This is the first comprehensive small-area analysis of osteosarcoma and Ewing sarcoma in 0–49 year olds from GB. Furthermore, it is the largest geographical study of these tumour types to date. GB is an ideal setting for this type of investigation due to the availability of highly accurate and complete cancer registration data, together with corresponding population census data. The study has revealed two novel findings: (a) for females lower incidence of osteosarcoma was associated with higher levels of deprivation; (b) lower incidence of Ewing sarcoma was associated with residence in more densely populated areas and higher levels of non-car ownership.
Our prior hypotheses were: a primary factor influencing geographical heterogeneity of incidence of osteosarcoma or Ewing sarcoma is modulated by differences between environmental exposures occurring in (i) less and more densely populated areas of residence; (ii) less and more socio-economically deprived areas of residence; and geographical heterogeneity of incidence of osteosarcoma or Ewing sarcoma is modulated by (iii) age; and (iv) gender.
For osteosarcoma the results suggest that, at least for females, geographical heterogeneity of incidence is modulated by differences in environmental exposures occurring in less and more socio-economically deprived areas of residence (providing support for prior hypotheses (ii) and (iv), but little support for prior hypotheses (i) and (iii)). For Ewing sarcoma the results suggest that geographical heterogeneity of incidence is modulated by differences in environmental exposures occurring in less and more densely populated areas and that incidence is also modulated by some aspect of differences between environmental exposures occurring in less and more socio-economically deprived areas of residence. However, some of the components of deprivation may be confounded with population density apart from non-car ownership (providing support for prior hypotheses (i) and (ii)). Comparison of the case counts for both osteosarcoma and Ewing sarcoma from the WMCIU for children aged 0–14 years across all regions confirmed virtually identical agreement with the counts from the NRCT dataset.
Two methodological caveats should be noted. First of all, census ward (or postcode sector) population density and Townsend deprivation scores are not necessarily related to characteristics of individual cases and should only be regarded as ecological measurements. Area-level data have been assigned to individual cases. Care should be exercised when using such grouped data to make inferences about individuals. There may be unknown confounding factors that display the same pattern of spatial heterogeneity . Secondly, the case, population and demographic data were analyzed using 2001 census boundaries. The method did not take into account the possible effects of migration, which may have diluted the results. Nevertheless, the findings were very clear cut, indicating that this does not appear to have been a major limitation.
The study has a number of particular strengths. First, it analyses high-quality population-based data. Secondly, the inclusion of ages 0 to 49 years includes the peak incidence of both osteosarcoma and Ewing sarcoma, which occur in the teenage years. There is a theoretical possibility that diagnosis delays vary according to some of the demographic factors that have been analyzed here. Consequently, a lower maximum age limit might have led to differential loss of some cases, according to demographics.
Previous studies have explored geographical patterning in the incidence of bone cancers, but have been focused on children, aged 0–14 years [7, 8]. An analysis of childhood incidence data in GB found space-time clustering amongst cases of osteosarcoma, but not Ewing sarcoma. The space-time clustering was significant for females, but not for males . This was interpreted as providing support for the involvement of a geographically heterogeneous and transient environmental exposure in the aetiology of osteosarcoma. Effects of such an exposure may be modulated by gender. Another analysis of the same national GB data set found increased risk of childhood Ewing sarcoma in areas of greater socio-economic affluence . However, the age-specific incidence of these tumours means that to cut off analyses at age 14 years is artefactual and an extended age range to cover the majority of the conditions is more appropriate, such as the one described here. It is possible that the splitting of age–groups at 0–14 and 15–29 years may have led to a dilution of the number of male cases in the peak age-range which straddle both groups and thus have led to the female-specific effect for deprivation amongst cases of osteosarcoma. However, a further supplementary analysis used age groups 0–29 and 30–49 years and found that the interaction between deprivation and gender was still present (data not shown).
The aetiology of osteosarcoma is likely to involve both genetic predisposition and environmental triggers. However, known genetic factors only account for a small proportion of cases [9, 27–33]. The present study has shown that increased levels of deprivation (i.e. less affluence) are protective against osteosarcoma. This suggests that differences in some aspect of lifestyle may predispose to greater risk of osteosarcoma. These differences may include both dietary and social factors. A meta-analysis of fourteen studies has found that the mean height of osteosarcoma patients was two to three centimetres greater than the reference population. The authors described this finding as a surrogate for affluence. However, there was no obvious bias towards females . Another pooled analysis (of seven studies) found that taller than average individuals had increased risk of osteosarcoma and very tall individuals had even greater risk . Such differences in height are characteristic of more affluent living conditions during childhood. A further recent descriptive analysis of incident data on cases of bone cancer, diagnosed in England during the period 1979–2003 showed that the female peak was earlier (10–14 years) than for males (15–19 years). The authors proposed that pubertal bone growth may be implicated . Our findings suggest that during this period females may be more vulnerable to a putative environmental hazard as a consequence of hormonal effects. Another small case–control study of juvenile bone tumours (in 88 patients aged 8–25 years) found increased risk associated with frequent change of residence and previous mumps . Together with finding of space–time clustering, this suggests that it is possible that one or more infectious agents may be implicated . The possible association with frequent change of residence would suggest that some aspect of population mixing may be implicated. We would postulate that the pathway is likely to be indirect. Such a mechanism has been proposed for childhood leukaemia, with unusual population mixing or delayed exposure to common infections in early life conferring greater risk . Further epidemiological studies (e.g. using a case–control design) are needed to determine if infections occurred more frequently prior to diagnosis in cases of osteosarcoma, compared with an unaffected control group. The nature and type of putative infections should also be investigated. However, it should be noted that the rarity of this condition would make the conducting of a case–control study relatively expensive.
Both genetic and environmental factors are also implicated in the aetiology of Ewing sarcoma. However, again genetic factors alone can only explain a small fraction of the total cases [39, 40]. The present study has shown a higher risk with residential living in less densely populated areas, but also with higher levels of car ownership. These are both characteristic of rural areas. Markedly higher incidence was apparent in East Midlands and Scotland, which both contain large areas of rural expanse. Rural living, together with high levels of car ownership, may also be consistent with a certain type of socio-economic affluence. Potential exposures that have been linked with Ewing sarcoma include both pesticides and zoonotic infectious agents [41–43]. If infectious agents are involved the mechanism is likely to be different from osteosarcoma, as Ewing sarcoma did not exhibit space-time clustering . Further studies should determine if higher risk of Ewing sarcoma is associated with residential living in close proximity to areas with predominantly agricultural land use. Analyses could include investigating possible associations with land use data, including types of crop grown and pesticides used.