Clustering of childhood leukaemia in Hong Kong: association with the childhood peak and common acute lymphoblastic leukaemia and with population mixing.

Incidence data of childhood leukaemia (CL) in Hong Kong (1984-90) have been analysed for evidence of variation between small areas. All cases (n=261) were classified by morphological cell type, with the majority (n=205) being acute lymphoblastic leukaemia (ALL), and haematological review has permitted immunophenotypic classification for 73% of these. The data have been examined for evidence of spatial clustering within small census areas (TPUs) and for association with population mixing, with attention focused on those subgroups (especially the childhood peak of ALL--taken here to be diagnoses in children from 24 months up to the seventh birthday--and common ALL) which, it has been hypothesized, may be caused by unusual patterns of exposure and response to common infections. For the whole of Hong Kong, there was evidence of spatial clustering of ALL at ages 0-4 years (P = 0.09) and in the childhood peak (P<0.05). When these analyses were restricted to TPUs where extreme population mixing may have occurred, overall incidence was elevated and significant evidence of clustering was found for ALL (P<0.007) at these ages and for the common ALL in the childhood peak (P = 0.032). Replication of the analyses for subsets of leukaemia that were not dominated by the childhood peak of ALL found no evidence of clustering. This is the first investigation of an association between population mixing and childhood leukaemia in Asia and the first to include clustering and to consider particular subsets. The results are supportive of the ''infectious'' aetiology hypothesis for subsets of childhood leukaemia, specifically common ALL in the childhood peak.     

Population mixing,childhood leukaemia,CNS tumours and other childhood cancers in Yorkshire

We tested the hypothesis that variation in population mixing attributable to the diversity of migrants moving to an area is associated with the incidence of childhood leukaemia and other childhood cancers. An ecological analysis was performed on 954 children (<15 years) diagnosed with a malignancy between 1986 and 1996 in 532 electoral wards in Yorkshire, UK. Incidence rate ratios (IRR) were calculated for all childhood leukaemias (n=325), acute lymphoblastic leukaemia (ALL) (n=248), central nervous system (CNS) tumours (n=236) and other solid tumours (n=393) Incidence of all childhood leukaemias was significantly lower in areas of high (top decile) population mixing (IRR 0.72, 95% Confidence Interval (CI) 0.54-0.97) and higher in areas of low (bottom decile) population mixing (IRR 1.56, 95% CI 0.73-3.34), but similar patterns of incidence were not observed for central nervous system or other solid tumours. Population mixing may be a proxy for the range of infections circulating in a community and these results are consistent with the hypothesis that greater exposure to infections reduces the risk of developing childhood leukaemia by conferring efficient modulation of the immune system.     

An ecologic study of childhood leukemia and population mixing in Ontario, Canada

Objective: To examine the association between population mixing and the incidence of childhood leukemia, specifically the acute lymphocytic leukemia (ALL) subtype among young children. Methods: This ecologic study was based on incidence rates of leukemia in children aged 0–14 years. The Ontario Cancer Registry was used to identify the residence of 1394 leukemia cases between 1978 and 1992. Ecologic units were composed of census subdivisions in a 5-year period. Percent population change, determined from the Census of Canada, was employed as a measure of population mixing. The relationship between population mixing and childhood leukemia was examined separately after stratifying by the level of geographic isolation, defined according to urban–rural status. Analyses were also conducted separately in specific age groups and for the ALL subtype. Results: Population growth in rural areas was associated with an increased incidence of leukemia, particularly for the ALL subtype in children aged 0–4 years (rate ratio = 1.8, 95% confidence interval 1.1–2.8, for a greater than 20% population change relative to no increase in population). In contrast, an elevated risk due to population mixing was not observed in urban areas. Conclusions: Results from this study are consistent with results from similar studies conducted in the United Kingdom, which are suggestive of a role for an infectious agent in the etiology of childhood leukemia, as proposed in the Kinlen hypothesis.     

Childhood leukaemia incidence and the population mixing hypothesis in US SEER data

We evaluated the infectious aetiology hypothesis of childhood leukaemia that rapid population influx into rural areas is associated with increased risk. Using data from the US SEER program, we found that in changes in rural county population sizes from 1980 to 1989 were associated with incidence rates for childhood acute lymphocytic leukaemia (ALL). The observed associations were strongest among children 0-4 years of age, born in the same state as diagnosis, in extremely rural counties, and when counties adjacent to nonrural counties were excluded. Similar analyses for brain and central nervous system (CNS) cancer in children, a disease less linked to this infectious hypothesis, provide evidence against methodologic bias. Similar evaluations for other decades were not meaningful due to limited sample sizes and, perhaps, increased population mobility.     

A case-control study of childhood leukaemia and paternal occupational contact level in rural Sweden

In a national case-control study in Sweden, we investigated whether in rural areas (where susceptible individuals are more prevalent than in urban areas) leukaemia risk was higher among the young children of fathers with many work contacts, as the infective hypothesis has predicted. A total of 1935 cases diagnosed in 1958-1998 together with 7736 age-matched (within 1 year) population controls (of whom 970 and 3880 respectively were aged 0-4) were linked to paternal occupational details as recorded in the census closest to the year of birth. Applying the two classifications of occupational contact level used in a study of rural Scotland, the odds ratios for children aged 0-4 years in the highest contact category (which includes teachers) in the most rural Swedish counties were 3.47 (95% CI 1.54, 7.85) and 1.59 (1.07, 2.38) respectively, relative to the medium and low (reference) category; no such excess was found in urban or intermediate counties. There was also a significant positive trend at ages 0-4 in the rural counties across the three levels of increasing occupational contact (P for trend 0.02 and 0.03, respectively), but again not in the urban or intermediate counties. No such effect or trend was found at ages 5-14 in any of the three county groupings. The findings confirm those of a recent study in rural Scotland, and also suggest that unusual population mixing (as occurred in Scotland as a result of the North Sea oil industry) is not a necessary requirement for the effect, since comparable mixing has not been a feature of rural Sweden.     

Paternal occupational contact level and childhood leukaemia in rural Scotland: a case-control study

In a national Scottish study of 809 cases of leukaemia and non-Hodgkins lymphoma diagnosed in 1950-89 among children aged 0-4 years who were born in Scotland, together with 2363 matched population controls, we investigated one aspect of the infective hypothesis. This concerns whether in rural areas (where the prevalence of susceptible individuals is likely to be higher) the risk is greater among the young children of men whose work involves contacts with many different people, particularly children, as noted in certain childhood infections. A positive trend was found in rural areas across 3 levels of increasing paternal occupational contact (as recorded at birth) by each of 2 previously defined classifications; no such effect was found in urban areas. The rural trend was more marked in that part of the study period with greater population mixing, but the difference from the period with less mixing was not itself significant, leaving open whether these rural findings reflect the extreme isolation of much of rural Scotland, or the effects in such areas of a degree of population mixing. In marked contrast, among the 850 cases and 2492 controls aged 5-14, those in rural areas in the higher population mixing period showed a significantly decreasing trend with increasing paternal occupational contact level. This would be consistent with immunity produced either by earlier infection at ages 0-4 years, or directly by low doses of the infective agent that were largely immunizing at these older ages. The findings overall provide further support for infection underlying childhood leukaemia and for the role of adults.     

Incidence of childhood leukaemia in The Netherlands (1973-1980).

The childhood leukaemia incidence rate for the Netherlands was estimated at 3.11 per 100.000 children (aged 0-15 year) per year, based on a complete nation-wide childhood leukaemia registry comprising the period 1973-1980. Acute lymphocytic leukaemia (ALL) accounted for 82.4% of the patients, acute non-lymphocytic leukaemia for 13.6% and chronic myeloid leukaemia for 2.9%. ALL occurred more frequently in boys (sex ratio 1.2). The highest ALL rate was observed in the 3-4 year age group. These figures corresponded with the data of the Manchester Children''s Tumour Registry. Neither the incidence rates according to year of diagnosis nor the incidence rates according to year of birth showed a significant trend with time. The total leukaemia incidence rate in urban areas was somewhat higher than in rural areas. While the direct comparison of the incidence rate between these areas is not significant, the trend over the three categories of urbanisation is significant.     

Space-time clustering of acute lymphoblastic leukaemia in parts of the U.K. (1984-1993)

Age-related differences in the incidence and immunological subtypes of acute lymphoblastic leukaemia (ALL) suggest that it may be composed of more than one disease entity, each with different aetiologies. Childhood leukaemia (of which the majority of cases are ALL) has been suspected of having an infectious aetiology, but few studies have systematically examined ALL for clustering by age group. The aim of this study was to examine ALL for evidence of space-time clustering of date and place of diagnosis by age group. Knox space-time analysis was carried out separately for three different age groups: childhood (0-14 years), young adult (15-34 years) and older adults (35-79 years). Data on 968 cases of ALL aged 0-79 years, arising during 1984-1993 in the areas covered by a specialist population based register of leukaemias and lymphomas in parts of the U.K., were used in the analysis. Space-time clustering of diagnoses was limited to children aged 0-14 years. It was more prominent in those diagnosed in the period 1984-1988, than in those diagnosed in 1989-1993. The clustering may indicate an infectious aetiology for childhood ALL, or could be the result of episodic exposures to some environmental hazard.     

Quantifying the effect of population mixing on childhood leukaemia risk: the Seascale cluster.

A statistical model was developed based on Poisson regression of incidence of childhood leukaemia and non-Hodgkin's lymphoma (NHL) in relation to population mixing among all 119 539 children born 1969-1989 to mothers living in Cumbria, north-west England, (excluding Seascale). This model was used to predict the number of cases in Seascale (the village adjacent to the Sellafield nuclear installation) children, born 1950-1989 and diagnosed before 1993. After allowing for age, the incidence of acute lymphoblastic leukaemia (ALL) and NHL was significantly higher among children born in areas with the highest levels of population mixing, relative risk (RR) = 11.7 (95% confidence interval (CI) 3.2-43) and was highest among children of incomers. The model predicted up to 3.0 (95% CI 1.3-6.0) cases of ALL/NHL in children born in Seascale compared to six observed and 2.0 (95% CI 1.0-3.4) cases in children resident, but not born, in Seascale compared to two observed. Population mixing is a significant risk factor for ALL/NHL, especially in young children, accounting for over 50% of cases in Cumbria and most cases in Seascale.     

Community lifestyle characteristics and incidence of Hodgkin's disease in young people

Risk of Hodgkin's disease (HD) in young adults has frequently been associated with limited access to social contact in childhood and related correlates of childhood social class. In addition, case clustering has sometimes been associated with influxes of population into relatively isolated communities. To investigate this further, disease incidence rates for HD at ages 0 to 24 from a specialist tumour registry have been regressed against relevant electoral ward characteristics derived from routine census and Ordnance Survey data for England and Wales. Proximity to built-up areas and higher socio-economic status (SES) emerge as significant risk factors. The relative risks are 1.21 (95% Cl: 1.01-1.46) for high SES wards and 1.29 (1.05-1.58) for "inner zone" wards. No association of disease risk with distance travelled to work was apparent. Regions farther from built-up areas have a lower overall incidence and a shift, particularly for males, of the age distribution towards older ages. The distribution resembles the intermediate pattern for HD reported from European rural areas of low SES but never previously for high SES. Isolated areas also show an increased intensity of spatial clustering (29% of cases being classified as clustered). These findings have implications for the 'late host response' model which suggest a viral aetiology for Hodgkin's disease in young people and provide a basis for future analytical studies.     

Childhood leukaemia and non-Hodgkin's lymphoma in relation to proximity to railways

We investigated whether living close to railway lines is a risk factor for childhood leukaemia and non-Hodgkin's lymphoma in electoral wards in England and Wales, 1966-1987. The national rail network, 1966-1987, was digitised and the numbers of cases in each ward were related to two measures of environmental exposure to railways: a proximity and a density function, contributions to these functions being weighted by the frequency of use and time in use of each stretch of railway. Poisson regression was used to derive rate ratios in relation to these measures of exposure to railways, both unadjusted and adjusted for population mixing. We found no association between risk of leukaemia and railway proximity (unadjusted rate ratio for trend from the lowest to the median value=1.006, 95% CI: 0.998 - 1.013, P=0.14) and a very small association with railway density, of marginal statistical significance (rate ratio for trend=1.001, 95% CI: 1.000 - 1.003, P=0.05). This effect depended on two deprived, urban wards with high railway density and high population mixing and became nonsignificant (P=0.09) after allowing for population mixing. The very weak association between railway density and risk of childhood leukaemia is likely to be a consequence of the association between population mixing and proximity to railways in very deprived, urban wards.     

Cancer incidence patterns by region and socioeconomic deprivation in teenagers and young adults in England

Data on 35,291 individuals with cancer, aged 13-24 years, in England from 1979 to 2001 were analysed by region and socio-economic deprivation of census ward of residence, as measured by the Townsend deprivation index. The incidence of leukaemia, lymphoma, central nervous system tumours, soft tissue sarcomas, gonadal germ cell tumours, melanoma and carcinomas varied by region (P<0.01, all groups) but bone tumour incidence did not. Lymphomas, central nervous system tumours and gonadal germ cell tumours all had higher incidence in less deprived census wards (P<0.01), while chronic myeloid leukaemia and carcinoma of the cervix had higher incidence in more deprived wards (P<0.01). In the least deprived wards, melanoma incidence was nearly twice that in the most deprived, but this trend varied between regions (P<0.001). These cancer incidence patterns differ from those seen in both children and older adults and have implications for aetiology and prevention.     

Spatial temporal patterns in childhood leukaemia: further evidence for an infectious origin. EUROCLUS project.

The EUROCLUS project included information on residence at diagnosis for 13351 cases of childhood leukaemia diagnosed in the period 1980-89 in defined geographical regions in 17 countries. A formal algorithm permits identification of small census areas as containing case excesses. The present analysis examines spatial-temporal patterns of the cases (n = 970) within these clustered areas. The objectives were, first, to compare these results with those from an analysis conducted for UK data for the period 1966-83, and, second, to extend them to consider infant leukaemias. A modification of the Knox test investigates, within the small areas, temporal overlap between cases in a subgroup of interest at a putative critical time and all other cases at any time between birth and diagnosis. Critical times were specified in advance as follows: for cases of acute lymphoblastic leukaemia aged 2-4 years, the 18-month period preceding diagnosis; for cases of total leukaemia aged 5-14 years, 1 year before to 1 year after birth; and for infant cases (diagnosed < 1 year), 1 year before to 6 months after birth. Each of the analyses found evidence of excess space-time overlap compared with that expected; these were 10% (P = 0.005), 15% (P= 0.0002) and 26% (P= 0.03) respectively. The results are interpreted in terms of an infectious origin of childhood leukaemia.     

Spatial clustering of childhood cancer in Great Britain during the period 1969–1993

The aetiology of childhood cancer is poorly understood. Both genetic and environmental factors are likely to be involved. The presence of spatial clustering is indicative of a very localized environmental component to aetiology. Spatial clustering is present when there are a small number of areas with greatly increased incidence or a large number of areas with moderately increased incidence. To determine whether localized environmental factors may play a part in childhood cancer aetiology, we analyzed for spatial clustering using a large set of national population‐based data from Great Britain diagnosed 1969–1993. The Potthoff‐Whittinghill method was used to test for extra‐Poisson variation (EPV). Thirty‐two thousand three hundred and twenty‐three cases were allocated to 10,444 wards using diagnosis addresses. Analyses showed statistically significant evidence of clustering for acute lymphoblastic leukaemia (ALL) over the whole age range (estimate of EPV = 0.05, p = 0.002) and for ages 1–4 years (estimate of EPV = 0.03, p = 0.015). Soft‐tissue sarcoma (estimate of EPV = 0.03, p = 0.04) and Wilms tumours (estimate of EPV = 0.04, p = 0.007) also showed significant clustering. Clustering tended to persist across different time periods for cases of ALL (estimate of between‐time period EPV = 0.04, p =0.003). In conclusion, we observed low level spatial clustering that is attributable to a limited number of cases. This suggests that environmental factors, which in some locations display localized clustering, may be important aetiological agents in these diseases. For ALL and soft tissue sarcoma, but not Wilms tumour, common infectious agents may be likely candidates. © 2008 Wiley‐Liss, Inc.     

Leukaemia and non-Hodgkin's lymphoma in young persons resident in small areas of West Cumbria in relation to paternal preconceptional irradiation.

The results of a previous study suggested that an association between childhood leukaemia and the radiation dose received occupationally by a father before the conception of his child might provide the explanation for the marked excess of childhood leukaemia and non-Hodgkin''s lymphoma in the village of Seascale, West Cumbria. The present study identifies other small areas (electoral wards) in West Cumbria where excess cases of leukaemia and non-Hodgkin''s lymphoma in young people have occurred and determines whether a recorded dose of radiation was received occupationally by the father before the conception of each of the affected individuals. Forty-one cases of leukaemia and non-Hodgkin''s lymphoma were diagnosed during 1968-85 in young people under 25 years of age resident in the 49 electoral wards lying within the boundary of West Cumbria and the adjacent ward of Broughton. Raised incidence rate ratios (two-sided P<0.01) were found for acute lymphoblastic leukaemia among those aged 0-14 years (concentrated among those aged 0-4 years) in Seascale ward and among those aged 0-24 years (also concentrated among those aged 0-4 years) in Egremont North ward, for acute myeloid leukaemia among those aged 0-14 years in Sandwith ward, for all leukaemias among those aged 0-14 years in Broughton ward (South Lakeland) and for non-Hodgkin''s lymphoma among those aged 0-14 years in Seascale ward. For West Cumbria as a whole, incidence rates were not usual. Apart from Seascale, for none of these electoral wards has a father of an affected child been linked definitely to an occupational dose of radiation recorded before the conception of the child. Particularly striking are the excesses of acute lymphoblastic leukaemia cases among young children living in the wards of Seascale and Egremont North, situated 11 km apart. The cases in Egremont North are not associated with recorded doses of radiation received occupationally by fathers before the conception of the affected children, even though the total numbers of children associated with such doses born in Seascale and Egremont North wards are similar. This finding is further evidence against a causal role for paternal preconceptional radiation exposure in the cases of childhood leukaemia in Seascale.     

Higher risk for acute childhood lymphoblastic leukaemia in Swedish population centres 1973-94. Swedish Child Leukaemia Group.

A population-based sample of acute childhood leukaemia cases in Sweden 1973-94 was analysed by a geographical information system (GIS) for spatial leukaemia distribution in relation to population density. The annual incidence rate for acute lymphoblastic leukaemia (ALL) was 3.6, and for acute non-lymphoblastic leukaemia (ANLL) 0.7, cases per 100,000 children. Incidence rates in population centres, constituting 1.3% of Sweden's land area and approximately 80% of the population, compared with the rest of Sweden showed a statistically significant excess of ALL [odds ratio (OR) 1.68; 95% confidence interval (CI) 1.44-1.95], but not ANLL (OR 1.13; 95% CI 0.98-1.32). An increasing trend, however not statistically significant, was found for ALL incidence with both increasing population density in parishes and increasing degree of urbanity in municipalities. These findings support the theories that some environmental factors associated with high population density, such as infectious agents, may be of aetiological importance for childhood acute lymphoblastic leukaemia.     

Community lifestyle characteristics and lymphoid malignancies in young people in the UK

Data from a specialist registry of haematopoietic malignancies in England and Wales (1984–1988) have been analysed to investigate variations of incidence by age and diagnostic subtype of lymphoid malignancies in young people (aged 0–24 years). Attention has been focussed on the role of community lifestyle indicators for small areas, derived from routine sources, in an ecological analysis. The predominant conditions were acute lymphoblastic leukaemia (ALL)—42.4%, and Hodgkin's disease (HD)—37.5%. Lowest overall incidence at approximately 8 years of age corresponded to the termination of the childhood peak for ALL. Opposite trends of incidence rates with distance from urban centres (urban distance) were observed for the two age groups: odds ratios (OR) for areas > 20 km from towns and cities were 1.46 (95% confidence interval 1.01–2.12) for ages 0–7 and 0.75 (95% confidence interval 0.56-0.99) for ages 8–24. For the younger group this was entirely attributable to ALL. HD, which was dominant in the older group, had highest incidence in connurbations but the gradient of risk for older onset ALL followed the overall pattern for this age group. A positive relationship with socioeconomic status was evident for both age groups but this was considerably stronger for the older cases (OR = 1.16, 95% confidence interval 1.01-1.33) than for the younger for whom it was not independent of urban distance. These results display an association between expression of lymphoid malignancies in young people and urban distance which is not attributable to socioeconomic status; for urban distances the distribution is shifted towards ALL and towards younger age at onset.     

Urbanisation and incidence of acute lymphocytic leukaemia among United States children aged 0-4

Acute lymphocytic leukaemia (ALL) incidence among children under 5 years of age was examined, utilising data from 24 United States cancer registries. County-based incidence rates among white children were compared across four levels of urbanisation: large and small metropolitan counties, and adjacent and nonadjacent rural counties. In metropolitan areas, the incidence of ALL was lower among blacks (rate ratio (RR)=0.38, confidence interval (CI)=0.33-0.44) and among Asians/Pacific Islanders (RR=0.78, CI=0.63-0.97) than among whites. Among white children, the incidence of ALL decreased across the four strata of urbanisation, from 67 to 62 to 65 to 54 cases per million person-years at-risk (two-sided trend P=0.009), such that rates were significantly lower in the most remote rural counties than in the most populous metropolitan counties (RR=0.80, 95% CI=0.70-0.91).     

Childhood acute leukaemia in a tropical population.

The clinical features of acute leukaemia (AL) were documented prospectively among Nigerian children resident in the South-Western rain-forest area of the country, and compared to the features in Caucasians. Twenty-nine of 51 newly diagnosed cases of AL occurred in childhood, including 19 cases of acute lymphoblastic leukaemia (ALL) and 11 of acute myelogenous leukaemia (AML). The incidence of ALL the AML in Ibadan children was the same, estimated as 0.8 X 10(-5). Thus childhood ALL was about one-third as common in Ibadan as in most developed Caucasian countries. ALL and AML occurred most frequently in the age groups 10-14 and 5-9 years respectively. Six cases of AML were associated with chloromas. Only 2 of the ALL patients survived more than one year after standard chemotherapy. The poor result appeared to be attributable to frequent occurrence among the ALL patients of adverse prognostic factors such as hyperleucocytosis, age less than 2 or greater than 7 years, L2 morphology and low PAS reactivity of the lymphoblasts. Unknown environmental factors are believed to be responsible for the unusual features of AL in children in Ibadan.