders are randomized between iceberg radiotherapy or no further treatment. Sixteen stage I patients have been treated (eight in the chemotherapy arm and eight in the radiotherapy arm) and all are in continuous complete remission at a median follow-up of 42 months. Treatment evaluation was possible in 19 of 28 stage II patients; 77% achieved a continuous complete remission after chemotherapy, with 57% of continuous remission at a median follow-up of 31 months. Another ongoing prospective study has been launched by the German Multicenter Study Group on GI-NHL (Koch et al, 1996). In this study primary surgery or conservative management depended on the physician's decision, followed by radiotherapy _+chemotherapy. After a median follow-up of 20 months, 152 patients are evaluable for therapy outcome. Over all stages there seems to be no difference in treatment outcome in surgically or conservatively treated patients. Even limited-stage patients after radical resection appear to have no better outcome than those who did not undergo surgical resection. There was no fatal bleeding or perforation during conservative therapy while additional treatment in operated patients was often delayed or incomplete because of reduced performance status. Moreover, even in patients with localized disease, the majority of treatment failures are the result of a distant relapse (Mittal et al, 1983; Durr et al, 1995), suggesting that local treatment alone may not be adequate. Taken together, the above mentioned results suggest that the value of primary surgery should also be re-examined in the treatment of localized GI lymphoma. However, confirmation of these results, with comparability of patient populations, is required and essential since the cure fraction with surgery + adjuvant chemotherapy is high, with 70 to 75% of stage I patients and 40 to 50% of stage II patients still alive at 5 years (Rossi and Lister, 1993). As in other chemosensitive tumours, it is nevertheless possible that, in future, surgery will be resorted to as a potential approach for salvage should complete remission not be achieved with conservative therapy.

Low-grade lymphoma of MALT type The concept of MALT has progressively developed during the past 10 years regarding the lymphoid component observed in various organs that

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do not correspond to peripheral sites of the immune system. Two types of MALT tissue can be identified; the native type which consists of the lymphoid tissue physiologically present in the gut (i.e. the Peyer's patches); and the acquired MALT which develops after inflammatory events in response either to infectious agents (e.g.H. pylori gastritis in the stomach) or autoimmune processes (e.g. Hashimoto's thyroiditis and Sjrgren's syndrome). In the context of these prolonged lymphoid reactive proliferations a pathological clone can progressively substitute the normal lymphoid population, so originating the MALT lymphoma (Piled et al, 1994; Isaacson, 1995). Low-grade gastric MALT lymphoma is characterized by an indolent natural history and prolonged confinement to the site of origin. Its morphological appearance is characterized by prominent and often mulfifocal lymphoepithelial lesions showing dense diffuse infiltrates of centrocytelike cells within the lamina propria in association with plasma cell differentiation and with the occurrence of reactive lymphoid follicles (Isaacson and Spencer, 1987; Wotherspoon et al, 1992a; Isaacson and Norton, 1994). This concept of MALT lymphoma has been widely accepted as a distinct entity within extra-nodal NHLs, challenging the pre-existing concept of pseudolymphoma (Isaacson, 1995). In fact, monoclonality is usually demonstrable (Diss et al, 1993; Wotherspoon et al, 1993; Pan et al, 1994) and, moreover, non-random chromosomal abnormalities can be detected (Wotherspoon et al, 1992b, 1995; Dierlamm et al, 1996) contributing to define a truly malignant entity that has been included as a distinct subtype in the recently proposed Revised European-American Classification of lymphoid neoplasms (REAL classification) (Harris et al, 1994; Piled et al, 1994). There is increasing epidemiological and histopathological evidence of a plausible aetiological correlation between gastric MALT lymphomas and H. pylori infection (Wotherspoon et al, 1991; Isaacson, 1994; Parsonnet et al, 1994). This association is also supported by in vitro experiments which have demonstrated that the tumour cells of low-grade MALT lymphoma proliferate in response to 14. pytori and that this response is strain-specific (Hussel et al, 1993). Moreover, clinical studies demonstrated histological and molecular regressions of gastric MALT lymphoma after eradication of H. pylori in more than one-half of the patients who received antibiotic therapy (Wotherspoon et al, 1993; Bayerdrrffer et al, 1995; Roggero et al, 1995). Local treatment has been used with excellent results (Durr et al, 1995). However, there is increasing evidence that eradication of H. pylori can have a major role as the sole initial treatment (Bayerdrrffer et al, 1995; Roggero et al, 1995; Montalban et al, 1996). We recently reviewed a large multicentre series of 93 patients with lowgrade gastric MALT lymphoma (Pinotti et al, 1977). In the stomach the disease was most often localized in the antrum (41%) or multifocal (33%); antrum involvement was documented in the majority of patients with multifocal disease. The lymphoma was confined to the stomach (stage I) in 88% of cases.

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The patients were treated by different modalities: 13 had surgery alone and 11 received additional chemotherapy or radiation therapy; 11 patients had chemotherapy alone, and one had radiotherapy only; 49 patients (all with clinical stage I) were given antibiotics against H. pyIori as their sole initial treatment, one patient had antibiotics and chlorambucil and seven patients refused any treatment. The antibiotic-treated group of patients was prospectively followed with regular endoscopic biopsies, and their responses were histologically evaluated. The 5-year overall survival is 82% (95% CI: 67 to 91%) in the whole series. At a median follow-up of 34 months, 10 of 93 patients had died; all but one of a second solid tumour. In fact, additional solid tumours were observed in 21.5% of the patients in this series (95% CI: 14 to 31%); the reason for the unexpectedly high incidence of other tumours in this population remains unclear (Zucca et al, 1995). There was no significant difference in overall survival and event-free survival between patients who received different treatments. In the antibiotic-treated group, eradication of H. pylori was achieved in 97% of patients (95% CI: 88.2 to 99.9%). All but one of the patients were symptomatic at presentation. The main symptoms were those of nonspecific dyspepsia; epigastric pain being the commonest manifestation. The endoscopic findings were usually those of non-specific gastritis and/or peptic ulcer, the presence of a mass being very unusual. Symptoms disappeared in 80% (36 of 45 patients) or markedly decreased after antibiotic treatment. In all the patients the endoscopic features improved after eradication of 14. pylori and all of the ulcers healed, but only one patient had a complete recovery of the gastric mucosa. Histological regression of the MALT lymphoma was scored using a previously published system (Wotherspoon et al, 1993) in which scores up to 2 were considered as responses (Table 3). Histological regression of MALT lymphoma was documented in 67% of patients (95% CI" 51% to 80%) after 14. pylori eradication. Thirteen patients had a complete disappearance of any histological evidence of lymphoma (histological score, 0 to 1), and 17 patients had residual lymphoid follicles but no longer had lymphoepithelial lesions (score, 2). Four patients showed persistent suspicious, but probably reactive, lymphoid infiltrate in the lamina propria (score, 3) and the remaining 11 patients showed no change or only partial improvement in the lymphoma histological pattern in repeated gastric biopsy specimens. Lymphoma regression may require a prolonged time. In only 11 patients was the histological response documented on the first biopsy after antibiotic treatment, but when endoscopic specimens were again obtained three or more months later, regression of lymphoma was clearly evident in 19 additional patients. The median time required to achieve a histological regression of the MALT lymphoma was 5 months with a range of 3 to 18 months. Long-term follow-up of the antibiotic-treated patients will be mandatory since gastric low-grade MALT lymphoma is usually an indolent disease, and it is still unknown whether or not treatment for H. pylori will definitely

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Table 3. Results of Helicobacter pylori eradication in 45 patients with low-grade mucosa-associated lymphoid tissue (MALT) lymphoma: post-treatment histological evaluation according to the histological score proposed by Wotherspoon et al (1993). Score

Description

0 1

Normal Scattered plasma cells in lamina propria Chronic active gastritis Small clusters of lymphocytes in lamina propria; no lymphoid follicles; no LELs Chronic active gastritis Prominent lymphoid follicles with surrounding with lymphoid mantle zone and plasma cells; no LELs follicles Suspicious lymphoid Lymphoid follicles surrounded by small infiltrate, probably lymphocytes that infiltrate diffusely in lamina reactive propria and occasionally into epithelium Suspicious lymphoid Lymphoid follicles surrounded by CCL cells that infiltrate, probably infiltrate diffusely in lamina propria and into lymphoma epithelium in small groups Low-grade MALT Dense diffuse infiltrate of CCL cells in lamina lymphoma propria with prominent LELs

2 3 4 5

Histological features

N of patients 1 (2%) 12 (27%) 17 (38%) 4 (9%) 8 (18%) 3 (6%)

LEL = lymphoepithelial lesion, CCL = centrocyte-like. Lymphoma complete regression is indicated by a post-treatment score of 0-2. The scores reported in this table represent the best response observed. Reproduced from Wotherspoon et al (1993, Lancet 342" 575-577 © The Lancet Ltd) with permission.

cure the lymphoma and prevent its relapse. The need for surgical resection and the relative roles of radiotherapy and chemotherapy still need to be defined. Surgical resection has been widely used in the past with excellent results for localized disease. However, follow-up endoscopy may reveal, in the remaining gastric mucosa, the re-appearance of lymphoepithelial lesions that might be responsible for local recurrence (Wotherspoon et al, 1992a). Indeed, the fact that MALT lymphoma is often a multifocal disease suggests that clear excision margins are not necessarily a guarantee of radical resection. Therefore, if surgery is chosen, a total gastrectomy may offer greater chances of cure. However, this operation carries a certain risk of mortality (Smith et al, 1991); moreover, the quality of life after total gastrectomy can be severely impaired. In our opinion, the lack of evidence of a survival advantage for any particular treatment modality, and the indolent nature of the disease make plausible a conservative approach, with antibiotic eradication of H. pylori as the sole initial treatment. The use of antibiotics as first-line therapy may avert or at least postpone the indication for surgical resection in the majority of patients, and we recommend the eradication of H. pylori before further therapeutic options are considered. It must be reiterated, however, that lymphoma regression may require a very prolonged time and patients need a regular careful endoscopic follow-up. Molecular follow-up (with monoclonality analysis of gastric biopsy) can be useful however, histological assessment by an experienced pathologist is still the method of choice for the evaluation of MALT lymphoma in gastric biopsies (Savio et al, 1996). Further studies are still needed to define the optimal management of MALT tymphoma. An international (British, Swiss, Italian and French) cooperative randomized trial designed by the United Kingdom Lymphoma

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Group is currently investigating whether the addition of chemotherapy (chlorambucil) to the anti-H, pylori therapy is of any benefit in low-grade gastric lymphomas. SUMMARY Gut lymphoma still remains the subject of much debate and controversy with respect to pathological classification, clinical staging and treatment. This is mainly due to the fact that most studies reported retrospective non-randomized evaluations of small series and lacked uniformity in histological classification, patients' characteristics and type of treatment. Moreover, most of the historical series were published before the recognition of MALT as the origin of most GI lymphomas. Hence, there is a compelling need for the use of modem histological criteria for primary GI lymphomas because of their unique histology, special features and origin in mucosal tissue. General adoption of the histological classification proposed in 1988 by Isaacson et al (Table 1) can be recommended which follows the general principles of the Kiel Classification and includes the MALT lymphomas as a particular disease entity. Combination chemotherapy is the treatment of choice for gut lymphomas with aggressive histology and multiple node involvement or disseminated disease. The effectiveness of combination chemotherapy in advanced disease has excited a reconsideration of the role of primary surgery in less advanced cases where surgery has, historically, been the initial procedure of choice. This is particularly true for gastric lymphomas where it is possible that, in future, surgery will be resorted to as a potential approach for salvage when complete remission is not achieved with conservative therapy. For primary intestinal lymphoma, however, there are as yet no studies which clearly demonstrate that surgery is not necessary. With respect to the group of localized low-grade MALT lymphomas of the stomach and the indolent nature of the disease make plausible a conservative approach, with antibiotic eradication of 11. pylori as the sole initial treatment. This may avert or at least postpone the indication for surgical resection in the majority of patients. REFERENCES Avilrs A, Dfaz-Maqueo JC, de la Torre Aet a| (1991) Is surgery necessary in the treatment of primary gastric non-Hodgkin lymphoma? Leukemia and Lymphoma 5: 365-369. Banks PM, Chan J, Cleary ML et al (1992) Mantle cell lymphoma; a proposal for unification of morphologic, immunologic and molecular data. American Journal of Surgical Pathology 16: 637--640. Bayerdrrffer E, Neubauer A, Rudolph B e t al (1995) Regression of primary gastric lymphoma of mucosa associated lymphoid tissue type after cure of Helicobacter pylori infection. Lancet 345: 1591-1594. Bellesi G, Alterini R, Messori A et al (1989) Combined surgery and chemotherapy for the treatment of primary gastrointestinal intermediate- or high-grade non-Hodgkin's lymphomas. British Journal of Cancer 60: 244-248. Blackledge G, Bush A, Dodge OG et al (1979) A study of gastrointestinal lymphoma. Clinical Oncology 5: 209-219.

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Brinoker H & D'Amore F (1995) A retrospective analysis of treatment outcome in 106 cases of localized gastric non-Hodgkin's lymphomas. Leukemia and Lymphoma 18: 281-288. Bron D, Monfardini S, Sacco C et ai (1996) Prospective randomized trial for the treatment of localized gastrointestinal (GI) tract lymphomas (NHL): preliminary report of a multicentric study. Annals ofOncology 7 (supplement 3): 129 (abstract 477). Brooks JJ • Enterline HT (1983) Primary gastric lymphomas. A clinicopathologic study of 58 cases with long-term follow-up and literature review. Cancer 51:701-711. Cogliatti SB, Schmid U, Sehumacher U et al (1991) Primary B-cell gastric lymphoma: A clinicopathological study of 145 patients. Gastroenterology 101: 1159-1170. D'Amore E Brincker H, GrCnbaek K et al (1994) Non Hodgkin's lymphoma of the gastrointestinal tract: A population-based analysis of incidence, geographic distribution, clinico-pathologic presentation features, and prognosis. Journal of Clinical Oncology 12: 1673-1684. D'Amore F, Christensen BE, Brincker H et al (1991) Clinico-pathological features and prognostic factors in extranodal non-Hodgkin's lymphomas. European Journal of Cancer 27: 1201-1208. Dawson IMP, Comes JS & Morson BC (1961) Primary malignant lymphoid tumours of the gastrointestinal tract: Report of 37 cases with a study of factors influencing prognosis. British Journal of Surgery 49: 80-89. De Vesa SS & Fears T (1992) Non-Hodgkin's lymphoma time trends: United States and international data. Cancer Research 52 (supplement): 5432s-5440s. Dierlamm J, Pittaluga S, Wlodarska Iet al (1996) Marginal zone B-cell lymphomas of different sites share similar cytogenetic and morphologic features. Blood 87: 299-307. Diss TC, Peng HZ, Wotherspoon AC et al (1993) Detection of monoclonality in low-grade B-cell lymphomas using the polymerase chain reaction is dependent on primer selection and lymphoma type. Journal of Pathology 169: 291-295. Dogiioni C, Wotherspoon AC, Moschini Aet al (1992) High incidence of primary gastric lymphoma in north-eastern Italy. Lancet 339: 834-835. Domizio P, Owen TA, Shepherd NA et al (1993) Primary lymphoma of the small intestine: A clinical pathological study of 119 cases. American Journal of Surgical Pathology 17: 429-442. Dragosics B, Bauer P & Radaszkiewicz T (1985) Primary gastrointestinal non-Hodgkin's lymphomas. Cancer 55: 1060-1073. Durr ED, Bonner JA, Strickler JG et al (i995) Management of stage IE primary gastric tymphoma. Acta Haematologica 94: 5948. Economopulos T, Alexopoulos C, Stathakis Net al (1985) Primary gastric lymphoma: The experience of a general hospital. British Journal of Cancer 52: 39t-397. Economopulos T, Alexopoulos C, Stathakis N et al (1990) Primary gastric lymphoma. European Journal of Cancer 26: 855. Freeman C, Berg JW & Cutler SJ (1972) Occurrence and prognosis of extranodal lymphomas. Cancer 29: 252-260. Gobbi PG, Dionigi P, Barbieri F et at (1990) The role of surgery in the multimodal treatment of primary gastric non-Hodgkin's lymphomas. A report of 76 cases and review of the literature. Cancer 65: 2528-2536. Gospodarowicz MK, Bush RS, Brown TC et al (1983) Curability of gastrointestinal lymphoma with combined surgery and radiation. International Journal of Radiation, Oncology and Biological Physics 9: 3-9. Gospodarowicz MK, Sutcliffe SB, Clark RM et al (1990) Outcome analysis of localized gastrointestinal lymphoma treated with surgery and postoperative irradiation. International Journal of Radiation, Oncology and Biological Physics 19: 1351-1355. Harris NL, Jaffe ES, Stein H e t aI (1994)A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 84: 1361t392. Hayes J & Dunn E (1989) Has the incidence of primary gastric lymphoma increased? Cancer 63: 2073-2076. Herrmann R, Panahon AM, Barcos M e t al (1980) Gastrointestinal involvement in non-Hodgkin's lymphoma. Cancer 46: 215-222. Hockey MS, Powell J, Crocker J e t al (1987) Primary gastric lymphoma. British Journal of Surgery 74: 483-487. Hussel T, Isaacson PG, Crabtree JE & Spencer J (1993) The response of cells from low-grade B-cell gastric lymphoma of mucosa associated lymphoid tissue to Helicobacter pylori. Lancet 342: 571-574.

740

E. ZUCCA AND F. CAVALL1

Isaacson PG (t994) Gastric lymphoma and Heficobacter pylori. New England Journal of Medicine 330: I310-1311. Isaacson PG (1995) The MALT lymphoma concept updated. Annals of Oncology 6:319-320. Isaacson PG & Norton AJ (eds) (1994) Malignant lymphoma of the gastrointestinal tract. In Extranodal Lymphomas, pp 15-65. Edinburgh: Churchill Livingstone. Isaacson PG & Spencer J (1987) Malignant lymphoma of mucosa-associated lymphoid tissue. Histopathology 11: 445-462. Isaacson PG, Spencer J & Wright DH (1988) Classifying primary gut lymphomas. Lancet ii: 1148-1149. Koch E Grothaus-Pinke B, Hiddemann Wet al (1996) Primary lymphoma of the stomach: 3-yearsresults of a prospective multicenter study. Annals of Oncology 7 (supplement 3): 25 (abstract 81 ). Lennert K & Feller AC (1992) Histopathology of Non-Hodgkin k Lymphomas (Based on the Updated Kiel Classification), pp 13-52.2nd edn New York: Springer-Verlag. Lewin KJ, Ranchod M & Dorfman RF (1978) Lymphomas of the gastrointestinal tract. Cancer 42: 693-707. Lim FE, Hartman AS, Tan EGC et al (1977) Factors in the prognosis of gastric lymphoma. Cancer 39: 1715-1720. List AE Greer JP, Cousar JC et al (1988) Non-Hodgkin's lymphoma of the gastrointestinal tract: an analysis of clinical and pathologic features affecting outcome. Journal of Clinical Oncology 6: 1125-1133. Loehr WJ, Mujahed Z, Zahn D et al (I969) Primary lymphoma of the gastrointestinal tract: a review of 100 cases. Annals of Surgery 170: 232-238. Maor MH, Maddux B, Osborne BM et al (1984) Stages IE and IIE non-Hodgkin's lymphoma of the stomach. Comparison of treatment modalities. Cancer 54: 2330-2337. Maor MH, Velasquez WS, Fuller LM et al (1990) Stomach conservation in stages IE and lIE gastric non-Hodgkin's lymphoma. Journal of Clinical Oncology 8: 266-271. Mentzer SJ, Osteen RT, Pappas TN et al (1988) Surgical therapy of localized abdominal nonHodgkin's lymphomas. Surgery' 103: 609-614. Mittal B, Wasserman TH & Griffith RC (1983) Non-Hodgkin's lymphoma of the stomach. American Journal of Gastroenterology 78- 780-787. Montalban C, Castrillo JM, Abraira Vet al (1995) Gastric B-cell mucosa-associated lymphoid tissue (MALT) lymphoma. Clinicopathological study and evaluation of the prognostic factors in 143 patients. Annals of Oncology 6: 355-362. Montalban C, Manzanal A, Boixeda D et al (1996) Helicobacter pylori eradication for the treatment of low grade gastric MALT lymphoma. Follow up together with sequential molecular studies. Annals of Oncology 7 (supplement 3): 65 (abstract 226). Morton JE, Leyland MJ, Vaughan Hudson G et al (1993) Primary gastrointestinal non-Hodgkin's lymphoma: a review of 175 British National Lymphoma Investigation cases. British Journal of Cancer 67: 776-782. Musshof K (1977) Klinische Stadieneinteilung der Nicht-Hodgkin-Lymphome. Strahlentherapie 153: 218-221. Otter R, Bieger R, Kluin PHM et al (1989a) Primary gastrointestinal non-Hodgkin's lymphoma in a population-based registry. British Journal of Cancer 60: 745-750. Otter R, Gerrits WBJ, Sandt MM et al (1989b) Primary extranodal and nodal non-Hodgkin's lymphoma: A survey of a population-based registry. European Journal of Cancer and Clinical Oncology 25: 1203-1210. Pan LX, Diss TC, Peng HZ & Isaacson PG (t994) Clonality analysis of defined B-cell populations in archival tissue sections using the potymerase chain reaction. Histopathotogy 24: 323-327. Parsonnet J, Hansen S, Rodriguez Let al (1994) Helicobacterpylori infection and gastric lymphoma. New England Journal of Medicine 330: 1267-1271. Pavlick AC, Gerdes H & Portlock CS (1996). Endoscopic ultrasound in the evaluation of gastric small-lymphocytic mucosa-associated lymphoid tumors. Annals of Oncology 7 (supplement 3): 65 (abstract 228). Pileri S, Piecaluga PP, De Vivo A et al (1994) Malignant lymphomas of the gastrointestinal tract: a reappraisal on the basis of the newly proposed Revised European-American Lymphoma Classification. Italian Journal of Gastroenterology 26:405-418. Pinotti G, Zucca E, Roggero E et al (1997) Clinical features, treatment and outcome in a series of 93 patients with low-grade gastric MALT lymphoma. Leukemia and Lymphoma (in press). Roggero E, Zucca E, Pinotti G e t al (1995) Eradication of Helicobacter pylori infection in primary

GUT LYMPHOMAS

741

low-grade gastric lymphoma of mucosa associated lymphoid tissue. Annals oflnternal Medicine 122: 767-769. Rohatiner A (1994) Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma. Annals of Oncology 5: 397-400. Rosen CB, van Heerden JA, Martin JK et al (1987) Is an aggressive surgical approach to the patient with gastric lymphorna warranted? Annals of Surgery 205: 634-640. Rosenfelt F & Rosenberg SA (1980) Diffuse histiocytic lymphoma presenting with gastrointestinal tract lesions. Cancer 45: 2188-2193. Rossi A & Lister TA (1993) Primary gastric non-Hodgkin's lymphoma: A therapeutic challenge. European Journal of Cancer 29A: 1924-1926. Rossi A, Rohatiuer AZS & Lister TA (1993) Primary gastrointestinal non-Hodgkin's lymphoma: Still an unresolved question? Annals of Oncology 4: 802-803. Salles G, Herbrecht R, Tilly H et al (1991) Aggressive primary gastrointestinal !ymphomas: review of 91 patients treated with the LNH-83 regimen. A study of the Groupe d'Etude des Lymphomes Agressifs. American Journal of Medicine 90: 77-83. Savio A, Franzin G, Wotherspoon AC et al (1996) Diagnosis and posttreatment follow-up of Helicobacterpylori-positive gastric lymphoma of mucosa-associaled lymphoid tissue: histology, polymerase chain reaction, or both? Blood 87: 1255-1260. Severson RK & Davis S (1990) Increasing incidence of primary gastric lymphoma. Cancer 66: 1283-1287. Shimm DS, Dosoretz DE, Anderson T et al (1983) Primary gastric lymphoma: an analysis with emphasis on prognostic factors and radiation therapy. Cancer 52: 2044-2048. Shiu MH, Nisce LZ, Pinna Aet al (1986) Recent results of multimodal therapy of gastric lymphoma. Cancer 58: 1389-1399. Smith JW, Shiu MH, Kelsey L e t al (!991) Morbidity of radical lymphadenectomy in the curative resection of gastric carcinoma. Archives of Surgery 126: 1469-1473. Stolte M & Eidt S (1993) Healing gastric MALT lymphomas by eradicating 11. pylori? Lancet 342: 568. Sutcliffe SB & Gospodarowicz MK (1992) In Keating A, Amitage J, Burnet A & Newland A (eds) Clinical features and management of localized extranodal lymphomas. Haematological Oncology, Vol 2, pp 189-223. Cambridge: Cambridge University Press. Taal BG, Den Hartog Jager FCA, Burgers JMV et al (1989) Primary non-Hodgkin's lymphoma of the stomach: changing aspects and therapeutic choices. European Journal of Cancer and Clinical Oncology 25: 439450. Talamonti MS, Dawes LG, Joeht RJ & Nahrwold DL (1990) Gastrointestinal lymphoma. Archives c~ Surgery 125: 972-977. The International Non-Hodgkin's Lymphoma Prognostic Factors Project (1993) A predictive model for aggressive non-Hodgkin's lymphoma. New England Journal of Medicine 329: 987-994. Tondini G, Giardini R, Buzzetti F et al (1993) Combined modality treatment for primary gastrointestinal non-Hodgkin's lymphoma. The Milan Cancer Institute experience. Annals of Oncology 4: 831-837. Weingrad DN, Decosse JJ, Sherlock P e t al (1982) Primary gastrointestinal lymphoma: a 30-year review. Cancer 49: 1258-1265. Williamson RCN, Welch CE & Malt RA (1983) Adenocarcinoma and lymphoma of the small intestine: Distribution and aetiologic association. Annals of Surgery 197: 172-178. Wotherspoon AC, Doglioni C & Isaacson PG (1992a) Low-grade gastric B-cell lymphoma of mucosaassociated lymphoid tissue (MALT): a multifocal disease. Histopatlwlogy 20: 29-34. Wotherspoon AC, Pan LX, Diss TC & Isaacson PG (1992b) Cytogenetic study of B-cell lymphoma of mucosa-associated lymphoid tissue. Cancer Genetics and Cytogenetic 58: 35-38. Wotherspoon AC, Finn TM & Isaacson PG (•995) Trisomy 3 in low-grade B-celt lymphomas of mucosa-associated lymphoid tissue. Blood 85: 2000-2004. Wotherspoon AC, Ortiz-Hildago C, Falzon MF et al (1991) Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet 338:1175-1176. Wotherspoon AC, Doglioni C, Diss TC et al (1993) Regression of primary tow-grade B-cell gastric lymphoma of mucosa associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet 342: 575-577. Wright DH, Jones DB, Clark H et al (1991) Is adult-onset coeliac disease due to a low-grade lymphoma of intraepithelial T lymphocytes. Lancet 337: 1373-1374. Zucca E, Pinotti G, Roggero E et al (1995) High incidence of other neoplasms in patients with lowgrade gastric MALT-lymphoma. Annals of Oncology 6: 726-728.