Monty's Corner research information aims to:
Childhood cancers - The main classifications of childhood cancers. Monty's Corner focuses on all types of childhood cancers.
What do we already know? - The research studies have been carried out since 1960s in childhood cancers. We present only the research results without any comments. References are provided at the end of the section. Please note that we have not covered all the research results here as we are still processing the content from other sources.
What does it mean to us? - We explain what these research results mean to all of us.
What does research involve? - The epidemiological research methods and why sometimes the research takes so long to find consistent and conclusive results.
When is an external factor considered to be a risk factor? - Methods and approaches are shown to consider an environmental factor a risk factor.
What "can we" do? - We heard many times from people who are in the same boat asking whether we, the parents, can do anything to help. Here we explain "what we can do to help".
The scientific information in the following chapters have been complied based on the review paper (Childhood Cancer Epidemiology, 2007) published by Dr. M. Tevfik Dorak, MD PHD - University of Miami.
Significant research into the cause, diagnosis, treatment and prognosis of childhood cancers is being conducted. Hundreds of clinical trials are being planned or conducted at any given time. Studies mainly focus on effective means of treatment, better ways of treating the disease, improving the quality of life for patients, or appropriate care in remission.
There are several good websites you can find comprehensive information about the childhood cancers such as symptoms, diagnosis, treatments and care.
Monty’s Corner focuses only on the causes and risk factors of childhood cancers; hence, in this section we have provided only the classifications of childhood cancers and statistical incidence results.
Childhood cancers are classified based mainly on morphology and tissue of origin as in the International Classification of Diseases (ICD).
Most childhood cancers are classified in the following broad categories:
Leukaemias (25%) - ALL, AML, CML and others
Lymphomas and reticuloendothelial neoplasms – Hodgkin lymphoma (5%) and non-Hodgkin lymphoma (6%)
Central nervous system neoplasms (20%) – Astrocytoma and other gliomas, primative neuroectodermal tumours (PNET), medulloblastoma and others
Sympathetic nervous system tumours – Neuroblastoma (7%), ganglioneuroblastoma and others
Renal tumours - Wilm’s tumour (6%), renal cell carcinoma and others
Hepatic tumours – Hepatoblastoma, hepatocellular carcinoma
Malignant bone tumours – Osteosarcoma (3%), Ewing’s sarcoma (2%)
Soft tissue sarcomas – Rhabdomyosarcoma (3%), fibrosarcoma and others
Germ cell, trophoblastic and other gonadal neoplasms
Malignant epithelial neoplasms – Thyroid carcinoma, malignant melanoma and others
It is true that we still do not know for sure why our children get cancer. Scientists are also asking the same questions. It is generally believed that the childhood cancer is caused by a complex interaction of genetic and environmental factors that the scientists do not fully understand yet. As numerous studies have been made to detangle the complex nature of cancer, it is becoming more evident that certain environmental and genetic factors may only affect cancer when combined. Environmental factors are normally examined in population-based studies. Due to the limited evidence or inconclusive results, researchers are giving great focus on the gene-environment interaction studies - this is where they investigate some genetic variants that may cause cancer when they are combined with specific environmental exposures, which otherwise may not be risk factors for childhood cancer.
Although it is difficult to unravel the environmental factors causing childhood cancer in population studies it does not mean that we have to stop such studies. Population studies give us clues on where to focus our detailed clinical research.
There are several well-established environmental causes of childhood cancer. The earliest known exposures were radiation, diethylstilbestrol and some chemotherapeutic agents. The studies of Japanese children who were exposed to atomic bomb radiation have found that these children, as they grew, had higher rates of childhood leukaemia than unexposed children. Many other agents such as electromagnetic fields, pesticides and some parental occupational exposures are suspected of playing roles, but the evidence is not yet conclusive.
Below is the list of potential causes that researches have studied to date. We have divided these studies into three time periods.
Research so far includes:
Some studies report associations between childhood cancer and parental exposure to pesticides. These studies suggest an increase in risk of brain tumour, leukaemia, non-Hodgkin lymphoma, Wilmâ€™s tumour, and Ewingâ€™s sarcoma and germ cell tumours associated with parental occupational and non-occupational exposure to pesticides.
Associations between hydrocarbon related parental jobs and CNS tumours, and between paint, benzene, wood dust and radiation exposure of parents and leukaemias have also been reported.
Possible associations were reported between recreational use of drugs such as marijuana and cocaine, and leukaemia and lymphoma.
Research so far include:
Animal studies have shown that N-nitroso compounds are powerful carcinogens to be able to pass placenta to the developing fetus. They are considered to be risk factors for certain adult cancers. It is hypothesised that these compounds synthesised from relevant food stuffs (e.g., excessive hot dog and cured meat consumptions) ingested by mothers during pregnancy might act as carcinogens passing through the placenta and that a high intake of fruit and vegetables or vitamin C supplements may play protective roles. This hypothesis has been tested in a number of studies focused on childhood brain tumours. The studies reported an association between these compounds during pregnancy and subsequent childhood brain tumour in offspring. It is also implied in childhood leukaemia.
Flavonoids, referred as bioflavonoid in media, are commonly known for their antioxidant activity. Good dietary sources of flavonoids include all citrus fruits, berries, onions, parsley, green tea, red wine and dark chocolate. Some of these flavonoids, known as DNA topoisomerase (DNAt2) inhibitors, have been shown to cause site-specific DNA cleavage in the MLL gene breakpoint cluster region on chromosome 11q23. It has been, therefore hypothesised that the infant leukaemias (of which 80% have the MLL abnormality) may occur as a result of maternal exposure to flavonoids in diet during pregnancy and medications that inhibit DNAt2. Contradictory associations have been reported in various studies.
DES is a synthetic non-steroidal oestrogen drug that was first synthesized in 1938. In 1971, it was found to be a teratogen (refers to disfiguring birth defects or malformation) when given to pregnant women. During the 1960s, DES was used as a growth hormone in the beef and poultry industry. It was later found to cause cancer and was phased out in the late 1970s. Studies demonstrated that cancer could be induced by DES passing through the placenta. Another study found that DES could be trans-generational meaning that the third generation may be effected by the DES used by the maternal grandmother.
Animal studies provided evidence that some genotoxic and carcinogenic compounds can pass placenta to the developing fetus. Because of this it is hypothesised that exposure to these agents during pregnancy is a risk factor for childhood cancers. However, no consistent associations were reported between maternal exposures to these agents and childhood cancers.
Studies did not find any consistent association between maternal tobacco smoking during pregnancy and any type of childhood cancer. Possible association has been reported between paternal smoking and ALL. Positive association has been reported between maternal alcohol consumption during pregnancy and AML.
It has been reported that there is an increased risk for AML with anemia detected during pregnancy. It has been also reported that anemia should be examined along with other factors.
ALL has been attributed to an infectious exposure of the fetus during the pregnancy but no evidence has been found to support this theory.
Children are not simply small adults. The major difference between children and adults is the fact that children are developing and growing. Exposures to environmental agents can result in more profound consequences in a child, than a similar exposure in an adult. These environmental agents may results in mutations in genes involved in control of cell division, apoptosis (programmed cell death), growth and differentiation. Infants and children differ from adults in their exposure both qualitatively and quantitatively. They eat more food, drink more water and breathe more air per unit of body weight than adults do, and the activity patterns of children further increase their exposure to environmental agents.
A recent study in the UK reports associations to childhood cancer development with proximity of birth places to sites of industrial combustion, volatile organic compounds (VOCs) uses and associated engine exhausts, 1,3-butadiene, dioxins and benz(a)pyrene.
Electromagnetic fields create low frequency non-ionising radiation which can cause molecular damage. Electromagnetic fields include static fields, power frequency fields, radio frequency fields and UV radiation. These fields are everywhere in modern societies. Examples of sources of exposure are production and use of electric power, electronic surveillance systems, wireless communications, tanning machines and solar exposure. The most visible source to extremely low frequency (ELF) magnetic fields is arguably power lines and in particular high voltage transmission lines. It was first pointed out in 1979 that long term-term exposure to low frequency magnetic fields (e.g., living near the power lines) may be associated with leukaemia risk in children. Further studies concluded that the data supporting residential electromagnetic fields as the principle risk factor are suggestive with small to moderate effect sizes. A study carried out in the UK in 1999 showed a trend of increasing incidence with increasing exposure but the study was not powerful enough to provide a statistically significant result. Recently, in a large case-control study it was concluded that a childâ€™s risk of leukaemia increased steadily with proximity to high voltage power lines of the home they lived in at birth and the distance up to 600m may increase the risk.
It is now internationally agreed that the electric and magnetic fields are a possible cause for concern in humans.
Associations between a childâ€™s exposure to pesticides and childhood cancer have been reported. Certain pesticides are classified as endocrine disruptors and linked to childhood cancer development.
Studies showed contradictory associations between asthma and other allergic diseases, and leukaemia, neuroblastoma and lymphoma.
Researchers suspected that infections can be a risk to children to develop cancer. There is some evidence supporting an infectious aetiology for childhood leukaemia, particularly c-ALL but the agents involved and the precise mechanisms are unclear. Studies mainly focused on early year (birth to 12 months) exposures to certain viruses which included influenza, measles, CMV, adenovirus, parvovirus, polyomavirus-JCV, polyomavirus-BKV, polyomovirus-SV40, herpes virus, HHV-6 virus, chicken pox and mumps. The only common feature of these studies is the lack of consistency.
There is weak evidence for the involvement of infections in childhood tumours. Some studies suggest an infectious aetiology for at least some CNS tumours and osteosarcomas.
There are various theories for the origin of infections focusing mainly on leukaemia:
Population mixing: It has been suggested that in areas where there is an influx of residents from other areas there would be an increased level of contacts between susceptible individuals and infected individuals (impaired herd immunity hypothesis). Non-exposed individuals living where the relevant infection is not endemic, subsequently become at risk when exposed by mixing with an incoming population of infected carriers. This hypothesis has been tested in the UK. Studies indicated an increased risk of ALL in such mixed populations. It is suggested that one or more specific agents are involved.
Two-independent mutation: It has been suggested for the common subtype of ALL (c-ALL) arises as a result of two independent mutations. The first (creation of pre-leukaemic clone of cells) is occurring during the pregnancy or soon after birth. The second mutation occurs after an average period of three years leading to onset of disease. It has been suggested that common childhood diseases can serve as a promoter of the second mutation. Therefore, if there is a delay in the normal pattern of exposure of the childâ€™s immune system to common childhood infections, this delay may increase the number of susceptible cells hence increasing the risk of the second mutation. Delay in the childâ€™s exposure to common infections might occur due to lifestyle changes associated with socio-economic development (delayed infection hypothesis). This hypothesis considers infections in general.
Seasonality: Seasonality of onset has been shown for ALL, which is presumed to be characteristics of infectious diseases.
Pre-school day care: Children are generally at risk of getting infectious diseases if they attend day care at an early age. This can be considered protective as well. No evidence has been reported to show any associations between day care attendance and leukaemia.
No or little breastfeeding: It has been reported that breastfeeding has great benefits to the infant as well as the mother. These include health, nutritional, immunologic, developmental, psychological, social, economic, and environmental benefits. Therefore, it has been hypothesised that no or perhaps little breastfeeding of the infant should expose the infant to infections by eliminating the protective effects, particularly immune stimulation, of breastfeeding. However, some studies found no or weak protective associations with childhood leukaemia whereas some others found a small but significant protective effect of breastfeeding for ALL, Hodgkinâ€™s lymphoma and neuroblastoma.
Clustering: Researchers have been concerned for many years by the existence of clusters of childhood cancer cases, particularly of leukaemia. Hypothesis was that the clusters might point to an infectious origin to localised environmental exposures. The strongest clusters have been observed for children with leukaemia diagnosed before six years of age in the UK. However, no known cause for clustering has been identified. Speculations included population mixing and environmental pollution. It should be remembered that the clustering does not mean cases diagnosed simultaneously as in an infectious disease outbreak. Evidence for the involvement of infections in childhood tumors is weak. However, space-time clustering among childhood CNS tumors in the UK has been reported. This could support an infectious etiology for at least some CNS tumors.
A few theories have been thought of:
IGF-1 is a polypeptide protein hormone similar in molecular structure to insulin (that's why it is called insulin-like). It plays an important role in childhood growth. IGF-1 has been shown to stimulate the growth of both myeloid and lymphoid cells in laboratory cultures. Hence, it has been proposed that high levels of IGF-1 may both produce a larger baby (higher birth weight) and contribute to leukaemogenesis. Studies investigated the birth weight (high and low) with leukaemia, neuroblastoma, Wilm's tumour, lymphoma, osteosarcoma and hepatoblastoma but mixed results have been reported.
Some observations on animals suggest that there may be an environmental cause for the first-born effect. Along the west coast of Florida, nearly all the firstborn bottlenose dolphin calves die before they separate from their mothers. This is thought to be due to the high levels of environmental toxins in the fat of marine mammals. Research suggests mother dolphins unload as much as 80 percent of their accumulation of pollutants into each of their calves, probably through nursing. By theory, the firstborn gets the highest dose of pollutant as the mother has been accumulating toxins for many years while subsequent siblings receive the toxins accumulated over shorter periods.
Some studies showed an increased risk of leukaemia, generally for those under 5 years of age, associated with being the firstborn. There are also negative results studies.
Maternal history of previous miscarriages is a frequently reported risk factor for development of childhood ALL in a subsequent child except for infant leukaemia.
An increased incidence of birth defects has been reported in childhood cancer, particularly in leukaemia.
Studies showed parental cancer as a risk factor to childhood cancer for nervous system cancers (CNS), lymphomas, endocrine tumours and retinoblastoma but no excess risk for leukaemia and Wilm's tumour.
The risk association have been reported between autoimmune disorders in the family and leukaemia (ALL) and lymphoma.
Researchers, or, to be specific, epidemiologists, attempt to determine what factors are associated with diseases (risk factors), and what factors may protect people or animals against disease (protective factors). The science of epidemiology was first developed to discover and understand possible causes of contagious diseases like smallpox, typhoid and polio among humans. It has since expanded to include the study of factors associated with non-transmissible diseases like cancer. These studies can only show evidence that a particular risk factor is associated with a higher incidence of disease in the population exposed to that risk factor. This is why you have read the word "association" a lot in the previous sections.
In order to prove that a particular risk factor is the factor "causing" the disease, laboratory studies need to be carried out.
The strength of a study depends on the number of cases and control included in the study. The more individual cases that are included in the study, the more likely it is that a significant association will be found between the disease and a risk factor.
Finding a risk factor for a disease is intensive work which comprises gathering data, generating a broad range of biomedical and psychosocial theories or expand theories, testing hypotheses and finally making educated, informed assertions about which relationships are causal and about how they are causal.
The below hierarchy shows typical studies starting from generating a hypothesis to establishing causality.
GENERATE HYPOTHESIS - Case reports -> Case series -> Ecological studies -> Cross-sectional studies -> Case-control studies -> Cohort studies -> Randomized controlled trials - ESTABLISH CAUSALITY
Some of these steps like the cohort studies can take years to conduct.
If you are a parent and your child has been diagnosed with cancer, your immediate reaction might be to find out where you fit. Are you the one who smoked during pregnancy, whose child was the first-born, who had miscarriages or perhaps none of the above? You are not alone; we all try to associate ourselves with something listed above so that we have some answers and perhaps someone or something to blame.
SEER (Surveillance Epidemiology and End Results) currently categorises the risk factors as:
Based on these categories, we can tell you that these research results do not tell us much. They just suggest there is an association between environmental factors and childhood cancers, but the most results are inconclusive or inconsistent. They also suggest that research needs to continue to know more, because we know very little.
Some studies have been carried out in one country but not in another. Some studies that were carried out in one location did not use the same methods for the same type of investigations, hence the results are incomparable and inconsistent. Some others studied only the young children but not the older ones.
We need to investigate environmental factors globally with a wider participation in order to:
This is the primary purpose of CCE Research Alliance - www.cce-researchalliance.com
We know so little. How can we increase our knowledge to know more?
We can increase our knowledge by investing more time and resources into research. However, having the time and resources would be useless if there is no large participation in sharing knowledge.
What we can do:
References used in the preparation of this book can be found in the following publications - For detailed citation click here.
American Journal of Epidemiology
American Journal of Obstetrics and Gynecology
American Journal of Public Health
Archives of Disease of Childhood
British Medical Journal (Clinical Research Edition)
Cancer Causes and Control
Cancer Epidemiology Biomarkers and Prevention (American Association of Cancer Research)
Current Opinion in Pulmonary Medicine
Environmental Health Perspectives
European Journal of Cancer
Human and Experimental Toxicology
International Journal of Cancer
Journal of Critical Pathology
Journal of Epidemiology and Community Health
Journal of Obstetric, Gynecologic and Neonatal Nursing
Journal of Occupational Medicine
Journal of the National Cancer Institute
Medical and Pediatric Oncology
Medical and Pediatric Oncology
Nutrition and Cancer
Paediatric and Perinatal Epidemiology
Pediatric Hematology and Oncology
Public Health Nutrition
The Journal of Reproductive Medicine
The Journal of Urology
The New England Journal of Medicine
Trends in Microbiology
UKCCS (UK Childhood Cancer Study)