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Descriptive epidemiology of gastrointestinal non-Hodgkin’s lymphoma in a population-based registry

Descriptive epidemiology of gastrointestinal non-Hodgkin’s lymphoma in a population-based registry British Journal of Cancer (1999) 79(11/12), 1929–1934 © 1999 Cancer Research Campaign Article no. bjoc.1998.0307 Descriptive epidemiology of gastrointestinal non- HodgkinÕs lymphoma in a population-based registry KA Gurney, RA Cartwright and EA Gilman Leukaemia Research Fund Centre for Clinical Epidemiology, University of Leeds, 17 Springfield Mount, Leeds LS2 9NG, UK Summary The incidence of non-Hodgkin’s lymphoma (NHL), particularly at certain extranodal sites, has been demonstrated to be rising, at least in the USA, more than for any other malignancy. One of the major sites of extranodal NHL is the gastrointestinal tract, though little is known of its epidemiological characteristics. Over an 8-year period (1986 to 1993) 1069 primary gastrointestinal NHL cases were reported to the Leukaemia Research Fund Data Collection Survey which covers many parts of England and Wales. Age-standardized incidence rates of 5 5 5 5 gastrointestinal NHL at all sites (0.58/10 per year), gastric (0.24/10 per year), small bowel (0.17/10 per year) and large bowel (0.06/10 per year) confirmed that the UK has the lowest rates of gastrointestinal NHL in Europe. An excess of males was observed at all ages and for all sites. Time-trend analyses showed annual increases in incidence rates for gastric (6.3%) and small bowel (5.9%) NHL although a concomitant decrease in gastrointestinal NHL of unknown site suggested that at least part of these increases had resulted from more accurate diagnoses. Overall, the incidence of gastrointestinal NHL significantly increased by 2.7% per annum and was limited to the population aged over 50 years in this series. Keywords: epidemiology; non-Hodgkin’s lymphoma; gastrointestinal; time-trend analysis Most non-Hodgkin’s lymphoma (NHL) originates in the lymph MATERIALS AND METHODS nodes or other lymphoid tissues. However, a significant proportion The DCS is a specialist registry of lymphomas, leukaemias and of NHL has a primary extranodal site such as the gastrointestinal related disorders held by the Leukaemia Research Centre for tract, skin or central nervous system. Primary gastrointestinal Clinical Epidemiology in Leeds. This survey has been collecting NHL is the commonest extranodal localization, representing data since 1 January 1984, with the aim of providing high quality around one-third of all extranodal cases in most series (Zucca et al, data for population-based epidemiological studies (Cartwright et 1997). Recently it has been shown that incidence rates for NHL al, 1990). The geographical area of case collection covers approx- have been increasing for many years with this trend being more imately half of England and Wales. Newly diagnosed cases are prevalent in extranodal disease than in nodal NHL (Devesa and reported directly to Leeds from collaborating histopathologists and Fears, 1992; Zheng et al, 1992). It is, as yet, uncertain as to haematologists and registrations completed by trained data collec- whether this is a real increase or due to more efficient case regis- tion clerks. In addition, regular checks are made with NHS cancer tration and improved diagnoses although it has been suggested that registries for the areas concerned and any missed cases registered the increase in incidence rates for gastric lymphoma in the United after review. States is independent of coding and diagnostic procedures NHL cases were registered by the DCS only after histopatho- (Severson and Davis, 1990). logical review by a minimum of two histopathologists with a In 1984 the Leukaemia Research Fund began the Data specialist interest in lymphomas. Data from the DCS and the Collection Survey (DCS), a specialist population-based register cancer registries for the years 1989–93 were compared using log- covering neoplastic haematological diseases in parts of England linear models and case coverage for all NHL was estimated to be and Wales based on diagnoses from collaborating haematologists nearly 96% (Cartwright et al, 1997). and histopathologists. Data collected by this Survey have been Gastrointestinal NHL was defined as cases where the initial shown to be more accurate, as they reflect modern clinical and symptoms and predominant disease were confined to the gastro- haematopathological opinions, and more complete than compara- intestinal tract (Lewin et al, 1978) including the pancreas and tive National Health Service cancer registry data (Alexander et al, oesophagus. Cases with a gastrointestinal site discovered during 1989; Cartwright et al, 1997). staging or other clinical investigation of NHL and mesenteric This paper describes the epidemiology of gastrointestinal NHL localizations were excluded from the study. In accordance with and investigates the changes in incidence in gastric and other DCS criteria, cases were registered as primary gastrointestinal intestinal NHL in those areas of England and Wales covered by the NHL, after histopathological review with no evidence of nodal DCS from 1986 to 1993. involvement. The localization of gastrointestinal NHL was further classified Received 14 August 1998 into gastric, small bowel and large bowel NHL, and gastrointestinal Revised 16 October 1998 (GI) tract, site unknown, NHL by review of the histopathology Accepted 27 October 1998 reports. The gastric site comprised those cases where the disease Correspondence to: RA Cartwright was localized in the stomach or in the stomach and intestine. Small 1929 1930 KA Gurney et al Table 1 Age-standardized incidence rates and site distribution for gastrointestinal non-Hodgkin’s lymphoma, 1986–1993 Male Female Total a a a Rate Number % Rate Number % Rate Number % M:F Site of cases of cases of cases ratio Gastric 0.29 252 41.1 0.20 211 46.2 0.24 463 43.3 1.5 Small bowel 0.22 167 27.3 0.13 126 27.6 0.17 293 27.4 1.7 lleum 29 23 52 Duodenum 11 7 18 NOS 127 96 223 Large bowel 0.09 71 11.6 0.04 48 10.5 0.06 119 11.1 2.3 Rectum 25 18 43 Colon 21 15 36 Caecum 20 9 29 NOS 5 6 11 Gl tract, site unknown 0.13 107 19.9 0.06 65 15.7 0.10 172 16.1 2.2 Gastrointestinal NOS 84 60 144 Intestine NOS 23 5 28 All sites 0.75 612 100.0 0.43 457 100.0 0.58 1069 100.0 1.7 a b Rate directly standardized to the World Standard population (cases/100 000/year). Includes gastrointestinal NHL with the primary site localized to the pancreas (n = 14) and oesophagus (n = 8). Table 2 Classification of gastrointestinal NHL by grade and age Age range Sex Low-grade High-grade T-cell All graded Unclassified Total (years) cases cases a b 0–14 M 0 11 (100.0%) 0 11 1 (8.3%) 12 F 0 1 (100.0%) 0 1 0 1 15–29 M 2 (10%) 16 (80.0%) 2 (10%) 20 1 (4.8%) 21 F 0 1 (50.0%) 0 1 1 (50.0%) 2 30–49 M 26 (36.6%) 40 (56.3%) 5 (7.1%) 71 9 (11.3%) 80 F 14 (35.0%) 24 (60.0%) 2 (5.0%) 40 10 (20.0%) 50 50–69 M 81 (37.0%) 117 (53.4%) 21 (9.6%) 219 47 (17.7%) 266 F 72 (45.3%) 76 (47.8%) 11 (6.9%) 159 34 (17.6%) 193 70+ M 76 (40.9%) 102 (54.8%) 8 (4.3%) 186 47 (20.2%) 233 F 53 (33.5%) 89 (56.3%) 16 (10.1%) 158 53 (25.1%) 211 a b % of all graded cases. % of total cases. bowel included duodenum, jejunum, ileum, ileo caecal junction method using the World Standard Population (Parkin et al, 1992) localizations and small intestine not otherwise specified. The large which required adjustment of the final age group to 85 years and bowel included appendix, caecum, colon, rectum localizations and older. Incidence trends were evaluated by Poisson regression large intestine not otherwise specified. A separate category of GI analysis over the full age range for all gastrointestinal NHL and tract, site unknown, NHL included cases where the primary site had for the individual sites. Incidence trends were also investigated, not been recorded and cases where the site was reported as where sufficient data were available, using four age ranges (0–29, intestinal or gastrointestinal with no further details. 30–49, 50–69 and 70+ years) to examine in more detail whether Gastrointestinal NHL was classified according to the updated changes in incidence rates were more prominent in some age Kiel classification and graded as either low- or high-grade malig- groups than in others. nancy (Stansfeld et al, 1988). This study was based on all gastrointestinal NHL cases RESULTS diagnosed between 1 January 1986 and 31 December 1993 and reported to the DCS. Age-specific incidence rates were calculated Incidence of gastrointestinal NHL for males, females and both sexes combined for all gastrointestinal NHL, and individually for gastric, small bowel, large bowel sites A total of 1069 cases of gastrointestinal NHL were diagnosed and GI tract, site unknown. To calculate age-specific incidence during the years from January 1986 to December 1993. During rates, cases were grouped into 5-year age groups with the excep- this time, 11 334 cases of NHL were diagnosed within the popula- tion of the final group which was 90 years and older. To facilitate tion covered by the Data Collection Survey, thus the gastro- geographical comparisons, rates were standardized by the direct intestinal NHL cases represented 9.43% of all NHL cases. British Journal of Cancer (1999) 79(11/12), 1929–1934 © Cancer Research Campaign 1999 Epidemiology of gastrointestinal NHL 1931 Table 3 Histological classification of gastrointestinal NHL for individual sites Histology Gastric Small bowel Large bowel Gl tract, site unknown Low grade 153 75 35 54 (43.3%) (30.4%) (33.0%) (33.8%) Lymphoplasmacytoid 10 4 3 4 Centrocytic 18 12 13 8 Centroblastic-centrocytic, follicular 28 19 5 8 Centroblastic-centrocytic, follicular and diffuse 6 9 1 6 Centroblastic-centrocytic, diffuse 31 14 5 16 Low grade, unclassified 60 17 8 12 High grade 191 131 62 81 (54.1%) (53.0%) (58.5%) (50.6%) Centroblastic 75 38 21 26 Lymphoblastic, Burkitt’s type 0 3 3 3 Lymphoblastic, convoluted cell 1 0 0 0 Lymphoblastic, other/unclassified 6 5 2 7 Immunoblastic 11 12 11 10 Histiocytic lymphoma 10 11 6 4 High grade, unclassified 88 62 19 31 T-cell lymphoma NOS 9 41 9 6 (2.5%) (16.6%) (8.5%) (3.8%) All classified cases 353 247 106 141 (100%) (100%) (100%) (100%) Malignant lymphoma, unspecified grade (% of total cases) 110 46 13 31 (23.8%) (15.7%) (10.9%) (18.0%) Total cases 463 293 119 172 Age-standardized (World standard population) incidence rates A B 5.0 9.0 for all gastrointestinal NHL and by individual site are presented in 8.0 I 4.0 7.0 I Table 1. The overall age-standardized incidence rates for gastro- 6.0 I 3.0 5.0 intestinal NHL all sites combined were 0.75 per 100 000 and 0.43 1', I 4.0 I \I 2.0 ,~ per 100 000 for males and females respectively. Ages ranged 3.0 2.0 1.0 between 5 years 1 month and 95 years 9 months (mean = 64 years 1.0 0.0 0.0 10 months, median = 67 years 6 months). An excess in male incidence was found for all gastrointestinal NHL and for the indi- Age (years) Age (years) vidual sites ranging from a male:female ratio of 1.5:1 for gastric NHL to 2.3:1 for large bowel NHL. This excess in male cases was even more pronounced in children and young adults where 11 of 3.0 1.4 12 cases in the 0–14 age range and 21 of 23 cases in the 15–29 age 1.2 2.5 1.0 2.0 range were male (Table 2). 0.8 1.5 0.6 1.0 0.4 0.5 0.2 Site of gastrointestinal NHL 0.0 0.0 Table 1 also shows that the most common site of gastrointestinal NHL for all age groups was gastric (43.3%) followed by small Age (years) Age (years) bowel (27.4%), large bowel (11.1%) with a further 172 cases classified as GI tract, site unknown, NHL (16.1%). However, for 1.0 children and young adults (< 30 years) small bowel NHL was ' / I \ I 0.8 predominant (44.4%), then GI tract, site unknown (25.0%), gastric 0.6 " (16.7%) and large bowel (13.9%). 0.4 0.2 0.0 Histology of gastrointestinal NHL Age (years) Overall, most gastrointestinal NHL cases in this series were high- grade (44.5%), with 30.4% low-grade, 19.0% unclassified and Figure 1 Age-specific incidence rates, male (– – –), female (- - -) and 6.1% T-cell lymphomas. The distribution of histological subtypes combined (— —), for all gastrointestinal NHL (A), gastric NHL (B), small bowel among gastrointestinal sites is given in Table 3. Gastric NHL had a NHL (C), large bowel NHL (D) and Gl tract, site unknown, NHL (E) in parts of higher proportion of low-grade cases whereas intestinal NHL England and Wales, 1986–1993 © Cancer Research Campaign 1999 British Journal of Cancer (1999) 79(11/12), 1929–1934 Cases/100 000/year Cases/100 000/year Cases/100 000/year 0–4 0–4 0–4 10–14 10–14 10–14 20–24 20–24 20–24 30–34 30–34 30–34 40–44 40–44 40–44 50–54 50–54 50–54 60–64 60–64 60–64 70–74 70–74 70–74 80–84 80–84 80–84 90+ 90+ 90+ Cases/100 000/year Cases/100 000/year 0–4 0–4 10–14 10–14 20–24 20–24 30–34 30–34 40–44 40–44 50–54 50–54 60–64 60–64 70–74 70–74 80–84 80–84 90+ 90+ 1932 KA Gurney et al Table 4 Time trend analysis of incidence rates of gastrointestinal NHL in parts of England and Wales, 1986–1993 Annual change 95% confidence in incidence intervals All gastrointestinal NHL Males + 2.19% NS Females + 3.16% NS Total + 2.66% P = 0.047 0.03, 5.30 Gastric Males + 6.88% P = 0.014 1.34, 12.72 Females + 5.37% NS Total + 6.25% P = 0.003 2.16, 10.51 Small bowel Males + 5.65% NS Females + 6.08% NS Total + 5.87% P = 0.023 0.78, 11.23 Large bowel Males – 0.03% NS Females + 3.45% NS Total + 1.44% NS Gl tract, site unknown Males – 13.29% P = 0.001 – 5.31, – 20.61 Females – 11.68% P = 0.026 – 1.21, – 21.04 Total – 12.62% P < 0.001 – 6.36, – 18.47 (small and large bowel cases combined) tended to be high-grade. significant except for GI tract, site unknown, NHL. In males, Over 75% of T-cell lymphomas were found in intestinal NHL gastric and GI tract, site unknown, NHL incidence rates showed a cases. For all gastrointestinal NHL the most common histological significant increase and decrease respectively. subtype was centroblastic, accounting for nearly 20% of all classi- More detailed analyses of the increase in incidence rates from fied lymphomas. All childhood, and the majority of young adult, 1986 to 1993 for all gastrointestinal NHL revealed that significant gastrointestinal NHL cases were high-grade malignancies. In chil- increases were restricted to the older age groups (0–29 years, dren (0–14 years) most cases were lymphoblastic, Burkitt’s type, + 5.5%, NS; 30–49 years, – 2.6%, NS; 50–69 years, + 3.5%, P = but in the young adults (15–29 years) centroblastic was again 0.09; 70+ years, + 5.3%, P = 0.01; males and females combined). predominant. In adults (³ 30 years old) the distribution of high- This pattern was also seen for gastric NHL (70+ years, + 8.5%, grade, low-grade and T-cell gastrointestinal NHL were broadly P = 0.02). Analyses for other sites and age ranges were unreliable similar for each age range. due to small numbers of cases. Age-specific incidence curves by sex for all gastrointestinal Time trend analyses for low- and high-grade gastrointestinal NHL and by individual site are shown in Figure 1. Incidence rates NHL at all sites showed no significant changes for either of these for both sexes show broadly similar patterns for all sites of groups (low-grade disease showed an annual decrease of 1.7%, gastrointestinal NHL. Rates are very low for the under 30s then NS; high-grade disease showed an annual increase of 1.5%, NS; rapidly increase to a major peak around 80 ± 5 years of age, except males and females combined). However, cases with unspecified in large bowel NHL where this peak occurs over a narrower age grade showed an annual increase of 7.15%, P = 0.02 reflecting the range and GI tract, site unknown, NHL, where the age range is relatively high proportion of gastric and small bowel cases with rather broader. All sites appear to show a minor peak in age- unknown grade. specific incidence rates for the 55–60 year age group with the exception of GI tract, site unknown, NHL where the peak occurs DISCUSSION much earlier at 40–45 years of age. The majority of studies investigating the epidemiology of gastro- intestinal NHL have been based on studies using selective data with Change in incidence the exception of four north European population-based studies From 1986 to 1993, incidence of gastrointestinal NHL for both [Otter et al, 1989a (96 cases); D’Amore et al, 1994 (306 cases); sexes combined increased by 2.66% per annum (P = 0.047; 95% Halme et al, 1997 (61 cases); Ducreux et al, 1998 (78 cases)]. To CI, 0.03, 5.30) (Table 4). Over this time period the incidence of our knowledge, this study comprising 1069 cases represents the NHL classified as having a primary site in the stomach or small largest population-based series of gastrointestinal NHL. This, along bowel showed significant annual increases of 6.25% and 5.87%, with uniform and highly complete collection of data, are the main respectively whilst that of large bowel NHL remained stable. A strengths of the current study. The principal disadvantages are those highly significant annual decrease of 12.62% in the incidence of shared by similar studies in that it is not known whether all extra- GI tract, site unknown, NHL was also observed. Similar values for nodal disease has been included, the site may be vague in some annual increases and decreases were seen in males and females cases and it is not always possible to distinguish a nodal condition separately but for the female population these trends were not infiltrating into the bowel from primary bowel disease. British Journal of Cancer (1999) 79(11/12), 1929–1934 © Cancer Research Campaign 1999 Epidemiology of gastrointestinal NHL 1933 The incidence rates found in this study for gastrointestinal NHL common in intestinal disease. T-cell lymphomas were found in parts of England and Wales are lower than those reported by mostly in intestinal NHL cases as expected. previous population-based studies in France, central Finland and There have been several reports recently that the incidence of Denmark (D’Amore et al, 1994; Halme et al, 1997; Ducreux et al, NHL malignancies is increasing rapidly, primarily in the devel- 1998). This difference is more marked for gastric NHL, where oped countries, by between 3–5% per annum (Devesa and Fears, incidence is less than half that found in other European countries, 1992; McNally et al, 1997; Morgan et al, 1997) and that this than for intestinal NHL where the rates are more similar to those increase is seen more in extranodal disease than in nodal NHL reported. Incidence rates calculated from cancer registry data for (Devesa and Fears, 1992; Zheng et al, 1992). 14 countries by Newton et al (1997) also showed that England and In the period from 1986 to 1993 the incidence of gastrointestinal Wales had the lowest rate of gastric NHL of all developed coun- NHL of all sites in England and Wales increased by more than tries and that small intestine NHL rates showed much less varia- 2.5% annually. This is the first report of an increase in gastro- tion. These authors calculated incidence rates of 0.21, 0.16 and intestinal NHL in Europe. More detailed analyses showed that this 0.08 per 100 000 for gastric, small intestine and colon NHL, increase was limited to the older age groups with a moderate respectively, which are very similar to the rates found in the increase in the 50 to 69-year-old age group and the largest increase present study. in the over 70-year-old group as has been found in the United Other epidemiological characteristics of gastrointestinal NHL in States for gastric lymphomas (Severson and Davis, 1990). the present study were comparable to earlier studies, with nearly Incidence rates of gastric and small bowel NHL each showed half of gastrointestinal NHL cases localized to the stomach, and annual increases of around 6%. In the United States an annual small bowel and large bowel lymphomas representing just over increase of 3.7% in small intestinal NHL was found during the one quarter and one-tenth of cases, respectively (Halme et al, period 1974 to 1988 and rises in incidence rates for gastric 1997; Zucca et al, 1997). Gastrointestinal NHL in children and lymphoma have been reported (Severson and Davis, 1990; Devesa young adults (< 30 years old) was more commonly found in the and Fears, 1992). small bowel rather than the stomach. A hospital-based series Epidemiological studies have identified a number of factors reviewed by Weingrad et al (1982) found that 73% of patients had which may be of importance in the aetiology of NHL, though not a primary gastric lymphoma but this series did not include children specifically to gastrointestinal NHL. These include exposure to who typically have relatively more intestinal disease than adults. ultraviolet light, to pesticides, solvents and other chemicals and the In other studies, a greater proportion of large bowel to small bowel excess of protein and fat in the diet (Franceschi et al, 1989; NHL probably reflects the inclusion of mesenteric presentations in Cartwright et al, 1994). Increasing exposure or susceptibility to the former group, whilst in this study these have been recorded as these environmental risk factors could be responsible for the nodal disease and have not been included in the analyses for increasing trend in gastrointestinal NHL. Greater awareness of H. gastrointestinal NHL (Otter et al, 1989b; Ducreux et al, 1998). In pylori may result in more cases of gastrointestinal NHL, and in addition, there is considerable evidence that geographical variation particular MALT lymphomas, being identified. This series exists. Among demographically similar communities in the UK included no data on MALT lymphomas, however, as these and Italy, large differences in the incidence of gastric lymphoma lymphomas are typically low-grade malignancies and no increase have been reported (Doglioni et al, 1992). The higher incidence of in low-grade disease was seen over the period from 1986–1993 it gastric lymphoma found in Italy was associated with excesses in seems unlikely that this could account for the observed increase in gastric adenocarcinoma and Helicobacter pylori infection which gastric NHL incidence. Alternatively, endoscopic biopsies and may be involved in the development of both neoplasms. H. pylori diagnostic techniques may have led to increased accuracy in the infection has been implicated in the development of low-grade diagnosis of gastrointestinal NHL. Worldwide, incidence rates of gastric lymphoma derived from mucosa-associated lymphoid gastric cancer have declined over recent years (Coleman et al, tissue (MALT) (Wotherspoon et al, 1991). In Middle Eastern and 1993). This has been cited as evidence against an improvement in Mediterranean populations there is a relatively high incidence of diagnoses but neoplasms previously diagnosed as gastric carci- small bowel NHL linked to immunoproliferative alpha-chain nomas may now be more accurately diagnosed as lymphomas. disease. A similar hypothesis, involving a putative microorganism, The most obvious conclusion in this series would be that has been postulated to operate in immunoproliferative small intes- improved diagnosis of gastrointestinal NHL in the 1990s may be tine lymphomas (Isaacson and Spencer, 1993). The importance of responsible, at least in part, for the observed increases in gastric H. pylori infection in the aetiology of gastric lymphoma is still and small bowel NHL, as a concomitant decrease in the incidence uncertain. There have been several reports of successful treatment of gastrointestinal NHL of unknown primary site was observed. of low-grade gastric lymphoma with antibiotics alone but MALT However, a real increase in gastric and small bowel lymphoma formation leading to B-cell clonality and lymphoma may not be cannot be excluded given that an annual increase of more than linked exclusively to H. pylori infection (Sorrentino et al, 1996). 2.5% in the incidence of gastrointestinal NHL at all sites was Gastrointestinal NHL is principally a disease of middle age and observed in England and Wales between 1986 and 1993. older with nearly 85% of cases in this series aged over 50 years. Male predominance, found to be around 2:1 depending on the site, ACKNOWLEDGEMENTS has been observed in all series whether population- or hospital- based, although there is as yet no explanation for this excess. The The Leukaemia Research Fund has financed all aspects of the distribution of low- and high-grade gastrointestinal NHLs in this work for this publication. Numerous haematologists, histopatholo- series is similar to that found in previous studies with more cases gists, radiotherapists and consultants in other specialities are thanked for their continued efforts to facilitate case ascertainment; of high-grade disease than low-grade disease overall. However, these are acknowledged in detail elsewhere (Cartwright et al, there are differences between the individual sites with low-grade 1990). 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Descriptive epidemiology of gastrointestinal non-Hodgkin’s lymphoma in a population-based registry

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Springer Journals
Copyright
Copyright © 1999 by The Author(s)
Subject
Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
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0007-0920
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1532-1827
DOI
10.1038/sj.bjc.6690307
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Abstract

British Journal of Cancer (1999) 79(11/12), 1929–1934 © 1999 Cancer Research Campaign Article no. bjoc.1998.0307 Descriptive epidemiology of gastrointestinal non- HodgkinÕs lymphoma in a population-based registry KA Gurney, RA Cartwright and EA Gilman Leukaemia Research Fund Centre for Clinical Epidemiology, University of Leeds, 17 Springfield Mount, Leeds LS2 9NG, UK Summary The incidence of non-Hodgkin’s lymphoma (NHL), particularly at certain extranodal sites, has been demonstrated to be rising, at least in the USA, more than for any other malignancy. One of the major sites of extranodal NHL is the gastrointestinal tract, though little is known of its epidemiological characteristics. Over an 8-year period (1986 to 1993) 1069 primary gastrointestinal NHL cases were reported to the Leukaemia Research Fund Data Collection Survey which covers many parts of England and Wales. Age-standardized incidence rates of 5 5 5 5 gastrointestinal NHL at all sites (0.58/10 per year), gastric (0.24/10 per year), small bowel (0.17/10 per year) and large bowel (0.06/10 per year) confirmed that the UK has the lowest rates of gastrointestinal NHL in Europe. An excess of males was observed at all ages and for all sites. Time-trend analyses showed annual increases in incidence rates for gastric (6.3%) and small bowel (5.9%) NHL although a concomitant decrease in gastrointestinal NHL of unknown site suggested that at least part of these increases had resulted from more accurate diagnoses. Overall, the incidence of gastrointestinal NHL significantly increased by 2.7% per annum and was limited to the population aged over 50 years in this series. Keywords: epidemiology; non-Hodgkin’s lymphoma; gastrointestinal; time-trend analysis Most non-Hodgkin’s lymphoma (NHL) originates in the lymph MATERIALS AND METHODS nodes or other lymphoid tissues. However, a significant proportion The DCS is a specialist registry of lymphomas, leukaemias and of NHL has a primary extranodal site such as the gastrointestinal related disorders held by the Leukaemia Research Centre for tract, skin or central nervous system. Primary gastrointestinal Clinical Epidemiology in Leeds. This survey has been collecting NHL is the commonest extranodal localization, representing data since 1 January 1984, with the aim of providing high quality around one-third of all extranodal cases in most series (Zucca et al, data for population-based epidemiological studies (Cartwright et 1997). Recently it has been shown that incidence rates for NHL al, 1990). The geographical area of case collection covers approx- have been increasing for many years with this trend being more imately half of England and Wales. Newly diagnosed cases are prevalent in extranodal disease than in nodal NHL (Devesa and reported directly to Leeds from collaborating histopathologists and Fears, 1992; Zheng et al, 1992). It is, as yet, uncertain as to haematologists and registrations completed by trained data collec- whether this is a real increase or due to more efficient case regis- tion clerks. In addition, regular checks are made with NHS cancer tration and improved diagnoses although it has been suggested that registries for the areas concerned and any missed cases registered the increase in incidence rates for gastric lymphoma in the United after review. States is independent of coding and diagnostic procedures NHL cases were registered by the DCS only after histopatho- (Severson and Davis, 1990). logical review by a minimum of two histopathologists with a In 1984 the Leukaemia Research Fund began the Data specialist interest in lymphomas. Data from the DCS and the Collection Survey (DCS), a specialist population-based register cancer registries for the years 1989–93 were compared using log- covering neoplastic haematological diseases in parts of England linear models and case coverage for all NHL was estimated to be and Wales based on diagnoses from collaborating haematologists nearly 96% (Cartwright et al, 1997). and histopathologists. Data collected by this Survey have been Gastrointestinal NHL was defined as cases where the initial shown to be more accurate, as they reflect modern clinical and symptoms and predominant disease were confined to the gastro- haematopathological opinions, and more complete than compara- intestinal tract (Lewin et al, 1978) including the pancreas and tive National Health Service cancer registry data (Alexander et al, oesophagus. Cases with a gastrointestinal site discovered during 1989; Cartwright et al, 1997). staging or other clinical investigation of NHL and mesenteric This paper describes the epidemiology of gastrointestinal NHL localizations were excluded from the study. In accordance with and investigates the changes in incidence in gastric and other DCS criteria, cases were registered as primary gastrointestinal intestinal NHL in those areas of England and Wales covered by the NHL, after histopathological review with no evidence of nodal DCS from 1986 to 1993. involvement. The localization of gastrointestinal NHL was further classified Received 14 August 1998 into gastric, small bowel and large bowel NHL, and gastrointestinal Revised 16 October 1998 (GI) tract, site unknown, NHL by review of the histopathology Accepted 27 October 1998 reports. The gastric site comprised those cases where the disease Correspondence to: RA Cartwright was localized in the stomach or in the stomach and intestine. Small 1929 1930 KA Gurney et al Table 1 Age-standardized incidence rates and site distribution for gastrointestinal non-Hodgkin’s lymphoma, 1986–1993 Male Female Total a a a Rate Number % Rate Number % Rate Number % M:F Site of cases of cases of cases ratio Gastric 0.29 252 41.1 0.20 211 46.2 0.24 463 43.3 1.5 Small bowel 0.22 167 27.3 0.13 126 27.6 0.17 293 27.4 1.7 lleum 29 23 52 Duodenum 11 7 18 NOS 127 96 223 Large bowel 0.09 71 11.6 0.04 48 10.5 0.06 119 11.1 2.3 Rectum 25 18 43 Colon 21 15 36 Caecum 20 9 29 NOS 5 6 11 Gl tract, site unknown 0.13 107 19.9 0.06 65 15.7 0.10 172 16.1 2.2 Gastrointestinal NOS 84 60 144 Intestine NOS 23 5 28 All sites 0.75 612 100.0 0.43 457 100.0 0.58 1069 100.0 1.7 a b Rate directly standardized to the World Standard population (cases/100 000/year). Includes gastrointestinal NHL with the primary site localized to the pancreas (n = 14) and oesophagus (n = 8). Table 2 Classification of gastrointestinal NHL by grade and age Age range Sex Low-grade High-grade T-cell All graded Unclassified Total (years) cases cases a b 0–14 M 0 11 (100.0%) 0 11 1 (8.3%) 12 F 0 1 (100.0%) 0 1 0 1 15–29 M 2 (10%) 16 (80.0%) 2 (10%) 20 1 (4.8%) 21 F 0 1 (50.0%) 0 1 1 (50.0%) 2 30–49 M 26 (36.6%) 40 (56.3%) 5 (7.1%) 71 9 (11.3%) 80 F 14 (35.0%) 24 (60.0%) 2 (5.0%) 40 10 (20.0%) 50 50–69 M 81 (37.0%) 117 (53.4%) 21 (9.6%) 219 47 (17.7%) 266 F 72 (45.3%) 76 (47.8%) 11 (6.9%) 159 34 (17.6%) 193 70+ M 76 (40.9%) 102 (54.8%) 8 (4.3%) 186 47 (20.2%) 233 F 53 (33.5%) 89 (56.3%) 16 (10.1%) 158 53 (25.1%) 211 a b % of all graded cases. % of total cases. bowel included duodenum, jejunum, ileum, ileo caecal junction method using the World Standard Population (Parkin et al, 1992) localizations and small intestine not otherwise specified. The large which required adjustment of the final age group to 85 years and bowel included appendix, caecum, colon, rectum localizations and older. Incidence trends were evaluated by Poisson regression large intestine not otherwise specified. A separate category of GI analysis over the full age range for all gastrointestinal NHL and tract, site unknown, NHL included cases where the primary site had for the individual sites. Incidence trends were also investigated, not been recorded and cases where the site was reported as where sufficient data were available, using four age ranges (0–29, intestinal or gastrointestinal with no further details. 30–49, 50–69 and 70+ years) to examine in more detail whether Gastrointestinal NHL was classified according to the updated changes in incidence rates were more prominent in some age Kiel classification and graded as either low- or high-grade malig- groups than in others. nancy (Stansfeld et al, 1988). This study was based on all gastrointestinal NHL cases RESULTS diagnosed between 1 January 1986 and 31 December 1993 and reported to the DCS. Age-specific incidence rates were calculated Incidence of gastrointestinal NHL for males, females and both sexes combined for all gastrointestinal NHL, and individually for gastric, small bowel, large bowel sites A total of 1069 cases of gastrointestinal NHL were diagnosed and GI tract, site unknown. To calculate age-specific incidence during the years from January 1986 to December 1993. During rates, cases were grouped into 5-year age groups with the excep- this time, 11 334 cases of NHL were diagnosed within the popula- tion of the final group which was 90 years and older. To facilitate tion covered by the Data Collection Survey, thus the gastro- geographical comparisons, rates were standardized by the direct intestinal NHL cases represented 9.43% of all NHL cases. British Journal of Cancer (1999) 79(11/12), 1929–1934 © Cancer Research Campaign 1999 Epidemiology of gastrointestinal NHL 1931 Table 3 Histological classification of gastrointestinal NHL for individual sites Histology Gastric Small bowel Large bowel Gl tract, site unknown Low grade 153 75 35 54 (43.3%) (30.4%) (33.0%) (33.8%) Lymphoplasmacytoid 10 4 3 4 Centrocytic 18 12 13 8 Centroblastic-centrocytic, follicular 28 19 5 8 Centroblastic-centrocytic, follicular and diffuse 6 9 1 6 Centroblastic-centrocytic, diffuse 31 14 5 16 Low grade, unclassified 60 17 8 12 High grade 191 131 62 81 (54.1%) (53.0%) (58.5%) (50.6%) Centroblastic 75 38 21 26 Lymphoblastic, Burkitt’s type 0 3 3 3 Lymphoblastic, convoluted cell 1 0 0 0 Lymphoblastic, other/unclassified 6 5 2 7 Immunoblastic 11 12 11 10 Histiocytic lymphoma 10 11 6 4 High grade, unclassified 88 62 19 31 T-cell lymphoma NOS 9 41 9 6 (2.5%) (16.6%) (8.5%) (3.8%) All classified cases 353 247 106 141 (100%) (100%) (100%) (100%) Malignant lymphoma, unspecified grade (% of total cases) 110 46 13 31 (23.8%) (15.7%) (10.9%) (18.0%) Total cases 463 293 119 172 Age-standardized (World standard population) incidence rates A B 5.0 9.0 for all gastrointestinal NHL and by individual site are presented in 8.0 I 4.0 7.0 I Table 1. The overall age-standardized incidence rates for gastro- 6.0 I 3.0 5.0 intestinal NHL all sites combined were 0.75 per 100 000 and 0.43 1', I 4.0 I \I 2.0 ,~ per 100 000 for males and females respectively. Ages ranged 3.0 2.0 1.0 between 5 years 1 month and 95 years 9 months (mean = 64 years 1.0 0.0 0.0 10 months, median = 67 years 6 months). An excess in male incidence was found for all gastrointestinal NHL and for the indi- Age (years) Age (years) vidual sites ranging from a male:female ratio of 1.5:1 for gastric NHL to 2.3:1 for large bowel NHL. This excess in male cases was even more pronounced in children and young adults where 11 of 3.0 1.4 12 cases in the 0–14 age range and 21 of 23 cases in the 15–29 age 1.2 2.5 1.0 2.0 range were male (Table 2). 0.8 1.5 0.6 1.0 0.4 0.5 0.2 Site of gastrointestinal NHL 0.0 0.0 Table 1 also shows that the most common site of gastrointestinal NHL for all age groups was gastric (43.3%) followed by small Age (years) Age (years) bowel (27.4%), large bowel (11.1%) with a further 172 cases classified as GI tract, site unknown, NHL (16.1%). However, for 1.0 children and young adults (< 30 years) small bowel NHL was ' / I \ I 0.8 predominant (44.4%), then GI tract, site unknown (25.0%), gastric 0.6 " (16.7%) and large bowel (13.9%). 0.4 0.2 0.0 Histology of gastrointestinal NHL Age (years) Overall, most gastrointestinal NHL cases in this series were high- grade (44.5%), with 30.4% low-grade, 19.0% unclassified and Figure 1 Age-specific incidence rates, male (– – –), female (- - -) and 6.1% T-cell lymphomas. The distribution of histological subtypes combined (— —), for all gastrointestinal NHL (A), gastric NHL (B), small bowel among gastrointestinal sites is given in Table 3. Gastric NHL had a NHL (C), large bowel NHL (D) and Gl tract, site unknown, NHL (E) in parts of higher proportion of low-grade cases whereas intestinal NHL England and Wales, 1986–1993 © Cancer Research Campaign 1999 British Journal of Cancer (1999) 79(11/12), 1929–1934 Cases/100 000/year Cases/100 000/year Cases/100 000/year 0–4 0–4 0–4 10–14 10–14 10–14 20–24 20–24 20–24 30–34 30–34 30–34 40–44 40–44 40–44 50–54 50–54 50–54 60–64 60–64 60–64 70–74 70–74 70–74 80–84 80–84 80–84 90+ 90+ 90+ Cases/100 000/year Cases/100 000/year 0–4 0–4 10–14 10–14 20–24 20–24 30–34 30–34 40–44 40–44 50–54 50–54 60–64 60–64 70–74 70–74 80–84 80–84 90+ 90+ 1932 KA Gurney et al Table 4 Time trend analysis of incidence rates of gastrointestinal NHL in parts of England and Wales, 1986–1993 Annual change 95% confidence in incidence intervals All gastrointestinal NHL Males + 2.19% NS Females + 3.16% NS Total + 2.66% P = 0.047 0.03, 5.30 Gastric Males + 6.88% P = 0.014 1.34, 12.72 Females + 5.37% NS Total + 6.25% P = 0.003 2.16, 10.51 Small bowel Males + 5.65% NS Females + 6.08% NS Total + 5.87% P = 0.023 0.78, 11.23 Large bowel Males – 0.03% NS Females + 3.45% NS Total + 1.44% NS Gl tract, site unknown Males – 13.29% P = 0.001 – 5.31, – 20.61 Females – 11.68% P = 0.026 – 1.21, – 21.04 Total – 12.62% P < 0.001 – 6.36, – 18.47 (small and large bowel cases combined) tended to be high-grade. significant except for GI tract, site unknown, NHL. In males, Over 75% of T-cell lymphomas were found in intestinal NHL gastric and GI tract, site unknown, NHL incidence rates showed a cases. For all gastrointestinal NHL the most common histological significant increase and decrease respectively. subtype was centroblastic, accounting for nearly 20% of all classi- More detailed analyses of the increase in incidence rates from fied lymphomas. All childhood, and the majority of young adult, 1986 to 1993 for all gastrointestinal NHL revealed that significant gastrointestinal NHL cases were high-grade malignancies. In chil- increases were restricted to the older age groups (0–29 years, dren (0–14 years) most cases were lymphoblastic, Burkitt’s type, + 5.5%, NS; 30–49 years, – 2.6%, NS; 50–69 years, + 3.5%, P = but in the young adults (15–29 years) centroblastic was again 0.09; 70+ years, + 5.3%, P = 0.01; males and females combined). predominant. In adults (³ 30 years old) the distribution of high- This pattern was also seen for gastric NHL (70+ years, + 8.5%, grade, low-grade and T-cell gastrointestinal NHL were broadly P = 0.02). Analyses for other sites and age ranges were unreliable similar for each age range. due to small numbers of cases. Age-specific incidence curves by sex for all gastrointestinal Time trend analyses for low- and high-grade gastrointestinal NHL and by individual site are shown in Figure 1. Incidence rates NHL at all sites showed no significant changes for either of these for both sexes show broadly similar patterns for all sites of groups (low-grade disease showed an annual decrease of 1.7%, gastrointestinal NHL. Rates are very low for the under 30s then NS; high-grade disease showed an annual increase of 1.5%, NS; rapidly increase to a major peak around 80 ± 5 years of age, except males and females combined). However, cases with unspecified in large bowel NHL where this peak occurs over a narrower age grade showed an annual increase of 7.15%, P = 0.02 reflecting the range and GI tract, site unknown, NHL, where the age range is relatively high proportion of gastric and small bowel cases with rather broader. All sites appear to show a minor peak in age- unknown grade. specific incidence rates for the 55–60 year age group with the exception of GI tract, site unknown, NHL where the peak occurs DISCUSSION much earlier at 40–45 years of age. The majority of studies investigating the epidemiology of gastro- intestinal NHL have been based on studies using selective data with Change in incidence the exception of four north European population-based studies From 1986 to 1993, incidence of gastrointestinal NHL for both [Otter et al, 1989a (96 cases); D’Amore et al, 1994 (306 cases); sexes combined increased by 2.66% per annum (P = 0.047; 95% Halme et al, 1997 (61 cases); Ducreux et al, 1998 (78 cases)]. To CI, 0.03, 5.30) (Table 4). Over this time period the incidence of our knowledge, this study comprising 1069 cases represents the NHL classified as having a primary site in the stomach or small largest population-based series of gastrointestinal NHL. This, along bowel showed significant annual increases of 6.25% and 5.87%, with uniform and highly complete collection of data, are the main respectively whilst that of large bowel NHL remained stable. A strengths of the current study. The principal disadvantages are those highly significant annual decrease of 12.62% in the incidence of shared by similar studies in that it is not known whether all extra- GI tract, site unknown, NHL was also observed. Similar values for nodal disease has been included, the site may be vague in some annual increases and decreases were seen in males and females cases and it is not always possible to distinguish a nodal condition separately but for the female population these trends were not infiltrating into the bowel from primary bowel disease. British Journal of Cancer (1999) 79(11/12), 1929–1934 © Cancer Research Campaign 1999 Epidemiology of gastrointestinal NHL 1933 The incidence rates found in this study for gastrointestinal NHL common in intestinal disease. T-cell lymphomas were found in parts of England and Wales are lower than those reported by mostly in intestinal NHL cases as expected. previous population-based studies in France, central Finland and There have been several reports recently that the incidence of Denmark (D’Amore et al, 1994; Halme et al, 1997; Ducreux et al, NHL malignancies is increasing rapidly, primarily in the devel- 1998). This difference is more marked for gastric NHL, where oped countries, by between 3–5% per annum (Devesa and Fears, incidence is less than half that found in other European countries, 1992; McNally et al, 1997; Morgan et al, 1997) and that this than for intestinal NHL where the rates are more similar to those increase is seen more in extranodal disease than in nodal NHL reported. Incidence rates calculated from cancer registry data for (Devesa and Fears, 1992; Zheng et al, 1992). 14 countries by Newton et al (1997) also showed that England and In the period from 1986 to 1993 the incidence of gastrointestinal Wales had the lowest rate of gastric NHL of all developed coun- NHL of all sites in England and Wales increased by more than tries and that small intestine NHL rates showed much less varia- 2.5% annually. This is the first report of an increase in gastro- tion. These authors calculated incidence rates of 0.21, 0.16 and intestinal NHL in Europe. More detailed analyses showed that this 0.08 per 100 000 for gastric, small intestine and colon NHL, increase was limited to the older age groups with a moderate respectively, which are very similar to the rates found in the increase in the 50 to 69-year-old age group and the largest increase present study. in the over 70-year-old group as has been found in the United Other epidemiological characteristics of gastrointestinal NHL in States for gastric lymphomas (Severson and Davis, 1990). the present study were comparable to earlier studies, with nearly Incidence rates of gastric and small bowel NHL each showed half of gastrointestinal NHL cases localized to the stomach, and annual increases of around 6%. In the United States an annual small bowel and large bowel lymphomas representing just over increase of 3.7% in small intestinal NHL was found during the one quarter and one-tenth of cases, respectively (Halme et al, period 1974 to 1988 and rises in incidence rates for gastric 1997; Zucca et al, 1997). Gastrointestinal NHL in children and lymphoma have been reported (Severson and Davis, 1990; Devesa young adults (< 30 years old) was more commonly found in the and Fears, 1992). small bowel rather than the stomach. A hospital-based series Epidemiological studies have identified a number of factors reviewed by Weingrad et al (1982) found that 73% of patients had which may be of importance in the aetiology of NHL, though not a primary gastric lymphoma but this series did not include children specifically to gastrointestinal NHL. These include exposure to who typically have relatively more intestinal disease than adults. ultraviolet light, to pesticides, solvents and other chemicals and the In other studies, a greater proportion of large bowel to small bowel excess of protein and fat in the diet (Franceschi et al, 1989; NHL probably reflects the inclusion of mesenteric presentations in Cartwright et al, 1994). Increasing exposure or susceptibility to the former group, whilst in this study these have been recorded as these environmental risk factors could be responsible for the nodal disease and have not been included in the analyses for increasing trend in gastrointestinal NHL. Greater awareness of H. gastrointestinal NHL (Otter et al, 1989b; Ducreux et al, 1998). In pylori may result in more cases of gastrointestinal NHL, and in addition, there is considerable evidence that geographical variation particular MALT lymphomas, being identified. This series exists. Among demographically similar communities in the UK included no data on MALT lymphomas, however, as these and Italy, large differences in the incidence of gastric lymphoma lymphomas are typically low-grade malignancies and no increase have been reported (Doglioni et al, 1992). The higher incidence of in low-grade disease was seen over the period from 1986–1993 it gastric lymphoma found in Italy was associated with excesses in seems unlikely that this could account for the observed increase in gastric adenocarcinoma and Helicobacter pylori infection which gastric NHL incidence. Alternatively, endoscopic biopsies and may be involved in the development of both neoplasms. H. pylori diagnostic techniques may have led to increased accuracy in the infection has been implicated in the development of low-grade diagnosis of gastrointestinal NHL. Worldwide, incidence rates of gastric lymphoma derived from mucosa-associated lymphoid gastric cancer have declined over recent years (Coleman et al, tissue (MALT) (Wotherspoon et al, 1991). In Middle Eastern and 1993). This has been cited as evidence against an improvement in Mediterranean populations there is a relatively high incidence of diagnoses but neoplasms previously diagnosed as gastric carci- small bowel NHL linked to immunoproliferative alpha-chain nomas may now be more accurately diagnosed as lymphomas. disease. A similar hypothesis, involving a putative microorganism, The most obvious conclusion in this series would be that has been postulated to operate in immunoproliferative small intes- improved diagnosis of gastrointestinal NHL in the 1990s may be tine lymphomas (Isaacson and Spencer, 1993). The importance of responsible, at least in part, for the observed increases in gastric H. pylori infection in the aetiology of gastric lymphoma is still and small bowel NHL, as a concomitant decrease in the incidence uncertain. There have been several reports of successful treatment of gastrointestinal NHL of unknown primary site was observed. of low-grade gastric lymphoma with antibiotics alone but MALT However, a real increase in gastric and small bowel lymphoma formation leading to B-cell clonality and lymphoma may not be cannot be excluded given that an annual increase of more than linked exclusively to H. pylori infection (Sorrentino et al, 1996). 2.5% in the incidence of gastrointestinal NHL at all sites was Gastrointestinal NHL is principally a disease of middle age and observed in England and Wales between 1986 and 1993. older with nearly 85% of cases in this series aged over 50 years. Male predominance, found to be around 2:1 depending on the site, ACKNOWLEDGEMENTS has been observed in all series whether population- or hospital- based, although there is as yet no explanation for this excess. The The Leukaemia Research Fund has financed all aspects of the distribution of low- and high-grade gastrointestinal NHLs in this work for this publication. Numerous haematologists, histopatholo- series is similar to that found in previous studies with more cases gists, radiotherapists and consultants in other specialities are thanked for their continued efforts to facilitate case ascertainment; of high-grade disease than low-grade disease overall. However, these are acknowledged in detail elsewhere (Cartwright et al, there are differences between the individual sites with low-grade 1990). 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