Controversies and consensus in the diagnosis, work-up and treatment of gastric lymphoma: An international survey

Annals of Oncology 10: 275-280, 1999. © 1999 Ktuwer Academic Publishers. Printed in the Netherlands.

Special article Controversies and consensus in the diagnosis, work-up and treatment of gastric lymphoma: An international survey D. de Jong,1 B. M. P. Aleman,2 B. G. Taal3 & H. Boot3 Departments of l Pathology, 2Radiation Therapy, iGastroenterology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

Introduction

Modern lymphoma classifications are based on the concept of defining clinico-pathological disease-entities [1]. These clinico-pathological entities are defined by a characteristic morphological spectrum, immunological marker pattern and preferably a discriminative chromosomal aberration in concert with a typical clinical presentation and prognosis. In contrast to the formerly preferred approach of the lumping of different types of lymphomas into broad prognostic groups, this approach enables more insight into the biological mechanisms in specific diseases and the characteristic clinical consequences in terms of dissemination patterns and response to different treatment protocols. Ultimately, this insight can serve as the basis for the development of treatment strategies, that are specifically tailored to the characteristics of the disease. The disease, in which this new approach has proven most successful thus far, is primary gastric mucosaassociated lymphoid tissue type lymphoma (MALTNHL). With the introduction of the MALT-concept, a group of extranodal low-grade B-cell lymphoma has been recognised as a separate entity since 1983 [2]. MALT-

NHL is most frequently found in the stomach and can be considered the prototype of the disease [3]. In 1991, Wotherspoon et al. described a consistent association of low-grade (LG) gastric MALT-NHL with Helicobacter pylori (H. pylori) infection [4]. Since the growth of MALT-NHL cells could be modulated in vitro by infection-related factors [5, 6], eradication of H. pylori was daringly tried as a means to influence tumour growth in vivo in patients with MALT-NHL [7]. This can be considered the prime example of a therapy tailored to the characteristics of the specific disease. Several clinical trials have now shown a 60% to 80% success rate of H. pylori eradication as single modality treatment in localised LG gastric MALT-NHL [8-10]. These studies have resulted in a considerable increase in knowledge, but also reveal controversies in opinions and beliefs. Many questions remain in the field of diagnostic criteria, staging requirements and treatment planning that are of direct consequence for patient management. To evaluate the present status of thinking in leading institutes in different countries and to get an insight into the topics of controversy and consensus in the management of gastric MALT-NHL, we have conducted an international survey on these subjects.

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between groups leaded by medical oncologists and gastroenterologists. This results in basically different patient selecBackground: Variations in diagnostic criteria and staging pro- tions and bias in treatment outcome. Similar effects were cedures in cancer patients have important consequences for recorded for the role of gastric resection and radiotherapy. patient selection and often preclude meaningful comparison of Conclusions: This study gives insight in the basis of the published series. In gastric lymphoma, these effects will play a decisions that result in different approaches in the managerole, since diagnostic criteria are controversial. Moreover, stag- ment of gastric MALT-NHL and in the effects for patient ing procedures and therapeutic choices are influenced by in- selection and treatment results and may help in the design of sights from different clinical specialisms. future clinical trials. Methods: To review the management of gastric lymphoma, formatted questonaires were mailed to leading institutes with a Key words: diagnostic criteria, gastric lymphoma, Helicospecial interest in this field in Europe, the United States and bacter pylori, mucosa-associated lymphoid tissue type lymJapan. phoma, staging procedures, therapy Results: Nineteen centers aggreed to contribute. Minimum histological criteria varied among pathologists with a notable Abbreviations: MALT-NHL - mucosa-associated lymphoid influence of the classification system used in the different tissue-type lymphoma; LG - low grade; HG - high grade; countries. Detailed evaluation of the lymphoma distribution DLBCL - diffuse large B-cell lymphoma; H. pylori - Helicoin the gastric wall and routine staging of the Gl-tract differed bacterpylori; LEL - lympho-epithelial lesion Summary

276 Table 1. Items included in the questionnaire. Surgical pathology Material

Number and site of endoscopical biopsies Formalin-fixed and/or fresh frozen biopsies Lympho-epithelial lesions Immunohistochemistry Clonality Grading Helwobacter pylori

Minimum criteria

Diagnostic work-up Standard lymphoma staging Specific techniques

Chemotherapy

Radiotherapy Surgery

Inclusion criteria Histology Staging Regimen Follow-up Inclusion criteria Follow-up Regimen Inclusion criteria Technique Inclusion criteria Technique

Table 2. Contributory institutes. The Netherlands

Switzerland Great Britain Spain France

Austria Belgium USA

Japan

The Netherlands Cancer Institute, Amsterdam University Hospital Free University, Amsterdam Leiden University Medical Center, Leiden University Hospital Maastricht University Hospital Nijmegen Dr. Daniel den Hoed Cancer Center, Rotterdam University Medical Center Utrecht Servizio Oncologico Cantonale, Bellinzona Royal Marsden Hospital, London Hospital Ramon y Cajal, Madrid Groupe d'Etude des Lymphomes Digestifs (national cooperative group) Groupe d'Etude des Lymphomes de l'Adulte (national cooperative group) University of Vienna, Vienna University Hospital Gasthuisberg, Leuven National Institutes of Health, Bethesda, MD Massachusetts General Hospital, Boston, MA M.D. Anderson Cancer Center, Houston, TX Stanford University, Stanford, CAa Nagoya University School of Medicine, Nagoya

a Only contribution on pathological items available, no clinical information from the center (cases only seen in consultation).

Methods Between November 1996 and July 1997. questionnaires with formatted items on surgical pathology, diagnostic work-up, therapeutic regimens and follow-up were mailed to all University Hospitals in the Netherlands and to leading groups of clinicians and pathologists with an active interest in the management of gastric MALT-NHL in Europe, the United States and Japan as reflected by contributions to leading medical journals and international meetings. Whenever possible, pathologists

Results

Nineteen centres agreed to co-operate in this effort; seven of the University Hospitals and Cancer Centres in the Netherlands, including the Netherlands Cancer Institute, seven centres in six European countries, four in the United States and one in Japan (Table 2). In spite of interest and enthusiasm, several of the approached centres had to decline their contribution because the management of gastric lymphoma patients could not be considered a multidisciplinary and structured effort in their institutes. In several Institutes, cases were only seen in consultation by surgical pathologists without further follow-up information. Surgical pathology Material

All contributors agreed on a minimum quality of the endoscopical biopsy samples. No specific minimum number of samples could be given, provided the samples were of adequate quality and were representative of the dominant lesion. Ten of nineteen contributors also required biopsy samples of macroscopically normal mucosa as a routine to asses the extent of the disease and to evaluate the presence of tumor components of diverging malignancy grade (especially LG components in predominantly transformed disease). Gastric resection as a diagnostic procedure was not considered, although one centre used this as a diagnostic option in case of repeatedly inconclusive biopsies. Minimum criteria All contributors agreed on the morphological characteristics of LG MALT-NHL as defined by a monotonous infiltrate of small to medium-sized lymphoid cells with a variable component of plasma cells. Four centres specifically stated the routine use of the diagnostic classification system of Wotherspoon and Isaacson into five grades of suspicion [7]. The mandatory requirement of lympho-epithelial lesions (LEL) in LG MALT-NHL and of the demonstration of monoclonality as minimum criteria were a matter of controversy (Table 3). Five of nineteen contributors explicitly stated that the diagnosis of gastric MALT-NHL is a morphological decision that may be supported by but is not dependent on additional techniques. Ten of nineteen contributors considered the presence of LEL an absolute requirement for the diagnosis. Nine of nineteen centres routinely used immunohistochemistry to demonstrate monoclonality as a minimum criterion. Four of these required fresh frozen material for immunofluorescence as a routine. Additionally, 8 of 19 centres used the demonstration of monoclonality in

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Therapeutic regimens H. pylori eradication

CT-scan Laboratory studies Bone marrow examination Endosonography Additional Gl-studies ENT-examination

and clinicians, including gastroenterologists, oncologists, haematologists, radiation therapists and surgeons were approached as a team. The subjects covered in the questionnaire are summarised in Table 1. Enrolment as a contributor was closed in December 1997.

277 Table 3. Diagnostic criteria for gastric MALT-NHL in endoscopical biopsy samples. Presence of LEL mandatory

Monoclonality

Grading

Routinely

Selected Cases

IHC PCR

IHC

General Minor possicompobility nents reported

PCR

1 2 3 4

_

5

difficult or morphologically equivocal cases (class 3 and 4 according to Wotherspoon and Isaacson). The same laboratories also considered immunoglobulin heavy chain gene PCR (and in one case also Southern blot) adequate to confirm monoclonality in these cases. No laboratory included molecular techniques in routine practice, but did include PCR in follow-up in clinical trials and formalised therapeutic protocols. For transformed MALT-NHL, irrespective of the use of the terminology of 'HG MALT-NHL' or 'DLBCL as transformation of MALT-NHL', sheets of blasts outside the context of germinal centres were required. LEL were not considered to play a role in the diagnosis of transformed MALT-NHL. Although several contributors stated that grading on the basis of endoscopical biopsies may be difficult, 16 of 19 considered this usually feasible and valuable in terms of consequences for clinical management. Minor components of diverging histological grade were considered to be more difficult to appreciate, especially in the absence of well-defined criteria. In 11 of 19 centres minor components of diverging malignancy grade were separately reported, although not always with consequences for therapeutic management.

Standard lymphoma Staging protocol staging (;i = 8) or no including Gl-tract full staging (n = 4) evaluation (n = 7) Only stage I treated with H. pylori eradication Stage I and II1 treated

9

3

with H. pylori

eradication

3

4

Diagnostic work-up All contributors agreed upon the requirement of full standardised staging as used for malignant lymphoma in general, including routine laboratory tests, chest CT and/or radiography, abdominal CT and bone marrow biopsy and/or aspiration. The evaluation of the local extent of the disease and of the specific aspects of dissemination differed significantly. Eight of seventeen contributors reported the routine use of endoscopical ultrasound (EUS) in addition to abdominal CT-scanning. Moreover, 5 of 18 contributors evaluated the status of the upper Gl-tract using radiological techniques (upper GI- and small bowel series), three of these contributors and two others included colonoscopy with biopsies in the routine staging protocol. Eight of eighteen included an ear-nose-throat (ENT)-examination with or without standardised biopsies. Taken together, 7 of 18 contributors used a standard staging protocol for lymphoma patients without any additional techniques to specifically evaluate the stomach wall and the rest of the gastrointestinal tract. Eleven of eighteen contributors used additional techniques to evaluate the gastro-intestinal tract, of which seven used very extensive protocols as a routine. Bulky disease was defined by 9 of 17 contributors with slightly varying criteria, but consensus was found in a diameter > 10 cm. In two cases, however, no consequences for therapy choice followed. None of the contributors explicitly state the influence of horizontal tumour extent in the stomach as a criterion for tumour bulk. Therapeutic regimens

H. pylori eradication All contributors used H. pylori eradication as monotherapy in LG MALT-NHL with disease limited to the gastric wall (stage I). Eight of nineteen centres also H. pylori treated patients with stage IIi disease with perigastric H. pylori was usually considered to be adequately recog- node involvement. Four centres did not require full stagnised in routine HE staining. Fifteen of nineteen labo- ing (according to their local staging protocols) before ratories used Giemsa, cresol-violet and thiazine staining embarking on H. pylori eradication therapy. The extenas an adjunct. In selected cases, usually in the context of siveness of the staging protocol used in the centre was H. pylori eradication as primary therapeutic approach, not directly related to the decision to include stage II patients in H. pylori eradication protocols (Table 4). The immunohistochmistry was added in six centres.

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The Netherlands 1 + 2 + 3 + 4 5 + 6 7 + European centers 1 2 3 + 4 + 5 + 6 + 7 + Non-European centers

Table 4. Relation of extent of the standard staging protocol to the decision to treat stage II disease LG MALT-NHL with H. pylon eradication as monotherapy (numbers indicate the number of centers).

278 Table 5. Strategies in H pylori eradication protocols. GE/ oncology oriented

5 6

O GE

7 GE Non-European centers 1 GE 2 GE 3 O 4 O 5 NA

Time to treatment failure (months)

Treatment after failure

++ + + ++ ++ + +

18 6-9 9 6-9 6-9 6 3

RT CT RT RT RT

+++ + + +++

12-18

S CT

+++ +++

6 12

CT

+++

12

S

-

+ +++ + + NA

12 2 NA 12 NA

CT

_ + + NA

6 18 8

S + RT RT

S + CT SorRT (trial) SorCT (trial)

S±CT NA RT NA

H. pylori

eradication as adjuvant + _ + + + +

Abbreviations: GE - center primarily headed by gastroenterologists; O - center primarily headed by oncologists/hematologists; CT chemotherapy; RT - radiation therapy; S - surgery (gastric resection); NA - no information available. a Staging: + - standard lymphoma staging, ++ - standard lymphoma staging + endoscopic ultrasound studies, +++ - standard lymphoma staging + full gastro-intestinal tract evaluation.

frequency of follow-up endoscopies did not differ essentially between centres with a frequency of every three months to every six months after reaching a complete remission. Interestingly, all contributors reported a far more extensive biopsy protocol during follow-up as compared to the requirements for the initial diagnostic endoscopies. Contributors reported a wide variation in time to treatment failure (TTF), i.e., the interval after successful eradication of H. pylori after which the disease is considered not to respond to antibiotic treatment; two centers decided within three months of follow-up, eight at six months of follow-up with an extension to nine months in four of these, six after twelve months of follow-up and three centers followed the patients for more than twelve months up to eighteen months (Table 5). Treatment after failure When it was concluded that H. pylori eradication as anti-lymphoma treatment was not successful, a choice between different classical anti-cancer treatments including chemotherapy, radiation therapy and surgery as monotherapy or a combination of these modalities can be made (Table 5). The centers in the Netherlands in

Other therapeutic regimens Patients who could not be included in H. pylori eradication protocols on the basis of histological grade, stage and/or tumour bulk according to the inclusion criteria in the centres, were in all cases treated according to standard therapeutical protocols for nodal non-Hodgkin's lymphomas. In 6 of 16 centres gastric resection was included in combination with chemotherapy or radiation therapy. Five of these were gastroenterology-oriented groups. Seven of eighteen centres also treated the H. pylori infection in addition to 'classical' anti-lymphoma treatment.

Discussion Although gastric MALT-NHL is a biologically and clinically extensively studied disease, there are many points of controversy [11]. Differences in the criteria for the diagnosis, the extent of the staging procedures and in the treatment modalities all have an influence on the final outcome in patient series [12]. The effects are not always fully predictable, precluding meaningful comparison of the data. Some controversies are inherent to the special character of the disease. Gastric MALT-NHL is thought to develop from a precursor phase of H. pylori related follicular gastritis. Accumulation of genetic alterations results in a gradual transition of a fully immunologically regulated process into an autonomously proliferating disease [11, 13]. The situation that is recognised as LG MALT-NHL can be successfully treated by eradication of H. pylori and therefore can not be considered as a fully autonomously proliferating phase. Based on morphological criteria, the dividing line between H. pylori related gastritis with suspicious lymphoid infiltrates (i.e., scores 3-4 of the diagnostic classification system of Wotherspoon and Isaacson [7] and LG MALT-NHL is not a sharp one and the criteria for the distinction are inherently arbitrary. The minimum criteria for the diagnosis of LG MALT-NHL of the contributors in this study varied between very strict, requiring the presence of lympho-epithelial lesions as well as proven monoclonality to more liberal, based on morphological cri-

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The Netherlands 1 GE 2 O 3 O 4 O 5 O 6 O 7 O European centers 1 GE 2 O 3 O 4 GE

Staging3

general preferred radiation therapy as monotherapy as their first choice (five of seven centres), whereas other centres rather preferred (partial) gastric resection and/ or chemotherapy, including chlorambucil or CVP. In two centres patients were entered in clinical trials that included a randomisation for chemotherapy versus gastric resection and radiation therapy versus gastric resection respectively. Interestingly, hematologically oriented groups preferred conservative treatment (8 of 10), in contrast to gastroenterology-oriented groups which were more inclined to choose a surgical approach with or without additional radiation therapy or chemotherapy (five of seven).

279

Since gastric MALT-NHL is at the cross-roads of the expertise of gastroenterologists, haematologists and medical oncologists, the approach to the management of patients may be expected to differ according to the primary responsible specialist group in the centers. This is reflected in staging protocols as well as in preferences in treatment. In centres with medical oncologists and haematologists as the primary responsible physicians in the management of gastric MALT-NHL patients, more often a work-up as for nodal NHL is done. On the other hand, when gastroenterologists are reported as the primary responsible group, extensive evaluation of the complete gastrointestinal tract is done. Apart from traditional reasons, the rationale for this approach may be found in the characteristic dissemination pattern of primary extranodal lymphomas to other extranodal sites [17]. Although the yield may probably be not very high, this approach results in relative 'up-staging' and an increased frequency of stage IV disease. Endoscopic ultrasound examination is generally considered to be the most sensitive and accurate method to determine the local extent of the disease [17] and is performed by centres from both sides of experitise. Interestingly, the extensiveness of the staging protocol does not influence the centres choice to include stage IIi patients in H. pylori eradication protocols, although it does influence patient selection. As expected, the time that patients are followed after successful H. pylori eradication before this anti-cancer treatment is considered to be not effective varies considerably. In general, follow-up was reported to be at least 6 months with the majority of the contributors waiting for 12 months or more. Far more extensive biopsy protocols were reported for follow-up than for making the initial diagnosis. This may be partially due to the disappearance of dominant lesions to be preferentially

biopsied during treatment urging for a more extensive protocol of random biopsies. The result may be, that sampling error is avoided and the chance to recognise minor foci of transformation to HG disease is increased. The treatment that is chosen after failure of//, pylori eradication as anti-lymphoma treatment is again dependent on the expertise of the primary responsible specialist group. Gastro-enterologists are far more inclined to perform a (partial) gastric resection (with or without additional radiation therapy or chemotherapy) than haematologists and medical oncologists. A tradition-driven parallel line of thinking to the one in the major patient groups seen by these specialists, gastric carcinoma versus nodal lymphoma, is obvious. Interestingly, the majority of the Dutch centres show a preference for stomach-conserving therapy using radiation therapy (five of seven) in contrast to centres in the other European and non-European countries. This may be well explained by the long experience with radiation therapy in gastric lymphoma in the Netherlands Cancer Institute and a very strong national advocate of this approach. Thus far, series reported in the literature indicate no significant differences in treatment outcome between the different strategies [10, 19-21]. Differences may be mainly expected in short term and long term complications. The results of this survey expose the variations in diagnostic criteria, work-up and treatment protocols in gastric MALT-NHL and indicate the basis for the decisions that result in different approaches in the management of gastric MALT-NHL. Awareness of these effects for patient selection and for treatment outcome may help in the design of future clinical trials.

Acknowledgements We would like to thank the pathologists, gastroenterologists, oncologists, haematologists, radiation therapists and surgeons from the 19 contributory centers for their careful effort infillingin the questionnaires and for their stimulating discussion in analysing the results and preparing this manuscript; Drs. P.M. Kluin, J.C. KJuinNelemans, E.M. Noordijk (Leiden, The Netherlands); M.J.J.T. Bogman, J.M.M. Raemaekers (Nijmegen, The Netherlands); S.C. Henzen-Logmans (Rotterdam, The Netherlands); A. Hagenbeek (Rotterdam, The Netherlands, presently Utrecht); F.J. Bot, H.C. Schouten (Maastricht, The Netherlands); C.J.L.M. Meijer, P. Huijgens (Amsterdam, The Netherlands); A. Dekker, D.M.D.S. Sie-Go (Utrecht, The Netherlands); A. Ruskone-Fourmestraux, A. Lavergne, N. Brousse (Paris, France); T. Nagasaka, M. Shimodaira, T. Nakamura (Nagoya, Japan); R.A. Warnke (Stanford, USA); E. Jaffe (Bethesda, USA); N.L. Harris (Boston USA); E. Zucca, E. Roggero (Bellinzona, Switzerland); C. Bellas, C. Montalban (Madrid, Spain); B. Dragosics (Vienna, Austria); D.Y. Graham, R.M. Genta, F. Cabanillas (Houston, USA);

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teria alone. This choice is not a matter of biologically based truth, but rather of putting an arbitrary line in a grey zone [14-16]. The different opinions on the minimum criteria for the diagnosis of LG MALT-NHL, however, do result in an essentially different patient selection in H. pylori eradication protocols for LG MALT-NHL and will therefore bias treatment outcome. Very strict criteria will select for a somewhat more 'progressed' group of LG MALT-NHL. In contrast, liberal criteria will include cases that might be still called non-malignant gastritis by others. The R.E.A.L. Classification is based on disease-entities and appreciates morphological features that are highly characteristic of distinct entities to help making the diagnosis [1]. Using these additional features, pathologists may not have to rely as heavily on the demonstration of monoclonality as a single decisive argument for malignancy as in other classification systems. Interestingly, in this survey leading advocates of the R.E.A.L. approach only use the demonstration of monoclonality in difficult and equivocal cases, while contributors who are more used to the Rappaport/ Working Formulation approach include the demonstration of monoclonality as a routine.

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Received 5 November 1998, accepted 23 December 1998. Correspondence to: D. deJong, MD, PhD Department of Pathology The Netherlands Cancer Institute Plesmanlaan 121 1066 CX Amsterdam The Netherlands E-mail. djong(gnki.nl

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