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© 2001 American Society for Clinical Oncology Primary Gastrointestinal Non-Hodgkin’s Lymphoma: I. Anatomic and Histologic Distribution, Clinical Features, and Survival Data of 371 Patients Registered in the German Multicenter Study GIT NHL 01/92ByFrom the Departments of Medicine, Hematology and Oncology, Radiation Oncology, and General Surgery, and Institute for Medical Informatics and Biomathematics, Westfälische-Wilhelms-Universität, Münster; Municipal Clinic, Department of Hematology/Oncology, and Pius-Hospital, Department of Radiooncology, Oldenburg; Department of Surgery, St-Antonius-Hospital, Kleve; Department of Medicine III–Großhadern, Ludwig-Maximilians-Universität, München; Department of Medicine/Gastroenterology and Oncology, Municipal Clinic, Dortmund; Departments of Medicine, Hematology and Oncology, and Radiation Oncology, Universität des Saarlands, Homburg; Departments of Gastroenterology and Radiation Oncology, Zentralklinikum, Augsburg; Department of Hematology/Oncology, Central Clinic, and Institute of Radiooncology, Minden; and Departments of Hematology/Oncology, Medical Clinic II, and Radiation Oncology, Christian-Albrechts-Universität, and Lymph Node Registry at the German Society of Pathology, Department of Hematopathology, Christian-Albrechts-Universität, Kiel, Germany. Address reprint requests to Peter Koch, MD, Medizinische Klinik A, Westfälische-Wilhelms-Universität, Albert-Schweitzer-Strasse 33, 48149 Münster, Germany; email: prfkoch{at}aol.com
PURPOSE: The study was initiated to obtain epidemiologic data and information on anatomic and histologic distribution, clinical features, and treatment results in patients with primary gastrointestinal non-Hodgkin’s lymphomas (PGI NHL). PATIENTS AND METHODS: Between October 1992 and November 1996, 371 PGI NHL patients were eligible to evaluate clinical features. Radiotherapy and chemotherapy were stratified according to histologic grading, stage, and whether surgery had been carried out or not. RESULTS: A total of 74.8% patients had gastric NHL (PGL). Within the intestine, the small bowel and the ileocecal region were involved in 8.6% and 7.0% of the cases, respectively. Multiple GI involvement (MGI) was 6.5%. Approximately 90% of the GI NHL were in stages IE/IIE. Aggressive NHL accounted for the majority, with a distinguishable pattern in several sites. Forty percent of PGL were of low-grade mucosa-associated lymphatic tissue type. One third of large-cell lymphomas had low-grade components. Most intestinal NHL were germinal-center lymphomas. The site of origin was prognostic. In gastric and ileocecal lymphoma, event-free (EFS) and overall survival (OS) were significantly higher as compared with the small intestine or MGI (median time of observation, 51 months). In PGL, localized disease was prognostic for EFS and OS. Histologic grade influenced only EFS significantly. Numbers in intestinal lymphomas were too small for subanalyses. CONCLUSION: PGI NHL are heterogeneous diseases. The number of localized PGL allowed for detailed analyses. Larger studies are needed for stages III and IV and for intestinal NHL. A uniform reporting system for PGI NHL, in terms of definitions and histologic and staging classifications, is needed to facilitate comparison of treatment results.
ALTHOUGH NUMEROUS reports have been published on primary gastrointestinal non-Hodgkin’s lymphoma (GI NHL), there remain many outstanding questions concerning its clinical features and the optimal method of treatment that have not been fully addressed over the years.1,2 The rarity of primary GI NHL (0.8 to 1.2 cases per 100,000 persons per year)3 lends itself to mainly retrospective studies reporting only small patient numbers or to studies that have been conducted over periods of up to two decades and more. These studies are often heterogeneous, combining different types of GI NHL and using varying histologic classifications, different staging systems, and different forms of treatment. There are at least two definitions of primary GI NHL in use. The one by Dawson et al4 is restricted to localized disease (stages IE, IIE), whereas that by Lewin et al5 requires that patients exhibit GI symptoms or predominant lesions in the GI tract. Several different histologic classifications have been published over the years, but for most studies on GI NHL, the Working Formulation or the Kiel classification have been applied.6,7 However, the mucosa-associated lymphatic tissue (MALT) concept published by Isaacson et al,8 which for the first time classified extranodal lymphomas, had not been widely used or was applied retrospectively during the last years. Although Musshoff’s modification of the Ann Arbor staging classification is applied in most series,9 special classifications for staging of primary gastric NHL were published and used by other authors.10-14 Treatment strategies in nodal NHL are well established, but there still remains much debate and controversy regarding the optimal approach in GI NHL, particularly in gastric lymphoma. Surgery, radiotherapy, and chemotherapy have been used alone or in various combinations.15-22 It was to answer some of the open questions that we initiated a prospective multicenter study to accrue a maximum number of patients within a time as short as possible to obtain epidemiologic data and information on anatomic and histologic distribution, clinical features, and treatment results for these diseases within a standardized diagnostic and therapeutic setting.
Patients From October 1992 through November 1996, every patient with a primary GI NHL reported in one of the participating centers (see Appendix) was considered eligible to evaluate the clinical features of this disease. Primary GI NHL were defined according to Lewin et al5: patients had to present GI symptoms of or predominant lesions in the GI tract. According to the study protocol for evaluation of treatment, patients who were older than 75 years and/or presented with second malignancies, had missing confirmation of histologic subtype by central review, or had comorbidity prohibiting therapy were excluded from study. For evaluation of histologic and clinical features, these patients were included.
Diagnostic and Staging Procedures Formalin-fixed specimens were reviewed by the central pathologic board of the study (M.T. and R.P.) according to the classification by Isaacson et al23 and the revised Kiel classification.7 Each biopsy was investigated immunohistochemically by staining for CD20 and CD3. Additionally, marginal-zone phenotype was proven by Ki-B3. Polymerase chain reaction–based amplifications of genes for immunoglobulin heavy chain or T-cell receptor gamma chain were added to show monoclonal disease. Patients were staged according to the Ann Arbor classification in its modification by Musshoff.9 In cases of tumor resection, the extent was analyzed retrospectively by two of the authors (B.R. and J.B.) based on operating sheets and histopathologic certificates according to the International Union Against Cancer.24
Study Design and Treatment Strategy It was, therefore, left to the participating center to decide whether therapy included surgery and conservative management or conservative management only. Especially for gastric lymphoma, this decision was made for all patients at each center, although patients whose stomach was resected and who were referred afterwards to a study center were also reported by the participating clinics, and their data were included in the study. Protocol radiotherapy and/or chemotherapy was obligatory and stratified according to histologic grading, stage of disease, and whether surgery had been carried out as follows: Low-grade lymphoma. After resection, patients in stages IE and IIE were treatd by extended-field radiotherapy (EF Rx) with total-abdominal irradiation (30 Gy) and, in case of residual tumor, by an additional boost (10 Gy). Patients in stages IIIE and IVE without symptoms after surgery were monitored. Without resection, patients in stages IE and IIE received EF Rx (30 Gy + 10 Gy boost). In addition, for patients with stage IIE disease, six cycles of COP (cyclophosphamide 500 mg/m2 on days 1 to 5; vincristine 1.4 mg/m2 [maximum, 2 mg] on day 1; prednisone 100 mg/m2 on days 1 to 5)25 preceded Rx for reduction of tumor load. For patients in stages IIIE and IVE, remission induction was strived for by chemotherapy alone (COP, six cycles). High-grade NHL (including all T-cell lymphoma, but excluding lymphoblastic and Burkitt’s lymphoma). Conservative treatment was unaffected by whether a resection had been performed or not. In stage IE, four cycles of CHOP (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 [maximum, 2 mg] each on day 1, plus prednisone 100 mg on days 1 to 5)26 were followed by EF Rx (30 Gy + 10 Gy boost on tumor or residue). Patients in stages IIE-IVE received six cycles of CHOP and additional involved-field (IF) Rx (40 Gy). Patients with lymphoblastic/Burkitt’s NHL were treated according to the protocol of the German Multicentre Acute Lymphoblastic Leukemia Group.27 Written informed consent was obtained from all patients, and the study was approved by the Ethics Committee of the University of Münster. The recruitment period of the study started in October 1992 and ended in November 1996.
Follow-Up and Statistical Analysis Survival was measured from the first day of treatment, and end points were defined as follows28: event-free survival (EFS; patients in complete or partial remission) was measured until any failure or death from any cause; overall survival (OS; all patients) was measured until death from any cause. Patients in remission or alive depending on the kind of survival analysis were censored at the last known date of follow-up evaluation and shown as tick marks on the survival curves. Survival fractions were calculated using the Kaplan-Meier product-limit method. For comparing survival curves, the log-rank test was used. P values were two-tailed. GraphPad Prism, version 3.0 (GraphPad Software, Inc, San Diego, CA), was used as software.
Patient Characteristics From October 1992 through November 1996, 371 patients with primary GI NHL were accrued to the study and treated according to protocol by medical, surgical, and/or radiotherapeutic departments throughout Germany (see Appendix). To define the site of origin in GI NHL, we distinguished first of all between gastric and intestinal lymphomas. Although we also anticipated primary NHL originating in the esophagus and the oral cavity, none of these were diagnosed among patients registered within the study. Intestinal lymphomas were subdivided as follows: (1) duodenum, (2) small bowel, (3) ileocecal region, defined as involvement of terminal ileum, cecum, appendix, and/or lower part of colon ascendens, (4) colon, and (5) rectum. We considered the ileocecal region and the rectum as separate sites, because they allow localized treatment in curative intention by localized Rx or resection, which we considered as being important, especially in low-grade NHL. Besides gastric and intestinal lymphomas, a third group was distinguished that included patients whose NHL was diagnosed simultaneously at several GI sites (n = 24). This group showed a very heterogeneous pattern in its presentation, with combinations of up to five regions, including the oral cavity. Additional involvement of lymph nodes occurred in only half of the patients (12 of 24), and involvement of non-GI sites occurred in seven of 24 cases. Simultaneous diagnosis of gastric and duodenal NHL was not considered as multiple GI involvement but as continuous growth from the stomach. Four main sites of origin for GI NHL could be distinguished at diagnosis (Table 1). The most frequent location was the stomach (74.7%). The second largest group was lymphoma originating in the small bowel (8.6%), followed by those of the ileocecal region (7.0%). Isolated involvement of the duodenum was very scarce (three of 371). The same applies to diffuse lymphoma of the colon (three of 371). If growth was localized, it originated in the rectum (six of 371). Multiple GI involvement as defined above occurred in 6.5% of the cases.
Pain was the main diagnostic symptom in most cases, followed by loss of appetite in both gastric and intestinal lymphoma (range, 78% [stomach] to 53.3% [multiple GI involvement]). Constipation and ileus were the second most frequent diagnostic symptoms for the intestine when combined as signs of occlusion. Occult loss of blood or macroscopic bleeding was most frequent when the stomach or the ileocecal region were involved. Perforation was scarce (1.8% in gastric and 9.4% in NHL of the small intestine). "B" symptoms occurred in a range from 11.9% (stomach) to 25% (multiple GI sites). Loss of weight was not rated as such but considered as caused by the lymphoma. Median time from onset of symptoms to diagnosis was the shortest for ileocecal lymphoma (76 days) and longest for multiple GI involvement (142 days) (Table 2).
The clinical features of all patients are listed in Table 3. There was just a slight predominance of the male sex for gastric lymphoma (1.1:1) as compared with NHL of the small intestine (1.9:1) and especially those of the ileocecal region (2.7:1). The median age differed little in patients with gastric or small intestinal lymphoma (61.2 and 62.3 years, respectively), but was markedly lower for cases with ileocecal NHL (48.7 years). This group also had the highest performance status (94% with Karnofsky performance score  90), which was also high in the total patient population (70% with Karnofsky performance score 90). Lactate dehydrogenase level, which is an important prognostic factor at least in high-grade nodal NHL, was elevated in approximately 20% of all patients.
GI NHL as such can be considered as a localized disease, with the exception of multiple GI involvement (Table 2). Stages III and IV were a minority of approximately 10% in the major sites. Lymphomas of the duodenum, colon, and rectum were localized in most cases (stage IE, 7 of 12; II1E, four of 12; II2E, one of 12). A slight tendency for higher spread could be noticed in NHL of the small bowel, which were predominantly in stages II1E and II2E compared with gastric and ileocecal lymphoma, of which more than 70% were diagnosed in the very localized stages IE and II1E. Lymphomas originating from more than one GI site do not fit into Musshoff’s classification other than stage IVE and must normally be considered as a generalized disease, although some of them still qualified for local treatment such as surgery or radiotherapy. Involvement of nonlymphatic or non-GI sites occurred in 22 patients (stages IVE). In 50% of these cases, the histology was of low-grade MALT type. The most frequently involved site was the bone marrow (n = 12), followed by the liver (n = 8). In three cases, the lung was involved (Table 4).
Histologic Subtypes In general, clinically aggressive subtypes accounted for the majority of GI lymphoma (including Burkitt’s, lymphoblastic, and T-cell lymphomas). Only in the case of multiple GI involvement were indolent and aggressive NHL nearly equally distributed (Fig 1). A more differentiated analysis of histologic subtypes revealed a distinguishable pattern in the sites of involvement (Table 5).
In gastric lymphoma, 40% are of low-grade MALT type,23 which corresponds to the marginal-zone cell lymphoma in the Revised European-American Lymphoma classification.29 In one third of the high-grade gastric lymphomas, a simultaneous low-grade MALT-type component could be demonstrated. The significance of this feature and its histopathologic classification is a subject of debate,30 but it does indicate that these lymphomas also originate in the marginal zone (secondary high-grade). The proportion might be even higher, since in most cases, diagnosis was made in biopsies which do not necessarily contain both components. Without regard to the grading, MALT-type lymphomas are the representative subtype of gastric lymphoma. Low-grade non–MALT-type NHL (mantle-cell lymphoma) as well as Burkitt’s/lymphoblastic lymphoma were small in numbers (1.4% and 3.2%, respectively). In the intestinum, most NHL were classified as germinal-center lymphoma, although there was a distinct difference between the small bowel and the ileocecal region. There were no Burkitt’s and lymphoblastic NHL in the small bowel, whereas only one T-cell NHL occurred in the ileocecal region. Numbers of MALT-type lymphoma were small in both regions (Table 5). When multiple GI sites were involved, low-grade lymphoma, mostly of MALT type, had the highest frequency (56%). Approximately 50% of these high-grade NHL had a simultaneous low-grade MALT-type component, which is more than for gastric lymphomas.
Treatment
The MTO of the complete cohort was 51 months from the onset of treatment (range, 0 to 92 months). The median MTO of patients alive was 56 months (range, 10 to 92 months). The EFS and the OS of the patients in the four major groups of GI NHL are shown in Fig 2. For this analysis, neither histologic subtype nor treatment strategy has been taken into account for two reasons: (1) numbers in intestinal lymphomas are too small for subanalyses, and (2) subanalyses have been made for early stages in gastric NHL,31 in which neither histology nor treatment strategy had a significant influence on EFS and OS.
Gastric and ileocecal lymphoma showed a higher EFS and OS as compared with NHL of the small bowel (OS, P = .0001 and P = .0423, respectively) and when compared with the situation where multiple GI sites were involved (OS, P < .0001 and P = .0177, respectively), as shown in Fig 2. The survival proportions at 5 years are listed in Table 7. Reasons for treatment failures (events) in primary GI lymphoma are shown in detail in Table 8 for the four main sites of origin. An independent review (M. Engelhard, C. Tirier) considered 13 of 20 deaths to be related to treatment or late effects.
Results for patients with lymphomas originating in the remaining sites (duodenum, colon, or rectum) are only described because of small numbers. All four patients with rectal lymphoma reached a complete remission (CR), none experienced relapse, and all are alive between 60.4 and 68.4 months. One patient with NHL of the colon died of myocardial infarction after 49 days, the other was in an ongoing CR at 70.4 months. The patient with a lymphoma of the duodenum relapsed after 48.4 and died after 67.7 months. Considering the extent of disease, stage was prognostic in gastric lymphoma (Fig 3). EFS and OS in stages IE and IIE were significantly longer compared with stages IIIE and IVE (P = .0007 and P = .0160, respectively) (Fig 4). The median EFS in stages IIIE and IVE was reached after 65.8 months. Medians for EFS or OS were not reached in stage IE/IIE patients. With respect to treatment strategy, localized stages are analyzed in part II of this report.31
The grading of gastric lymphoma was not prognostic for OS (Fig 5). Regarding EFS only, high-grade lymphoma with low-grade components had a significantly worse outcome as compared with low-grade lymphoma (P = .0107). None of the patients with Burkitt’s/lymphoblastic lymphomas have experienced relapse.
We could not detect any influence of stage or histologic subtype in the intestinal NHL. This is due to the small numbers within the different sites of origin. In the NHL of the small bowel, the rate of treatment failures was almost equally distributed in each histologic subtype (approximately 50%). In the ileocecal region, there were just two low-grade NHL and one T-cell lymphoma, none of which relapsed, whereas the failure rate in high-grade and Burkitt’s/lymphoblastic NHL was approximately 20%. In lymphomas originating at multiples sites of the GI tract, seven of nine low-grade NHL relapsed as compared with four of seven high-grade NHL.
Primary GI lymphoma is a heterogeneous disease with regard to patients’ characteristics, stage, histologic subtypes, and treatment results, depending mostly on site of origin. Published major series differ between lymphomas originating in the stomach and the intestine. The latter is often subdivided into small bowel and colon (Table 9).5,12,15,16,20,32-36 The stomach is the main affected site, with a frequency ranging from 51.0% to 86% (mean, 59.8%), with the exception of two studies showing a lower frequency of gastric lymphoma (37.8%5 and 44.6%,16 respectively). The percentage for primary intestinal involvement reported in the literature varied accordingly (Table 10).
In our series of 371 patients registered prospectively, the stomach is the main site in approximately 75% of cases (Table 1), which is clearly higher than in other published series. The only other major prospective study reported 60.4%.15 Registry data ranged between 51.0% and 62.8%.33-36 A pathologic referral center reported the highest rate (86%), although only stages IE and IIE were considered.12 Single-institution data ranged from 37.8% to 56.4%.5,20,32 The difference between the reported series is difficult to interpret. The reasons could be manifold. All but one study15 were carried out retrospectively, and the period of recruitment ranged from 5 to 15 years (Table 9). Both facts suggest possible mechanisms of selection in the reported cohorts. This might even be true for registry data because of an increasing awareness of GI NHL in the histopathologic differential diagnosis such as cancer or pseudolymphoma as suggested by Radaszkiewicz et al.12 Selection by treatment intentions might also be of influence, as one author discussed for his series.16 In comparison with the policy of our study group, which offered the choice between surgical and organ-preserving treatment, a prospective study with the primary aim of resection will inevitably not register conservatively treated patients.15 This assumption is supported by our ongoing second study, in which the distribution of sites seems to be reproduced in the 393 patients registered so far. Again, the stomach was the primary site in 78% of the cases. Another factor that influences the reported rates for the different GI sites is whether children have been included in an analysis. Primary intestinal NHL is more frequent in patients younger than 18 years as compared with adults.1,33,34,36 In some series, simultaneous involvement of different GI sites is not reported as a separate entity.5,20,36 It therefore remains uncertain whether it was not diagnosed in the first place or was classified as primary gastric or primary intestinal lymphoma. This represents another reason for a possible variability in the stated rates for GI NHL. Within the lymphomas of the intestine, two main sites are distinguished in the literature, the small bowel and the colon. Further differentiation within these two groups is used very nonuniformly (Table 10). Subgroups of the small bowel referred to are the duodenum, jejunum, and ileum. In the colon, the rectum often is specified separately. In five of nine of the cited publications, the ileocecal region is distinguished from small bowel and colon, as we did in our analysis (Table 1). For these reasons, the rates of primary sites within the intestine vary considerably. This is especially noticeable for lymphoma of the ileocecal region. The data range from 6.9% in the largest series36 and 9.5% in the other study from Great Britain16 to 37.1% in our report. The range in the remainder of the cited publications is 20.3% to 30.4%. The main reason for these differences is probably a question of the definition of the ileocecal region, which is missing in most reports.
In our opinion it is important to define this region precisely and to distinguish it from the small bowel and the colon as a separate site, because our data show distinct differences in patients’ characteristics for this region (Table 3). Patients are of a younger age (median, 48.7 years) in combination with the best performance status (94.4% with Karnofsky performance score To describe the extent of the disease, most authors applied the Ann Arbor classification or its modification by Musshoff.9,37 Localized stages (IE, IIE) are predominant in gastric lymphoma. Two authors report 84% and 87%,15,32 which is comparable to our data (89%), whereas published registry data are lower (68%).34 The rate for localized intestinal lymphoma is slightly lower, with a range of 52% to 80%. Only one study states the distribution of stages in different sites of intestinal lymphoma32 and reports a percentage in localized disease (stages IE and IIE) of 78% for the small bowel and 80% for the ileocecal region comparable to our data (84% and 96%, respectively; Table 3). Just one study, which applied the Manchester staging system,10 published rates of less than 50% for the stomach as well as for the intestine.20 This is also in contrast to two other studies, which stated 73% and 71% for GI NHL in localized stages as a whole.16,35 The majority of gastrointestinal lymphoma is of high grading in all series, but the usage of different histologic classifications makes a comparison difficult, especially in intestinal lymphomas. So far, the classification by Isaacson et al23 has been used in only two publications,12,38 but both reports are restricted to localized gastric lymphoma and will be discussed in part II of this report.31 In the only published major prospective study, the Working Formulation had been applied primarily.15 After the study was closed, pathologic material was reviewed to identify lymphomas of MALT type, but published data were not very detailed. It was stated that 22 of 28 low-grade GI NHL were MALT type NHL and located in the stomach (40%), which is comparable to our data (Table 5). It was also stated, that in 18% of gastric high-grade NHL, a simultaneous low-grade component was found. In the retrospective analysis of the British National Lymphoma Investigation, the Working Formulation was used in most cases, but evidence of origin from MALT was found in 50% of gastric and in 27% of intestinal involvement.16 In our series of primary GI NHL, the site of origin was prognostic in the four major groups (Fig 2). MGI had the worst outcome, with a median survival of 37.4 months and a survival rate (SR) at 5 years of 46% (Table 7). This was 37% in the French series15 and was even poorer in the only other data published on MGI (median survival, 0.7 years; SR at 5 years, 7%).34 For primary NHL of the small intestine, the SR at 5 years was 56% in our study (Table 7) compared with 37% in another major series.20 Most publications have just stated an SR for all intestinal lymphomas together, with a range of 24% to 67%, which was 69.5% in our series and 67% the other prospective study.15 A more detailed analysis, concerning stage and histologic subtype, is impossible because of diverging definitions as mentioned above, small numbers in most series, and different histologic definitions. Gastric lymphomas have a comparatively good treatment outcome, although data vary again for the aforementioned reasons. Different treatment strategies make a differentiated analysis even more difficult. SRs at 5 years range between 48% and 55%, including all stages and histologic subtypes. The highest rates are reported from this study (82.6%) and by the French group (91%).15 Treatment results in localized stages (IE, IIE) in gastric lymphoma will be discussed in part II of this report.31 Extended disease (stage IIIE, IVE) is reported nonuniformly. Some authors34 apply the Lugano classification (which unites stages IIIE and IVE as stage IVE),13 include stage II2E in their definition of extended disease because treatment results are thought to be the same as in stages IIIE and IVE, and report that stage is prognostic (P = .0450) without stating a survival proportion. Otter et al33 report an SR at 5 years of 35% (stages IIIE and IVE); Morton et al16 state approximately 45%. In our series there is a high significance (P < .0001) comparing stages IE and II1E with stages II2E to IVE (SR at 5 years, 87.4% and 64.4%, respectively). Combining stages IIIE and IVE, the SR at 5 years is 66.8% (Fig 4). Some authors report SR in advanced disease, combining gastric and intestinal lymphomas.5,15,20,32,35 The stated rates range from 25% to 47%. Independent of the definitions of advanced disease, all but one study state a worse prognosis for this group of patients. Morton et al16 did not find a difference but discuss treatment selection as a possible cause. In summary, GI NHL is a heterogeneous disease depending on the site of origin within the GI tract, which is a prognostic factor as such. Primary gastric lymphoma is by far the largest group, which has its own distinct histopathologic and clinical features. Stage is the most important prognostic factor, with a significantly better survival for localized disease. The frequency of gastric lymphoma in stages IE and IIE allows an analysis of the treatment strategy concerning combined surgical and conservative versus conservative treatment alone, which is described in part II of this report.31 As for analysis of advanced disease in lymphoma of the stomach, as well as in intestinal NHL, larger numbers of patients are required. We therefore did not change the treatment strategy for these lymphomas in our ongoing second study (GIT NHL 02/96). In general, there is a demand for a standardized staging system. In our opinion, none of the existing classifications take into account the varying meaning of the suffix "E" describing invading growth as well as extranodal origin of NHL. Also, simultaneous origin at various sites mostly classified as stage IV cannot be compared with generalized lymphomas involving non-GI or nonlymphatic organs. Therefore, we had proposed to use the basic framework of the Ann Arbor classification,37 incorporating Musshoff’s subdivision of stage II9 and the one by Radaszkiewicz et al12 for stage I. The suffix "E" should be restricted to describe invading growth, whereas the suffix "X" was proposed for extranodal origin, followed by the information of the actual stage (eg, X[stomach]II). In case of simultaneous multiple primary GI involvement, the organs should be enumerated after the suffix "X" (eg, X[stomach, colon]II).39 Although the Revised European-American Lymphoma classification and the World Health Organization classification for the first time include extranodal lymphomas, the detailed subclassification of high-grade lymphoma of MALT type as published by Isaacson et al23 has not been taken into account as discussed earlier because of its clinical implications.40 The importance of a grading system is at hand if low-grade and high-grade components coexist in MALT-type lymphomas.30 In all reports, numbers of intestinal lymphoma are small. To allow better comparison, the different parts of the intestine should be clearly defined, which from our point of view is of importance especially for lymphoma of the ileocecal region, which seems to have a prognosis comparable to that of gastric lymphoma. Ileocecal NHL can be diagnosed by endoscopy, a fact raising the question of whether surgery is really necessary for cure. In conclusion, it seems that intestinal lymphomas had raised less interest in the past but should become the aim of prospective studies.
Zentralklinikum (K. Füger, A. Probst), Krankenhauszweckverband (G. Jaenke), Augsburg; Kreiskrankenhaus (D. Unverferth), Aurich; Stadtkrankenhaus (P. Dravoj), Bad Arolsen; Paracelsus Klinik (H. Hohl), Bad Ems; Evangelisches Krankenhaus (R. Zahn), Bad Gandersheim; Gemeinschaftspraxis (P. Harms), Bad Oeynhausen; Vinzenz -Palotti-Hospital (S. Korsten), Bergisch Gladbach; Universitätsklinikum Charité (K. Possinger, S. Koswig), Robert-Rössle-Klinik (T. Benter), Berlin; Franziskus Hospital (B. Angrick, F. Jentsch, J.O. Jost), Städtische Kliniken (M. Sure), Städtische Kliniken Rosenhöhe (U. Junge), Bielefeld; St Josefs-Hospital der Universitätskliniken (M. Kißler), Bochum; Malteser Krankenhaus (A. Löffler), Universitätsklinik (H. Vetter), Bonn; Marienhospital (E. Musch), Bottrop; Kreiskrankenhaus Großburgwedel (C. Schönborn), Burgwedel; St Elisabeth-Stift (R.D. Schopen), Damme; Städtische Kliniken (K.-H. Funke), Delmenhorst; Gemeinschaftspraxis (F.W. Kleinsorge), Detmold; Städtische Kliniken, (B. Theophil), St-Johannes-Hospital (H.-J. Pielken), Dortmund; St Johannes Hospital (M. Westerhausen), Duisburg; Medizinische Einrichtungen der Heinrich-Heine-Universität (K.A. Hartmann), Dominikus-Krankenhaus (V. Cautius), Evangelisches Krankenhaus (H. Neuhaus), Düsseldorf; Hans-Susemihl-Krankenhaus (H. Becker), Emden; St-Antonius-Hospital (R. Fuchs), Eschweiler; Universitätsklinikum (M. Engelhard), Essen; Evangelisches Krankenhaus (C. Tirier), Essen-Werden; Ev-luth Diakonissenanstalt (W. Staemmler), Malteser Krankenhaus St Franziskus-Hospital (J. Benk, H.-J. Brodersen, W. Neugebauer), Flensburg; Ev Diakoniekrankenhaus (U. Brand), Freiburg; Georg-August-Universität (C. Binder, H. Schmidberger), Göttingen; Ernst-Moritz-Arndt-Universitätsklinik (C. Hirt), Greifswald; St Elisabeth Hospital (W.M. Glöckner), Gütersloh; Allgemeines Krankenhaus Altona (F. Hagenmüller, D. Braumann), Allgemeines Krankenhaus St Georg (H.-P. Heilmann), Hamburg; St Marien-Hospital (R. Jany, P. Rohde), St Barbara-Klinik Heessen (W. Frontzek), Hamm; Henriettenstiftung (C. Grotjahn), Medizinische Hochschule (D. Peest), Hannover; Lungenklinik (B. Wahlers), Hemer; Kreiskrankenhaus (H. Behr, I. Czichowski-Vieweger), Herford; Gemeinschaftspraxis (V. Bendel), Hildesheim; Universitätskliniken des Saarlandes (R. Schmitz, C. Rübe), Homburg/Saar; St Ansgar Krankenhaus (E. Wilhelms), Höxter; Gem ökumenische Krankenhausgesellschaft (M. Niemöller, D. Schenk), Ibbenbüren; Städtisches Klinikum (M. Haag), Karlsruhe; Städtisches Klinikum (E.U. Steinhauer), Kurhessisches Diakonissenhaus (H.-J. Bröker), Kassel; Städtisches Krankenhaus (C. Pott), Christian-Albrechts-Universität (F. Gieseler, J. Schultze, B. Kremer), Kiel; Gemeinschaftspraxis (J. Heymanns), Koblenz; Universitätsklinik (M. Reiser), Evangelisches Krankenhaus Kalk (C. Pohl), St Elisabeth-Krankenhaus (J. Schönemann), Köln; Städtische Krankenanstalten (K. Becker, U. Skutta), Krankenhaus Maria-Hilf (U. Peters), Krefeld; Klinikum Lippe-Lemgo (H. Middeke, M. Schütz), Lemgo; Medizinische Universität (K. Weber, T. Feyerabend), Lübeck; Städtisches Klinikum (R. Jakobs, Th. Schnabel), Ludwigshafen; Johannes Gutenberg Universität (M. Thelen), Mainz; Klinikum der Philipps-Universität (I. Uebelacker, R. Engenhart-Cabillic), Marburg; Klinikum (H. Bodenstein), Radioonkologische Praxis (A. Junker), Minden; Krankenhaus Maria-Hilf (D. Kohl; I. Stapels), Mönchengladbach; Evangelisches Krankenhaus (J. Freise, D. Völzke), St Marien-Hospital (M. Schweickert), Mühlheim a. d. Ruhr; Universitätsklinik (P. Koch, G. Reinartz, J. Brockmann), St Franziskus-Hospital (H.A. Schmidt-Wilcke), Münster; Herz-Jesu-Krankenhaus (W. Wiegelmann), Münste-Hiltrup; Städtisches Krankenhaus (H. Appenrodt), Nettetal; Lukaskrankenhaus (W.D. Maier), Neuss; DRK-Krankenhaus (L. Heuser), Neuwied; Albert-Schweitzer-Krankenhaus (M. Wirth), Gemeinschaftspraxis (S. Detken), Northeim; Kreiskrankenhaus (W. Ebert), Nürtingen; Pius-Hospital (A. Temmesfeld, H. Klasen), Internistische Fachpraxis (H.-F. Hinrichs), Städtische Kliniken (F. del Valle, L. Müller, M. Schmidt-Lauber), Oldenburg; Paracelsus-Strahlenklinik (W. Wagner), Osnabrück; Paracelsus Krankenhaus Ruit (H. Gnann), Ostfildern; Brüderkrankenhaus St Josef (H. Keller), Paderborn; Knappschaftskrankenhaus (M. Maier), Püttlingen; Knappschafts-Krankenhaus (K.-A. Husemeyer, V. Schachinger), Recklinghausen; Jakobi-Krankenhaus (D. Bauer), Matthias-Spital (M. Lausen), Rheine; Kreiskrankenhaus (H.-H. Krause), Rinteln; Universitätsklinik (M. Freund, T. Libera), Klinikum Südstadt (P. Ketterer), Rostock; Winterbergkliniken (H. Liehr, H. Jacobs), Saarbrücken; Kreiskrankenhaus St Franziskus (K. Krause), Saarburg; Martin Luther Krankenhaus (G. Paetzmann), Internistische Fachpraxis (C. Petersen), Schleswig; St Marien-Krankenhaus (P. Fritz, E. Strunk), Siegen; Marienkrankenhaus (G. Schütte), Soest; St Lukas Klinik (K.H. Beckers), Solingen-Ohligs; Klinik Dr Hancken (A. Scherpe, C. Thiel), Stade; Kreiskrankenhaus (H.-G. Biedermann, M. Gluth-Stender), Traunstein; Krankenhaus der Barmherzigen Brüder (C.B. Kölbel), Mutterhaus der Borromäerinnen (R. Mahlberg, W. Dornoff), Trier; Kreiskrankenhaus (J. Popp), Vietach; Josephs-Hospital (H. Bauer), Warendorf; Kreiskrankenhaus (K. Heunisch), Weißenfels; and Heinrich-Braun-Krankenhaus (G. Schott, J. Stöltzner), Zwickau, Germany.
Supported in part by Hoffmann-LaRoche AG, Germany. We thank M. Engelhard, MD, and C. Tirier, MD (Essen), for their independent case review, R. Bongartz (Münster) for her secretarial assistance, and N. Eaton-Gray (Chagford, United Kingdom) for his help in preparing the manuscript.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
