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Primary gastrointestinal non-Hodgkin's lymphoma: a review of 175 British National Lymphoma Investigation cases.

A retrospective analysis was performed upon 175 patients with Non-Hodgkin's Lymphoma involving the gastrointestinal tract and entered into BNLI trials and studies between 1974-1988. Malignant histiocytosis of the intestine (MHI), which was present in 16 patients, was associated with a survival of less than 25% at 18 months, and probably accounted for the poor survival of patients with jejunal involvement. Histopathological evidence of tumour origin from mucosa-associated lymphoid tissue (MALT) was found in 50% of patients with gastric involvement and in 27% of those with intestinal involvement. The overall survival of the series as a whole was 44% at 10 years. Multivariate analysis identified evidence of tumour origin from MALT as the only factor to attain prognostic significance in patients with gastric involvement, and clinical stage and the presence of MHI as the only factors to attain prognostic significance in patients with intestinal involvement. It is suggested that there is a need for a large multicentre prospective study of GIT lymphoma.

Non-Hodgkin's lymphoma of the gastrointestinal tract (GIT) is rare, accounting for less than five per cent of all GIT malignancies (Loehr et al., 1969;Gupta et al., 1981). However, apart from the tonsil the GIT is the commonest site for extranodal lymphomas (Freeman et al., 1972;Gospodarowicz et al., 1987). The organisation and histological features of the lymphoid tissue in the GIT differs from that of peripheral lymph nodes, occurring in the form of mucosa associated lymphoid tissue (MALT) which has unique immuno-physiological characteristics. The lymphoid tissue of MALT may be a normal tissue component, as in the intestine; or it may be acquired as a consequence of an autoimmune or inflammatory disorder, as in the stomach (Isaacson et al., 1988;Dixon et al., 1988). Lymphomas of the GIT may therefore behave differently from primary nodal disease. Because of this, and also because of the difficulty in applying the standard staging classification, these lymphomas may require different management strategies to nodal NHL.
A retrospective analysis of patients entered into the various clinical trials and studies undertaken by the BNLI (British National Lymphoma Investigation) over 14 years is reported in this work, in an attempt to define the natural history of this group of lymphomas, identify prognostic factors, and evaluate the effects of therapy. This may help to define the questions that need to be addressed in future studies.

Methods
The series consisted of 175 patients with primary gastrointestinal (GI) NHL, namely those whose main presenting feature was related to the GI tract or in which the predominant lesion was clearly in the GI tract, who were entered into BNLI studies between 1974 and 1988. Diagnostic material was obtained either at laparotomy or by endoscopic biopsy. Patients received either full, partial, or no surgical resection, followed by either chemotherapy (CT), radiotherapy (RT), both of these modalities in combination (RT + CT), or no further treatment, according to the protocol of the time. Surgery was not always performed at the referral centre and operation details were unavailable for 42 patients. Data concerning pre-existing conditions (malabsorption, inflammatory bowel disease etc.) were too incomplete for meaningful analysis.
The histopathology of all patients was reviewed by two members the BNLI pathology panel (KAM,MHB), with the exception of 4 patients whose sections were unavailable for analysis. The analysis included histopathological subtyping and grading according to the BNLI classification (Bennett et al., 1974) and the Working Formulation (WF) (NCI., 1982). Especial emphasis was placed on the identification of lymphomas of the intestine with histological features typical of the entity described by Isaacson and Wright (1978) as a malignant histiocytosis of the intestine (MHI), and later demonstrated to be T-cell lymphoma (Isaacson et al., 1985), termed by some as enteropathy associated T-cell lymphoma. Special emphasis was also placed upon the identification of lymphomas with histological features typical of multiple lymphomatous polyposis (MLP: , and of lymphomas with histological features indicating an origin from mucosa-associated lymphoid tissue (MALT) (Isaacson et al., 1983;Isaacson & Wright, 1984;Isaacson, 1990); briefly, these were the presence of a superficial plasma cellrich zone, the presence of an irregular B-cell population termed centrocyte-like cells, and the occurrence of lymphoeopithelial lesions. Cases were classified as high grade MALT lymphoma when areas of confluent large cell cytology were found in association with other histological features typical of MALT lymphomas. MALT status was not evaluable in nine patients. In all cases of high grade T and B cell lymphoma cell lineage was confirmed by paraffin section immunocytochemistry for T-cell restricted antigens recognised by UCHLI (CD45RO; Norton et al., 1986), polyclonal CD3 (Mason et al., 1989), and by the B-cell restricted antigen recognised by L26 (CD20; Ishii et al., 1984;Mason et al., 1990).
Patients were staged according to the Ann Arbor classification (Crowther et al., 1982), and also where possible retrospectively according to the Manchester classification described by Blackledge et al. (1979). Patients were classified as stage 4 if disease was present in marrow, liver, lung, pleura, bone or other extranodal site in addition to disease in the stomach or intestine.
Survival was calculated by the life-table method, the curves including deaths from all causes, and statistical comparison of curves by means of the log-rank test as described by Peto et al (Peto et al., 1971). Multivariate analysis was performed 777 by the use of a stepwise proportional hazards model (Cox, 1972).

Patients characteristics
The age, sex, and stage distribution in the series, together with the frequency of mediastinal involvement, systemic 'B' symptoms, and abnormal haematological parameters are shown in Table I. The sites of GIT disease are shown in Table II. The stomach was involved in 45% of patients, the intestine in 54%, and both together in 1%. The most frequent sites of intestinal involvement were ileum (36%), jejunum, (21%), and colon (14%). Two separate intestinal entities were involved together in 11% of patients, (Ileum and caecum or colon = 9%, Jejunum and caecum or colon = 2%): it was uncertain from the data available as to whether spread by direct extension was involved.
The commonest mode of presentation was abdominal pain (38%) ( Table III).
Diagnosis was by laparotomy in 90% and by endoscopic biopsy in 10% of patients.
Complete surgical excision was performed in 63%, partial surgical excision in 16%, and biopsy alone in 21% of the 133 patients for whom details of surgery were available. The treatment given is shown in Table IV. CHOP was given to 57% of patients, Chlorambucil to 7%, RT to 15%, RT + COP to 7%; one patient received COP and one patient PACE BOM; 11% received surgery alone.
A comparison of characteristics between patients with gastric and patients with intestinal involvement showed that patients with intestinal involvement tended to be older, and to have a higher frequency of stage 4 disease and of low presentation lymphocyte counts, than patients with gastric involvement.    whole, and also on patients with gastric and intestinal in the series as a whole was involvement separately (Table IX). For the series as a whole, associated with NHL or its only stage and MALT status were significant prognostic xception of eight patients; of factors (P = 0.0009 and 0.01 respectively). For patients with es (four MI, one CVA), and gastric involvement, only MALT status was significant .s uncertain. Fifteen patients (P = 0.02); for patients with intestinal involvement, only I only RT, one only surgery: stage and the presence of MHI were significant (P = 0.001 d CT either as initial treat-and 0.006 respectively). ment (eight CHOP, four RT + COP) or as salvage therapy (one COP), and 12 were receiving CT at time of death (five CHOP, one BEAM, one COP, 2RT + COP, one Chlorambucil, two Mitoxantrone).
Prognostic factors On univariate analysis the most markedly significant factors related to overall survival were stage (P = 0.003) and MALT status (P = 0.004), with localised stage and evidence of tumour origin from MALT being associated with relatively high survival. There was no significant difference in survival between low and high grade MALT lymphoma (P> 0.4). There was however a significant difference in survival between high grade MALT lymphoma and diffuse large cell lymphoma (P < 0.04). There was no significant difference between the overall survival of patients with gastric and intestinal involvement. There was a significant difference in the survival of patients with different sites of intestinal involvement (P = 0.03), due mainly to the relatively high survival of patients whose GIT involvement was confined to the ileum and the poor survival of patients in whom it was confined to the jejunum. The survival of patients with MHI was very poor, being less than 25% at 18 months. The poor  Figure 3.

Discussion
The site, age, and sex distribution of the present series were similar to those described in previous reports (Loehr et al., 1969;Contreary et al., 1980;Herrman et al., 1980;Kaufman et al., 1984;Ampil, 1987;Kajanti et al., 1988), although some investigators found small gut involvement to be relatively more common (Blackledge et al., 1979;Makepeace et al., 1987;Baildam et al., 1989); in the present series this was possibly due to failure to refer patients with Stage IE/IIE gastric lymphoma who had undergone complete resection. As in other reports abdominal pain was the commonest presenting feature (Novak et al., 1979;Contreary et al., 1980;Herrmann et al., 1980;Kaufman et al., 1984;Rao et al., 1984;Bonadonna & Valagussa, 1986;Makepeace et al., 1987;Kajanti et al., 1988;List et al., 1988;Jones et al., 1988). Although comparisons of overall survival between different published series do not take account of differences in risk factors within the series, it is perhaps worth noting that the overall survival of 44% at 5 years in the present series compares favourably with previous reports, in which it ranges from 33% to 55% (Rao et al., 1984;Bonadonna & Valagussa, 1986;Ampil, 1987;Makepeace et al., 1987;Baildam et al., 1989).
For those patients with gastric involvement, 50% had histopathological evidence of tumour origin from MALT. This frequency of occurrence was of the same order as that reported by De las Heras et al. (1989) t.
--W; a a --: from that reported by Johnsson et al. (1990) (33%). The survival of these patients was significantly higher than those without evidence of tumour origin from MALT, as was also reported by De las Heras et al. (1989). The lack of any significant difference in survival between different stages of disease in patients with gastric involvement in the present series is surprising, particularly the low survival of patients with Stage IE disease. This may have been due to the difficulties inherent in staging extranodal lymphomas (Blackledge et al., 1979;Green et al., 1981;Crowther et al., 1982;Rao et al., 1984;Bonadonna & Valagussa, 1986;Cajozzo et al., 1987) by the Ann Arbor method, which the Manchester system was designed to circumvent. However no significant difference was found when either the Ann Arbor or the Manchester system was used, although it should be observed that the latter system was applied retrospectively. It is possible that the lack of any prognostic effect from stage in patients with gastric involvement and its strong prognostic effect found in patients with intestinal involvement may have been due to the different origins of lymphoid tissue, and hence histologic differences in the lymphomas arising in these two organs. However, treatment of patients in the series was preselected in respect of stage, with relatively aggressive treatment usually being given to patients with advanced stage, and less aggressive treatment given to those clinically localised disease. It is possible that this procedure effectively masked a prognostic effect of stage in patients with gastric involvement, though this remains unproven.
Patients received a wide range of treatments, depending on the BNLI protocols current at the time. Treatment groups available for comparison were small, and in many cases treatment was tailored to prognostic factors deemed to be important at the time, including histological grade, stage, and symptoms, thereby confounding the overall effects of therapy  Fiue h oeal uvva fpains ih T ndwtou N T )eidneofM I and making statistically valid inferences hazardous. Thus the relatively high survival of patients who received complete surgical resection alone, compared to the survival of those who received CHOP or chlorambucil in addition, was probably due to the high proportion of patients in the former group with evidence of MALT type gastric lymphoma, since the survival of such patients was high in the series overall. In general, it would appear that survival depended primarily upon whether the extranodal involvement was of the stomach or of the intestine, the stage of the patient, whether the tumour originated from mucosa associated lymphoid tissue, and whether the tumour was a malignant histiocytosis of the intestine. There is disagreement in the literature as to the need for surgical debulking. Those in favour of it argue that physical removal of as much tumour as possible reduces the risk of complications, such as haemorrhage or perforation, during subsequent chemotherapy or radiotherapy, as well as reducing the tumour load requiring treatment (Green et al., 1981;Paulson et al., 1983;Sheridan et al., 1985;Bonadonna & Valagussa, 1986;Ampil, 1987;List et al., 1988;Haber & Mayer, 1988;Baildam et al., 1989); whilst other investigators have argued that this is not the case (Herrman et al., 1980;Rao et al., 1984;Cajozzo et al., 1987;Gobbi et al., 1990). In the present series two patients perforated, both after having undergone radical surgery followed by chemotherapy. However three patients who were only biopsied experienced fatal haematemesis and melaena during subsequent chemotherapy. In addition, there was one post-operative death which occurred following major surgery. These results suggest that surgical debulking does not necessarily protect the patients from complications. There is also disagreement as to whether adjuvant therapy following complete excision is necessary (Lim et al., 1977;Herrmann et al., 1980;Gospodarowicz et al., 1983;Kaufman et al., 1984;Rao et al., 1984;Sheridan et al., 1985;Bonadonna & Valagussa, 1986;Kajanti et al., 1988;Jones et al., 1988;Haber & Mayer, 1988;Mentzer et al., 1988). It is of interest that in the present study, patients who received chemotherapy had a worrying incidence of side effects: of the 15 patients who died with infection, 12 were receiving chemotherapy at the time.
Individual centres see only small numbers of patients with GIT lymphoma over a long period, and there is therefore a need for a multicentre prospective study in order to create a database large enough for definitive analyses to be made in order to rationalise the treatment of such patients.