BRAIN TUMOURS: INCIDENCE, SURVIVAL, AND AETIOLOGY

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1 ii12 Correspondene to: Dr Patriia A MKinney, Paediatri Epidemiology Group, Unit of Epidemiology and Health Servies Researh, University of Leeds, 32 Hyde Terrae, Leeds LS2 9LN, UK; p.a.mkinney@leeds.a.uk BRAIN TUMOURS: INCIDENCE, SURVIVAL, AND AETIOLOGY T P A MKinney J Neurol Neurosurg Psyhiatry 2004; 75(Suppl II):ii12 ii17. doi: /jnnp he term brain tumours refers to a mixed group of neoplasms originating from intraranial tissues and the meninges with degrees of malignany ranging from benign to aggressive. Eah type of tumour has its own biology, treatment, and prognosis and eah is likely to be aused by different risk fators. Even benign tumours an be lethal due to their site in the brain, their ability to infiltrate loally, and their propensity to transform to malignany. This makes the lassifiation of brain tumours a diffiult siene and reates problems in desribing the epidemiology of these onditions. Publi pereption generally fails to distinguish between different tumour subtypes and although treatments and prognosis may vary, the funtional neurologial onsequenes are frequently similar. This artile will give an overview of the burden of brain tumours in the population, looking at the major subtypes where possible, in addition to giving a summary of urrent views on possible auses. INCIDENCE The desriptions in this paper fous on primary tumours of the brain. It exludes data on spinal ord tumours, metastati tumours, whose origins are external to the entral nervous system, and primary brain lymphomas, whih are essentially haematologial malignanies. Malignant tumours of the brain are a rare ourrene aounting for approximately 2% of all aners in adults. Approximately 4400 people are newly diagnosed with a brain tumour eah year in the UK ompared to over women with breast aner and approximately men with prostate aner. Figure 1 shows additional omparative data for different aners. The overall annual inidene rate of all brain tumours is 7 per population. UK data are listed in table 1. The greatest proportion of adult tumours are supratentorial, arising in the frontal, temporal and parietal lobes, and the majority (86%) are gliomas whih inlude astroytomas, glioblastomas, oligodendroblastomas, and unspeified gliomas. Threefold differenes in the inidene of brain tumours have been reported between ountries worldwide and differenes are also seen between ethni groups within the same ountry. Developed ountries appear to have the highest rates of brain tumours but this may be a result of better registration systems whih inlude benign tumours. However, the magnitude of the variation is less ompared to other aners for example, up to 10-fold differenes are seen for breast aner. Geographial variation has to be autiously interpreted as, unlike other aners, the riteria and registration of brain tumours is not always onsistent. The inidene of brain tumours rises with age from approximately 30 years old onwards, in ommon with virtually all other adult aners. Figure 2 illustrates the age inidene urve showing a drop in inidene in those over 75 years. It is thought this may well be artefatual and ourring as a onsequene of tumours of the brain being less likely to be investigated and deteted in the elderly. Symptoms in older people may be explained by other o-morbid onditions suh as strokes or physiians may be relutant to undertake thorough investigations. Males are more likely to be diagnosed with brain tumours than females, with a male:female ratio of 1.5:1. However, this disguises the fat that women are more likely to develop meningiomas than men. Despite its relative rarity the burden of these tumours is onsiderable for the individuals, their families, and the health are system. Poor survival for many tumour types results in a disproportionate number of years of life lost ompared to other aners. TIME TRENDS There have been reports of inreasing inidene of primary brain tumours in reent deades whih need to be interpreted with aution. Trends over time an only be onsidered valid when based upon data olleted aording to the same definitions and reporting pratie. Inonsistenies and hanges over time may be the explanation for the observed rises whih have been attributed to various fators. Improved diagnosti imaging, following introdution of radio isotope imaging,

2 NEUROLOGY IN PRACTICE Table 1 Brain and entral nervous system tumours: UK inidene 1999 omputed tomography, and magneti resonane imaging in the 1970s and 1980s, will have resulted in higher detetion rates and better differential diagnosis of brain tumours whih might have previously been diagnosed as strokes or metastati tumours. Aess to servies will have improved, making it more likely that a patient with a tumour is registered. In addition, histopathologial tehnology has inreased the speifiity of tumour diagnosis and thus an apparent inrease in speifi tumour types for example, astroytomas may merely be a onsequene of fewer non-speifi diagnoses being registered. In Norway and the USA speifi studies investigating whether time trends an be aounted by these fators suggest that the reported inrease in brain tumours is likely to be an artefat of hanging diagnosti and reporting pratie. The levelling off of inidene in the 1990s in the USA supports this assertion. Steady rises in the rates of brain tumours in hildren under 14 years and the elderly over 70 years are most learly doumented. For hildren this may be explained by hanges in the environment, but the inrease over time in older patients is more likely attributed to hanges in the delivery of are assoiated with a greater likelihood of full evaluation and intervention. England Wales Sotland Northern Ireland UK Numbers Males Females Persons Age standardised rates* Males Females Persons % onfidene intervals Males (8.0 to 8.7) (8.5 to 11.7) (6.5 to 8.6) (8.1 to 12.7) (8.1 to 8.7) Females (5.1 to 5.6) (6.4 to 8.9) (4.4 to 6.0) (3.0 to 5.8) (5.2 to 5.7) Persons (6.5 to 7.0) (7.8 to 9.8) (5.6 to 6.9) (5.9 to 8.5) (6.6 to 7.0) *Diretly age standardised (European) rate per population at risk. Soure: SURVIVAL The length of survival following diagnosis of a brain tumour is dependent on both the age of the patient, histologi subtype and grade of the tumour, and presenting symptoms. Survival hanes have improved gradually over the last 30 years but remain poor; for all adults diagnosed with a malignant brain tumour in England and Wales during , 30% survived to one year and 15% to five years. For patients diagnosed between only 8% survived to 10 years. There are known to be geographial differenes in the delivery of are to aner patients within the UK and this may be refleted in long term survival. Reent omparisons of survival from adult brain tumours in eight former National Health Servie (NHS) regions (in 1999) and Wales have shown differenes between regions and over time within a region. Differenes may be aounted for by temporal hanges in registration pratie, but one partiular aspet whih is diffiult to explain is the observed variation in survival for men and women within a region. It seems unlikely that are and treatment would vary aording to sex for patients living in the same area and these differenes Figure 1 UK inidene 1999: aners whih ontribute 1% or more to total aner burden. ii13

3 ii14 Figure 2 Number of new ases diagnosed and age speifi rates per population, brain and entral nervous system aner, by sex, UK, Soure: remain unexplained. Levels of soial lass measured in deprivation ategories are seen to influene survival, with those living in more affluent areas generally having improved survival with the effet seen most prominently at one year post-diagnosis. Geographial differenes in survival exist between ountries. The five year survival of patients diagnosed with any type of brain tumour in England, Wales, and Sotland is approximately 13% in men and 16% in women. Aross Europe equivalent figures are 17% and 20% in men and women, respetively, and generally the UK figures are 10% below the USA. The disrepany is potentially explained by the fat that figures from the USA inlude tumours lassified as benign whih would not be registered in many of the UK aner registration shemes. The overall poor survival for this group of tumours masks differenes for subtypes. Meningiomas, both benign and malignant, for example, have a muh better prognosis whereas glioblastoma multiforme (GBM) has the poorest survival in all age groups. Other fators assoiated with survival hanes inlude age, with younger adults faring better, being female, whih slightly improves survival, as well as the loation of the tumour and the extent of tumour resetion. More reent studies have shown that further haraterisation of tumours by moleular and geneti markers an provide useful prognosti indiators although there is little information in the literature as markers are not routinely reorded for the majority of patients. However, with improved and systemati reording of the moleular harateristis of tumours, the relation to progression and prognosis will be larified. CHILDHOOD BRAIN TUMOURS Brain tumours are the seond most ommon aner in hildren, omprising 15 25% of all paediatri malignanies, and they are the most ommon solid tumour. Different Table 2 Summary of environmental risk fators for brain tumours investigated in epidemiologial studies Fator Speifi aspets Evaluation of risk Ionising radiation Therapeuti, diagnosti Therapeuti doses inrease risk but diagnosti x rays do not appear to be assoiated Mobile phones Radiofrequeny exposure Current epidemiologial and biologial evidene does not support any link between mobile use and the risk of brain tumours Extremely low frequeny eletromagneti fields Residential and oupational exposure Little onsistent evidene but researh is ongoing Speifi infetions Viruses, Toxoplasma gondii, in utero influenza and variella No andidate viruses onsistently assoiated or found in tumour tissue. Few links to in utero exposure Allergies Atopy The presene of atopy appears to be protetive but further work needed to identify mehanisms Diet Nitrosamine/nitrosamide/ No onsistent evidene nitrite/nitrate onsumption. Aspartame Tobao Cigarettes, igars, pipes No assoiations Alohol No assoiations Chemial agents Hair dyes, solvents, pestiides, No onsistent evidene traffi related air pollution Oupations Rubber manufature, vinyl hloride, petroleum refining Small risks assoiated with working in the petroleum/oil industry but no mehanism or speifi hemial known Head trauma/injury No onsistent evidene NEUROLOGY IN PRACTICE

4 NEUROLOGY IN PRACTICE proportions of histologial subtypes are present in hildren ompared to adults, with gliomas (approximately 40%) and medulloblastomas (approximately 25%) mainly arising infratentorially, with the remainder, germ ell tumours and raniopharyngiomas, ourring in the midline. There is a small peak in inidene in early hildhood aounted for by medulloblastomas. Studies in the USA, Sweden, and the UK have reported what appear to be true rises in inidene over the last three deades whih are unexplained by hanges in diagnosti pratie, treatment, or lassifiation. The question of whether this is a real and ontinuing effet an only be answered by future surveillane using aurate and omplete population based registers. Survival for hildren with brain tumours has improved by 16% sine 1971 in England and Wales. The prognosis in hildren is superior to that of adults with an overall probability of surviving to five years of 59% in England and Wales for those diagnosed ompared to 72% in the USA. RISK FACTORS Current thinking suggests that brain tumours develop as a onsequene of aumulated geneti alterations that permit ells to evade normal regulatory mehanisms and destrution by the immune system. These alterations may be in part or wholly inherited but any agents hemial, physial or biologial that damage DNA are possible neuroarinogens. Investigations of the auses of brain tumours should ideally address the simultaneous influene of both geneti fators and environmental exposures. Table 2 lists the environmental fators whih have reeived attention as possible auses of brain tumours. GENETICS Geneti predisposition to developing brain tumours is assoiated with ertain inherited syndromes suh as tuberous slerosis, neurofibromatosis types 1 and 2, nevoid basal ell arinoma syndrome, and syndromes involving adenomatous polyps. These syndromes aount for 1 2% of all tumours. The Li-Fraumeni aner family syndrome is also assoiated with a predisposition to brain tumours and speifially with mutations in the TP53 gene. Mutations in onstitutional (that is, non-tumour tissue) TP53 have been linked to patients with gliomas. Future work on ausality should be able to aount for possible interations between known geneti predisposition in the investigation of environmental risk fators. Familial aggregations of brain tumours ourring in different generations and sibships our very rarely and the patterns of inheritane are inonsistent. In these situations ommon environmental exposures annot be exluded as an explanation. Overall, it appears that only a very small proportion of brain tumours an be attributed to the effet of inherited predisposition. Common variations in the struture of speifi genes are known to be assoiated with basi ellular metaboli proesses suh as oxidation, detoxifiation, DNA stability and repair, and immune funtioning. Suh geneti polymorphisms may well be assoiated with the development of brain tumours in the presene or absene of environmental arinogens. However, the limited findings available so far have failed to onsistently identify any speifi polymorphisms, but this remains a potentially fruitful line of researh and future large sample studies are needed. IONISING RADIATION Ionising radiation given in therapeuti doses is one of the few known risk fators for brain tumours. The now disontinued low dose radiation treatment of tinea apitis and skin disorders in hildren inreased the risk of brain tumours well into adulthood as does radiotherapy for hildhood aners and leukaemia. Survivors of the atomi bomb in Hiroshima have inreased risks of meningioma in proportion to their level of exposure. In utero exposure does not appear to affet the risk for the developing fetus. Diagnosti x rays do not appear to be linked to gliomas, but full mouth dental x rays have been assoiated with meningiomas in a small number of studies. MOBILE PHONES Radiofrequeny (RF) signals whih fall within the mirowave region of the eletromagneti spetrum are emitted and reeived by mobile phone handsets. The energy levels of these waves are insuffiient to damage or disrupt ellular DNA. However, publi onern over the possible detrimental health effets of using mobile phones have resulted in a number of investigations of possible links with brain tumours. When assessing the literature on this topi interpretation of a small number of early studies from the USA and Sweden must be autious. They were onduted on relatively small populations, relating to a time when analogue phones predominated, they had relatively short follow up periods, or they suffered from methodologial shortomings. To date five further reports from substantial well onduted studies in the USA, Finland, and Denmark using different epidemiologial methods have observed the same outome. They found no inreased risk of brain aners or any subtype of brain tumour assoiated with exposure to mobile phones using measures of the type of phone, duration and frequeny of use, and umulative hours of use. Thus, so far the onsensus of evidene is that mobile phone use does not inrease the risk of developing a brain tumour. However, with the exponential inrease in the ownership and duration of use of these hand held devies it will be important to ontinue investigations with respet to digital phones, allowing for a latent period of several deades in the development of a tumour. EXTREMELY LOW FREQUENCY MAGNETIC FIELDS Power frequeny extremely low frequeny magneti fields (ELF-MF) of Hz are used in domesti and industrial eletriity supplies presenting a virtually ubiquitous exposure to the population, although levels of exposure do vary. The possibility of adverse health effets has generated onsiderable publi onern, despite sant epidemiologial and biologial support in the researh literature. The biologial basis for ELF-MF being involved in malignant transformation is not strong as there is no onsistent researh whih shows this low energy exposure has any diret effets on disrupting ellular DNA or metaboli pathways. Studies of oupational exposure to high levels of ELF-MF and the risk of brain tumours have mixed findings. Variation in results an be explained by differing study methodologies and sample size, the latter affeting the power to detet inreased risk. One substantial differene is the method used to assess ELF-MF exposure; this varies from the use of proxies suh as wiring onfiguration odes, distane from distribution equipment, and histori load data to diret measures of exposure. The lak of onsisteny between ii15

5 ii16 independent researh projets and the diffiulties with measuring the exat exposure levels of the individuals at work makes interpretation problemati. For mothers exposed at work during their pregnany there does not appear to be any inreased risk of their hild subsequently developing a brain tumour. Overhead power ables and wiring onfigurations in houses affet the levels of exposure to ELF-MF in a domesti residene. Early reports in the late 1980s of hildhood brain tumours assoiated with high levels of domesti exposure have not been repliated. Current evidene shows that at levels experiened by the general population no risk of brain tumours in hildren appears to be present. However, for extremely high levels of exposure further investigations are underway. IMMUNE FACTORS: VIRUSES, ALLERGIES, INFECTIONS In experimental animal models brain tumours an be indued by a number of viruses, inluding retroviruses, papovaviruses, and adenoviruses but there is little epidemiologial support for this ourring in humans. At one time it was thought that live polio vaines ontaminated with SV40 might inrease the risk of brain tumours, but the initial observations were not supported by more detailed powerful studies. Diret examination of brain tumour tissue for evidene of a viral ause has shown the presene of different viral DNA sequenes in a proportion of ases within separate pathologial series. However, the mehanisms of how a virus might initiate malignant transformation remain unknown and more work is needed to disentangle the putative role of viruses in ausing brain tumours. Atopi diseases suh as asthma, ezema, and allergies an be markers of immune dysfuntion. In a number of independent studies from different ountries atopi onditions have been shown to be protetive, partiularly in the development of gliomas. Patients with gliomas report fewer symptoms of atopy ompared to ontrol subjets. This relation is an interesting one and might indiate a role for immunologi fators in ausation. In utero infetions with influenza and hiken pox (variella) have been ited as a risk fator but the ase for this is not strong. Some reent epidemiologial work on a series of hildren from the north west of England diagnosed with brain tumours has shown geographial distributions whih are suggestive of an infetious aetiology for some of the tumour types. Clustering in time and spae and seasonality of diagnosis indiate infetions may be risk fators. The involvement of infetions and immune responses in brain tumour aetiology is an area of researh that learly warrants further attention. CHEMICALS N-nitroso ompounds are found in the environment but the most ommon soure of human exposure is through foods, with vegetables and ured meats being major soures. Certain alkylating agents, suh as ethyl and methyl nitrosurea, are known transplaental arinogens, partiularly for brain tumours in rats. Their ability to ross the blood brain barrier and their mutageni potential makes them ideal andidates as initiators in the arinogeni proess. In humans, dietary and environmental N-nitroso ompounds have been studied as potential brain tumour arinogens along with the NEUROLOGY IN PRACTICE potentially protetive effet of onsuming antioxidants. The soures of antioxidants inlude fresh fruit and vegetables, supplements, and endogenous metaboli pathways. Attributing the ause of brain tumours to these ompounds or other dietary fators suh as vitamin supplements has reeived mixed support in the published literature. Dietary assessment is fraught with problems and it may be that the ingestion of potentially toxi ompounds is offset by the ingestion of antioxidants whih promote DNA repair. Nitrate levels in drinking water have also been investigated but no onsistent assoiations found. The low alorie sweetener aspartame has been ommonly used in a number of food produts for over 15 years. It has been suggested to be involved in the aetiology of some brain tumours based prinipally on the results of laboratory experiments. The biologial basis for any influene whih aspartame ould have on the risk of developing a brain tumour is unlear. Tobao smoke is arinogeni but many onstituents do not pass the blood brain barrier. Smoking does not appear to be strongly linked to brain tumours either in adults who smoke themselves or via maternal smoking in pregnany. A similar lak of assoiation is seen for alohol onsumption. Various other hemials have reeived attention. Hair dyes and hair sprays were impliated as risk fators for brain tumours in some early epidemiologial studies but the observations remain unonfirmed. Further inonsistent reports have linked hildhood brain tumours to pestiide exposure, traffi pollution, and parental oupations. The possibility of fathers sperm being damaged and the developing fetus being affeted by parental oupation and the development of hildhood brain tumours has been extensively studied, but few onlusions have been drawn. A reent large sale ase ontrol study of hildhood aners in the UK failed to show any signifiant assoiations between brain tumours and the oupations of either mothers during pregnany or fathers around the time of oneption. In the working population many jobs in various industries involve exposure to arinogeni or neurotoxi ompounds inluding organi solvents, polyyli aromati hydroarbons, lubriating oils, and phenols and the question has been frequently asked as to whether suh exposure is related to brain tumours. Despite numerous studies no onsistent risks have been isolated for any hemial or group of workers apart from those in the petrohemial and oil industry. In these irumstanes no speifi hemial has been identified and the possibility of multiple exposures has to be onsidered. HEAD TRAUMA AND INJURY Patients with brain tumours inevitably reall ourrenes of trauma or injury to the head with greater frequeny than the general population, and studies of patients reports are therefore subjet to reall bias. Some epidemiologial investigations of the relation between head trauma/injury and the subsequent development of a tumour have attempted to overome this by examining medial reords, but these mainly fail to demonstrate any relation. The inevitable pitfall of reall bias as an explanation of a raised risk renders most work in this area virtually impossible to interpret. SUMMARY Brain tumours in adults are a rare disease from whih survival is generally poor ompared to many other aners. Reports of rising trends need to be autiously interpreted as

6 NEUROLOGY IN PRACTICE they may well be explained by hanges in diagnosti and linial pratie. In hildhood a different profile of tumour types is present and survival has improved over reent years and is higher than in adults. Apart from geneti predisposition, the most well established environmental risk fator for brain tumours is exposure to high doses of ionising radiation. Researh into infetions and immune fators may prove a fruitful avenue of investigation. SOURCES OF INFORMATION International The International Ageny for Researh on Caner ( Central Brain Tumour Registry of the United States (CBTRUS) ( The UK Caner Researh UK ( ) UK Assoiation of Caner Registries (UKACR) (www. UKACR.org.uk) England: National Caner Intelligene Centre, Offie for National Statistis ( Wales: Welsh Caner Intelligene and Surveillane Unit ( Sotland: Information and Statistis Division, NHS in Sotland ( Northern Ireland: Northern Ireland Caner Registry ( REFERENCES 1 Coleman MP, Babb P, Damieki D, et al. Caner survival trends in England and Wales, : deprivation and NHS region. Studies in medial and population subjets no. 61. London: Stationery Offie, Davis FG, MCarthy BJ. Current epidemiologial trends and surveillane issues in brain tumours. Expert Rev Antianer Ther 2001;1: Little J. Epidemiology of hildhood aner. IARC Sientifi Publiation no.149. Lyon, Frane: International Ageny for Researh on Caner, MKinney PA, Fear NT, Stokton D, on behalf of the UK Childhood Caner Study Investigators. Parental oupation at perioneption: findings from the United Kingdom hildhood aner study. Oup Environ Med 2003;60: Wrensh M, Minn Y, Chew T, et al. Epidemiology of primary brain tumours: urrent onepts and review of the literature. Neuro-onology 2002;4: ii17