General Aspects

Malignant neoplasms or ‘cancers’ develop because of deoxyribonucleic acid (DNA) mutations – some spontaneously (possibly due to oxygen radicals), others from chemical carcinogens (e.g. tobacco, alcohol or betel), ionizing and ultraviolet radiation, or oncogenic microorganisms (e.g. hepatitis, herpesviruses and human papillomaviruses (HPVs); Fig. 22.1). Important chemical carcinogens are aromatic amines (including arylamines and heterocyclic amines) found in tobacco smoke and cooked foods. The list of known carcinogens is long; the most important – relevant in tobacco and alcoholic beverages – are shown in Box 22.1.

Various liver enzymes termed xenobiotic-metabolizing enzymes (XMEs) are involved in the metabolism of carcinogens or pro-carcinogens (Table 22.1); several are polymorphic and they may be involved in carcinogen activation or degradation. Other enzymes can reverse or repair some of the damage from mutations (DNA repair enzymes) but, when mutations involve genes such as tumour suppressor genes, the cell may become autonomous, despite attempts at DNA and cell repair, and the cell then proliferates and invades – the hallmark of cancer. Eventually, the tumour spreads elsewhere (metastasizes) to lymph nodes and through the blood.

Carcinomas are malignant neoplasms that arise from epithelia; they are a leading cause of morbidity and mortality, mainly in persons who are middle-aged or older, and are most common in the lung, breast, colon, cervix, stomach, pancreas, ovary, prostate and skin. They metastasize mainly to the brain, liver and bones.

Oral cancer is discussed below. Lung tumours are discussed in Chapter 15, breast, ovary and prostate cancer in Chapter 25, gastrointestinal and pancreatic cancer in Chapter 7, haematological malignancies in Chapter 8, brain tumours in Chapter 13, liver cancer in Chapter 9 and skin cancer in Chapter 11.

Cancer Prevention

The prognosis of malignant disease is generally poor and unfortunately treatment can also have significant adverse effects, so prevention and early detection are important. The European Code against Cancer summarizes the preventive aspects (Box 22.2). The World Cancer Research Fund advocates measures in addition to not using tobacco and alcohol, and avoiding sun exposure, as in Table 22.2.

Avoidance of Tobacco

Tobacco is best avoided; up to 30% of cancers in developed countries are tobacco-related. Tobacco smoke is a mixture of at least 50 compounds, including polycyclic aromatic hydrocarbons (PAHs), nitrosamines, aldehydes and aromatic amines. Tobacco, acting either singly or jointly with the consumption of alcohol, is responsible for 87% of lung cancer, and between 43% and 60% of cancers in oesophagus, larynx and oral cavity. Tobacco consumption is also linked to cancers of the bladder and pancreas, a minority of cancers of the kidney, stomach, cervix and nose, and myeloid leukaemia. On smoking cessation, the risk of cancer rapidly declines; benefit is evident within 5 years and is progressively greater over time.

Although the greatest cancer hazard is caused by cigarette smoking, cigars can cause similar hazards, and both cigar smoking and pipe smoking are implicated in cancers of the oral cavity, pharynx, larynx and oesophagus. Bidi, a type of cigarette made of tobacco rolled in a dried temburni leaf, is smoked in India and is associated with a high incidence of oral leukoplakia and oral cancer. Tobacco smoke released to the environment by smokers, commonly referred to as environmental tobacco smoke (ETS) and which is responsible for ‘passive smoking’, has several deleterious effects on people who inhale it. It causes a small rise in the risk of lung cancer, and also some increase in the risk of heart disease and respiratory disease. It is particularly harmful to small children.

Tobacco-chewing in peoples from parts of Asia, along with a variety of ingredients in a ‘betel quid’ (betel vine leaf, areca nut, catechu and slaked lime, together with tobacco) appears to predispose to oral squamous cell carcinoma (OSCC). Smokeless tobacco, for example snuff-dipping in women in the south-eastern USA who place snuff in the buccal sulcus, predisposes to gingival and alveolar carcinoma close to where the snuff is placed, but the risk is low.

Avoidance of Alcohol

Alcoholic beverages may contain carcinogens or pro-carcinogens, including ethanol, nitrosamines and urethane contaminants. The total amount of ethanol ingested appears to be the key factor. Alcoholic beverages increase the risk of squamous cell cancers of the oral cavity, pharynx, larynx and oesophagus. Alcohol-drinking raises the risk of neoplasms, even in the absence of smoking, but alcohol-drinking and tobacco-smoking together greatly increase the risk. A probable carcinogenic mechanism of alcohol is the facilitation of the effect of tobacco and possibly of other carcinogens to which the upper digestive and respiratory tracts are exposed, particularly those of dietary origin. However, a direct carcinogenic effect of acetaldehyde, the main metabolite of ethanol, and of other agents present in alcoholic beverages, is likely. A diet poor in fruits and vegetables, typical of heavy drinkers, may also play a role.

Alcohol-drinking is also strongly associated with the risk of primary liver cancer, particularly among smokers and among people chronically infected with hepatitis C virus. A higher risk of colorectal cancer seems to be linearly correlated with the amount of alcohol consumed and independent of the type of alcohol. A greater risk of breast cancer has been consistently reported. More cases of breast cancer than of any other cancer are attributable to alcohol-drinking among European women. It has been suggested that alcohol acts on hormonal factors involved in breast carcinogenesis.

Few studies have analysed the relation between stopping alcohol-drinking and the risk of cancers of the upper respiratory and digestive tracts, but there is clear evidence that the risk of oesophageal cancer falls by 60%, 10 years or more after drinking cessation.

Other Factors

Weight reduction

Obesity is associated with a greater risk of cancer of the colon, breast (post-menopausal), endometrium, kidney and oesophagus (adenocarcinoma). In Western Europe, it has been estimated that being overweight or obese accounts for approximately 11% of all colon and breast cancers, 39% of endometrial cancers, 27% of oesophageal adenocarcinomas and 25% of renal cell cancers. A body mass index of below 25 kg/m2 should, if possible, be maintained.

Greater physical activity

There is consistent evidence that regular physical activity is associated with a 40% reduction in the risk of colorectal, breast and oesophageal cancer and may possibly also lower the risk of prostate cancer. The protective effect of physical activity improves with increasing levels of activity. One hour per day of moderate physical activity, such as walking, may also be needed to maintain a healthy body weight, particularly for people with sedentary lifestyles.

Greater intake of fruit and vegetables

A low-fat diet with at least 11 servings of fruits, vegetables, wholegrains and beans daily may reduce the chances of colon cancer by 75%, breast cancer by 50% and lung cancer by 30%. There may also be a protective effect on the risk of a wide variety of other cancers, in particular oral, oesophagus, stomach, rectum and pancreas.

‘Five-a-day’ (minimum 400 g/day, i.e. two pieces of fruit and 200 g of vegetables) is advocated to lead to a lower cancer risk. Vegetables and fruits contain many potentially anticarcinogenic agents. Antioxidant activity seems important in cancer protection but the exact molecule(s) in vegetables and fruits that confer(s) protection is/are unknown and the mechanism of action unclear.

Avoidance of sun exposure

Ninety per cent of skin cancers are seen in white-skinned peoples and are caused by the sun’s ultraviolet rays (Ch. 11). Squamous cell carcinoma of the skin or lip shows the clearest relationship with sun exposure and the risk is greatest in outdoor workers. The recipients of transplanted organs are particularly at risk as a result of the combined effects of the unchecked growth of human papillomavirus (HPV) due to immunosuppression, and exposure to the sun (Ch. 35).

Malignant melanoma is more common in people of high socioeconomic status who work inside but who have the opportunity to spend leisure time in the sun, and this includes dentists. The incidence of melanoma has doubled in Europe in 30 years, and this is attributed to longer intense sun exposure. The fair-skinned are more susceptible, particularly those with red hair, freckles and a tendency to burn in the sun. These characteristics are genetically determined at least partially by the MCIR gene, which codes for the melanocyte-stimulating hormone receptor. Variants in the MCIR gene control the ratio of black melanin (eumelanin) to red (phaeomelanin) in the skin. The strongest phenotypic risk factor for melanoma, however, is the presence of large numbers of moles or melanocytic naevi, which may be normal in appearance but are also usually accompanied by so-called atypical moles. The latter are larger than 5 mm in diameter with variable colour and an irregular shape. The phenotype, described as the atypical mole syndrome (AMS) phenotype, is present in around 2% of the Caucasian population and is associated with an approximately tenfold higher risk of melanoma. Advice on sun protection is of particular importance to this population.

The best protection from the summer sun is to stay out of it. If outdoors, keep out of the sun between 11.00 a.m. and 3.00 p.m., wear close-weave heavy cotton and use sunscreens with high sun protection factor (SPF). Do not rely upon sunscreens for protection.

Avoidance of occupational exposures

The cancers that have most frequently been associated with occupational exposures are those of the lung, urinary bladder, mesothelioma, larynx, liver, nose and nasal cavity, and skin, as well as leukaemia (non-melanoma). The more common occupational exposures are solar radiation, passive smoking, crystalline silica, diesel exhaust, radon, wood dust, benzene, asbestos, formaldehyde, PAHs, chromium, cadmium and nickel compounds. There is no reliable evidence of a risk from power plants, power lines or mobile telephones.

Many chemicals are known or suspected carcinogens. Many are still widely used: for example, 1,3-butadiene and formaldehyde. Prevention of workplace exposures can be effective; the incidence of occupational bladder cancer fell after the ban on the use of beta-naphthylamine in the rubber and chemical industries.

Avoidance of environmental exposures

The term ‘environmental exposures’ usually refers to exposures of the general population that cannot be directly controlled by the individual; these include air pollution, drinking water contaminants, passive smoking, radon gas in buildings, exposure to solar radiation, food contaminants such as pesticide residues, dioxins or environmental oestrogens, chemicals from industrial emissions, ionizing radiation, waste from nuclear processes, and others. These exposures have been associated with cancers of the lung, urinary bladder, leukaemia and skin. The impact of several exposures that are widespread, such as disinfection by-products in drinking water, is still inconclusive. Agents in the general environment to which many are exposed for long periods (such as passive smoking or air pollution) may increase the relative risk for certain cancers only modestly, but may be responsible for a significant number of cases overall.

Avoidance of hormones that may play a role

Hormone replacement therapy (HRT) for menopausal symptoms appears to raise the risk of breast cancer.