Smoking and alcohol

Smoking and alcohol are established risk factors for SCC, particularly in the West. Smokers have a fivefold higher risk than non-smokers, which doubles again in heavy smokers. There is a positive dose–response effect for both duration and intensity of smoking, although long-term use of tobacco appears to be the stronger influence. The risk reduces after stopping. In the USA tobacco consumption decreased between the 1960s and 1990s, and this is reflected in the decrease in disease incidence. However, the reduction in smoking was less apparent in the black population, in which SCC rates have remained high.

The effect of alcohol is similar to smoking, although the amount consumed appears to be the greater risk factor. Several studies have demonstrated relative risks ranging from 2.9 to 7.4 for heavy drinkers. As with smoking, abstention from alcohol does appear to decrease the risk. Alcohol and smoking seem to have both synergistic and independent effects. The mechanism of action for the damaging effect of alcohol is unclear: it may directly damage the oesophageal mucosa or increase its susceptibility to other carcinogens, or may have its effect via the secondarily associated dietary deficiencies. There also seem to be individual influences reflecting variations on genes coding for enzymes involved in alcohol metabolism (see below).

Socio-economic and dietary influences

Areas of highest incidence are those countries of low socio-economic status where poverty and malnutrition predominate. The development of SCC appears to be related to a type of chronic oesophagitis that is different from that found in the West and is often complicated by atrophy and dysplasia (see Chapter 1). It is not usually associated with gastro-oesophageal reflux and is often asymptomatic.

SCC has been associated with ingestion of very hot beverages, a family history of oesophageal cancer, prevalence of oesophagitis among siblings, and a low intake of fresh fruits and wheat flour products.⁶ Furthermore, riboflavin deficiency and vitamin A and C deficiency⁷ have been identified as risk factors that are particularly important at a young age. By contrast, vitamin C intake confers a protective benefit; Hu et al.,⁸ in a case–control study, found that 100 mg of vitamin C per day decreased risk by 39%.

Associated conditions

SCC is associated with a variety of uncommon conditions that relate to some form of inflammatory injury. Oesophageal strictures developing after ingestion of corrosive agents, particularly in childhood, are associated with a 1000-fold increase in the risk of carcinoma. There is a time delay of 20–40 years after ingestion of the corrosive, and as a result tumours are seen at a younger age than normal.

Achalasia is associated with SCC, but the magnitude of the risk is unclear. Brucher et al.⁹ report from their single institution series that the risk of developing a carcinoma in long-standing achalasia is increased 140-fold when compared with the general population. The risk appears to relate to retention oesophagitis secondary to stasis and exposure to possible carcinogens in fermenting food residue. There is a lead time of approximately 15–20 years and these cases probably warrant long-term surveillance. Treatment of the achalasia does not seem to reduce the risk.

Tylosis palmarum is a rare inherited autosomal dominant condition in which there is a very high incidence of SCC. Perhaps of greater significance is the finding of the increased risk in low-risk areas for offspring of parents with oesophageal cancer.¹⁰ There are numerical and structural chromosomal aberrations in patients with a family history not seen in those without a family history (see below).

Gastro-oesophageal reflux disease (GORD)

Gastro-oesophageal reflux is now the most common symptomatic presentation of all conditions affecting the upper gastrointestinal tract. Estimates suggest that 4–9% of all adults experience daily heartburn and up to 20% experience symptoms on a weekly basis.¹¹ Of these, 60% have no endoscopic abnormality, 30% have oesophagitis and 10% have Barrett’s columnar lined oesophagus. Many are self-treated and do not attend for further investigation, yet 80% with Barrett’s are asymptomatic. The relationship of GORD and oesophageal ACA has been evaluated in case–control studies.¹² The individual cancer risk is small because of the high frequency of GORD. Lagergen et al.¹³ have estimated the risk of developing ACA of the oesophagus by scoring symptoms of heartburn and regurgitation (alone or in combination), timing of symptoms (particularly at night) and frequency of symptoms. Among those with recurrent symptoms of reflux, the odds ratio of developing cancer was 7.7 in comparison with those without symptoms. More frequent, more severe and longer-lasting symptoms of reflux were associated with a much greater risk (odds ratio 44). The risk associated with GORD is related to the development of Barrett’s metaplasia, which is greatest among Caucasian males with a history of alcohol consumption and continuous smoking. Further detailed discussion of the role of Barrett’s in the aetiology of ACA is presented in Chapter 15.

Obesity and dietary factors

In the last 20 years the incidence of junctional cancer has increased in parallel with the epidemic of obesity. There is a three- to sixfold excess risk among overweight individuals.¹⁴ Obesity predisposes to hiatus hernia and reflux, and hence contributes mechanically to increase risk. However, data from a number of studies demonstrate an effect independent of reflux. Lindblad et al.¹⁵ have reported a 67% increase in the risk of oesophageal ACA in patients with a body mass index (BMI) greater than 25, and this increases with increasing BMI. This effect was noted irrespective of the presence of reflux symptoms.

There appears to be a sex difference in that the effect was only found in women with a BMI greater than 30, whereas in men it was observed in both overweight and obese individuals. Recently this effect in women has been confirmed, with 50% of cases of oesophageal adenocarcinoma in postmenopausal women in the Million Women study being attributed to obesity.¹⁶

Evidence is accumulating to support different types of obesity. The distribution of abdominal fat tends to be central and retroperitoneal. This acts as a potent source of growth factors, hormones and regulators of the cell cycle. Such individuals develop the metabolic syndrome, which is linked to raised serum cholesterol and triglycerides, hypertension and hyperglycaemia. In the general population the metabolic syndrome occurs in 10–20%. Power et al.¹⁷ have demonstrated that 46% of those with Barrett’s oesophagus and 36% of those with GORD have features of the metabolic syndrome.

The factors released by centrally deposited fat may have an effect on the process of metaplasia transforming to dysplasia. Vaughan et al.¹⁸ have examined the potential relationship between a series of biological markers of progression from metaplasia to cancer in obese and overweight patients. There was little evidence of change in the biomarkers in association with increasing obesity. However, abnormalities in the biomarkers were observed in individuals with high anthropometric measures of abdominal fat. The study concluded that increased BMI contributed to reflux and development of metaplasia but it was the ‘male pattern’ of abdominal obesity that was actually associated with malignant transformation.

Helicobacter pylori

The role of Helicobacter pylori infection in the aetiology of junctional cancer is unclear but appears to be evolving. Gastric infection with H. pylori is characterised by gastric atrophy and hypochlorhydria. It has been suggested that this reduction in acid production could, in association with ammonia production from urea by the bacteria, protect the lower oesophagus by changing the content of the refluxing gastric juice. In countries with an increase in junctional cancer, there has been a corresponding decrease in incidence of H. pylori infection. Furthermore, community-based approaches to eradicate H. pylori infection in the treatment of ulcer and non-ulcer dyspepsia may be inadvertently contributing to the increase in these cancers.

There is accumulating evidence that there may be two distinct types of junctional cancer reflecting the two potential sites of origin. McColl and Going¹⁹ have suggested that one is similar to oesophageal cancer and the other gastric cancer. In a series of studies of patients with junctional cancer, they evaluated H. pylori infection from serology, gastric atrophy from pepsinogen I and II ratios, symptoms of reflux and histological subtype of diffuse or intestinal type. They also included biopsies of the distal stomach to document atrophy associated with Helicobacter. Tumours of oesophageal origin are intestinal type with no evidence of gastric atrophy or Helicobacter infection and occur in the context of reflux. By contrast, tumours of gastric origin are diffuse type or intestinal but with evidence of atrophy and Helicobacter infection and without a history of reflux (Table 2.1). Such different characteristics would imply a different carcinogenic process at the two sites and should be considered in prognosis and patient management.

Socio-economic factors

Lifestyle has an effect on the risk for junctional cancers. There is an association with lower socio-economic class but this is not as strong as for SCC. Powell and McConkey²⁰ demonstrated that the increase of ACA of the lower third of the oesophagus and the cardia was mainly in social classes I and II – that is, in professional and managerial occupations. In addition, in a large surgical series, Siewert and Ott²¹ reported that patients with ACA were more frequently from an educated background, a characteristic not present in the population with SCC. However, the effect of socio-economic class may not be independent as, when adjusted for GORD, BMI and smoking, Jansson et al.²² found the effect to be less apparent.

Socio-economic influences

Gastric cancer is a disease of lower socio-economic groups. The incidence of tobacco smoking tends to be higher in these groups and there is a 1.6-fold risk of developing stomach cancer for smokers in comparison to non-smokers.

An excess risk has been linked to certain occupations such as coalmining. Evidence for such a relationship is circumstantial, and as certain occupations reflect social background the risk may equally reflect lifestyle, particularly dietary habits, rather than actual occupational risk.

Exposure to potentially carcinogenic agents at an early age is clearly crucial to the risk of developing both precursor lesions and subsequent gastric cancer. Evidence for this risk is available from migrant studies. Japanese migrants to the USA had a far lower rate of intestinal-type cancers than the equivalent population who remained in Japan, indicating environmental or dietary aetiology, whereas the rates of diffuse-type cancer remained the same, suggesting a hereditary component.²⁴

Diet

The prevalence of gastric cancer in poor communities reflects both malnutrition and intake of a poor-quality diet. Foodstuffs that are cheap prevail, as well as low-cost methods of food preservation and preparation. High carbohydrate intake has been implicated. Areas with a high dietary carbohydrate content have a low protein intake. Protein deficiency will impair gastric mucosal repair and indeed high carbohydrate/low protein may impair defence mechanisms against injurious agents.

Salt preservation of food was common during the early years of the 20th century throughout the world; in some landlocked parts of the world this still occurs. In such areas and in those still using salt preservation there have been high rates of gastric cancer. The consumption of salted and pickled fish is high in Japanese and Colombians and correlates with their disease incidence. On the basis that salt induces injury to the gastric mucosa it may act like high carbohydrate intake, as an initiator to allow access for more potent carcinogens. By contrast, the rapid and widespread adoption of refrigerators in the 1950s and 1960s has significantly affected the preservation of fresh foods. The reduction in mortality observed in Japan shows an inverse relationship with the increase in ownership of domestic refrigerators.²⁵

Fresh vegetables and fruit theoretically act to protect against gastric carcinogenesis. Vitamin C inhibits intragastric formation of nitrosamines from nitrite and amino precursors. Both vitamins A and E act as antioxidants within cells, as well as regulating cell differentiation and protecting the gastric mucosal barrier. However, dietary studies have failed to confirm these proposed effects. An inter-country variation in fruit and vegetable intake has not paralleled differences in gastric cancer incidence. It is possible, however, that prolonged exposure is more relevant, again supporting the philosophy of a balanced diet rather than one supplemented with a potentially beneficial foodstuff.

Helicobacter pylori

In 1994 the International Agency for Research on Cancer designated H. pylori to be a type I carcinogen²⁶ for gastric cancer. The initial effect of H. pylori is acute inflammation. Since the infection does not resolve spontaneously, an effect is likely to persist and may proceed to chronic gastritis and associated mucosal atrophy and intestinal metaplasia, dysplasia and eventually cancer. The evidence for its role is from a number of sources. Areas of high cancer incidence have a high rate of H. pylori infection. In a prospective population-based study in Japan, 2.9% of those infected developed gastric cancer compared with none from the uninfected population; 4.7% of those infected who had non-ulcer dyspepsia progressed to cancer.²⁷ In high incidence areas H. pylori infection tends to occur early in life. These early rates of infection are linked to low income, poor education, poor sanitation and overcrowding. There has, however, been a progressive fall in rates of H. pylori serology positivity in longitudinal studies, which have paralled the decline in gastric cancer incidence.

Although the evidence for H. pylori inducing gastric cancer is convincing, not all those infected develop the disease. The risk of malignant transformation appears to be enhanced by bacterial virulence and host factors (see below). Helicobacter pylori with cytotoxin-associated gene A (cagA) appears to be associated with the greatest risk.²⁸ In the West, 60% of H. pylori infections are cagA positive compared with 100% in Japan.^29,30 It is likely that H. pylori induces an environment that is susceptible to malignant transformation. It induces tissue monocytes to produce reactive oxygen intermediates, which are potent carcinogens. Infection is associated with a significant reduction in gastric juice ascorbic acid,³¹ which acts to scavenge and suppress N-nitroso compounds and oxygen free radicals. It also facilitates the proliferation of nitrosating bacteria, which promote the development of N-nitroso compounds.

Precancerous conditions

Pernicious anaemia imposes a three- to fourfold increased risk of gastric cancer compared with the normal population. Patients who have undergone gastric resection for benign disease are considered to have a greater risk, possibly because of increased alkaline reflux.

Prevention of oesophageal and gastric cancer

Prevention strategies are either primary or secondary. Primary approaches aim to prevent cancer developing, whereas secondary prevention is intended to identify precancerous processes and conditions and to intervene to prevent progression to cancer.

In oesophageal and gastric cancer primary prevention approaches are currently limited to population education to alter social habits (such as decreasing or stopping tobacco or alcohol consumption) and dietary habits (such as maintaining a diet containing fresh fruit and vegetables with a low or minimal salt intake). In addition, the need to prevent obesity is now well established. The role of H. pylori eradication is important but programmes of eradication should only be considered according to the level of risk for oesophageal or gastric cancer in the population. In populations with a high risk of gastric cancer, eradication is indicated; however, in populations in which oesophageal ACA is common, eradication may have an adverse effect. The overall benefit of these approaches would be greatly enhanced if specific markers of risk could be identified to focus prevention strategies (see Chapter 15).

Secondary prevention depends upon understanding the natural history and detection of premalignant conditions. In SCC there is limited evidence that secondary measures could be effective because of lack of understanding of the histological changes leading to cancer. In oesophageal ACA, surveillance of Barrett’s metaplasia to identify progression to dysplasia is theoretically a positive approach (see Chapter 15). Identification of p53 expression and aneuploidy in biopsies of Barrett’s has been shown to predict the risk of progression.³² In both gastric and oesophageal cancer there is a potential role for chemoprevention. Increasing levels of cyclo-oxygenase-2 (COX-2) are present in the progression of atrophic gastritis to intestinal metaplasia and gastric cancer.³³ Smoking, acid and H. pylori are all associated with COX-2 expression. Aspirin and other non-steroidal agents inhibit COX-2 and their use may act as a chemopreventive for gastric cancer. Aspirin also seems to have an effect in Barrett’s metaplasia and in combination with acid suppression may minimise progression to dysplasia. The ASPECT trial in the UK is assessing whether such a strategy can have a secondary preventive effect.³⁴