CARCINOMA OF THE OESOPHAGUS
1. DEFINITION
This is one of the more frequent malignancies in humans. Attracting the ICD 10AM Code C25, it means a primary malignancy of the lining of the oesophagus which begins proximally at the pharyngo-oesophageal sphincter.
As the oesophagus is lined with squamous epithelium, the usual malignancy is squamous carcinoma. However, with intrusion of the gastric glandular epithelium into the lower oesophagus, adenocarcinoma may affect the lower oesophagus and cardial region, a growing problem in western societies.
Among the clinical features of oesophageal carcinoma are:
• progressive dysphagia, generally painless,
• it is, in general incurable, with a relatively stable 5 year survival rate of about 5%
• it is rare under the age of 40,
• there is a marked racial variation in incidence.
Squamous carcinoma has an incidence of 2.6/10
5in the U.S. where is it
four to five times more common in blacks than whites. Adenocarcinoma is
rising in incidence in whites in recent years throughout most affluent
societies; it has quadrupled in white males in the U.S. in recent decades
whereas squamous carcinoma in blacks has doubled in the last 30 years, so
that adenocarcinoma has overtaken squamous in incidence in the U.S. in
whites. Males are affected more frequently than females overall in ratio of
three or four to one.
2. EPIDEMIOLOGY
Squamous carcinoma and adenocarcinoma exhibit considerable differences in their epidemiological and other characteristics and will be considered separately.
2.1 Squamous Carcinoma
One of the remarkable features of this malignancy is the extraordinary variation in its incidence throughout the world leading to the view that there are major environmental and / or dietary factors in its causation. This is seen especially in China where 60% of the world’s cancers occur. The incidence has been recorded as varying from 1.3 to 132/10
5in different Chinese counties and it seems that the incidence of carcinoma in humans mirrors the incidence of it in the gullet of chickens. (1) In Northern Asia there is a high carcinoma incidence belt extending through Kazakstan, Uzbekistan, Turkmenistan, Northern Afghanistan and the Caspian littoral of Iran.
Whereas the incidence is high in the Transkei of South Africa and varying rates are seen in southern and eastern Africa, the disease is rare in the rest of Africa. These and similar factors lead inevitably to a dietary or environmental cause, at present unknown.
Suggested factors include:
• constituents of smoke from soft coal used for cooking – females who do not smoke are affected as often as males who do,
• nutritional deficiency, especially retinol, ascorbic acid, riboflavin, Į tocopherol,
• a low fruit intake and ascorbic acid deficiency,
• selenium and molybdenum deficiency,
• nitrates and nitrites in high levels in plant tissue associated with a low soil molybdenum levels,
• contamination of water supplies by petroleum products.
2.1.1 Smoking and Alcohol
These are both associated with the development of squamous carcinoma
and often coexist in the same patient; disentangling their relative importance
is difficult. It is important to note that among well nourished, abstemious
non-smoking males squamous carcinoma is virtually unknown. A group in
Milan looked at 250 oesophageal cancer patients and 1089 controls. For 38
life-long non-smokers there was no difference between teetotallers and those
having up to three drinks per day, with a statistically significant rise in OR to
3.6 for over eight drinks per day. On the other hand for 30 non-drinkers
there was a significant rise in trend with increasing smoking extending to an OR of 6.2 for smokers of more than 24 cigarettes per day (2). The same group attempted to estimate the Population Attributable Risk for these factors. In a study of 300 patients with oesophageal cancer and controls not only smoking and drinking but dietary ȕ carotene were examined and found to be relevant (3) (Table 4.1). A study of 6701 Japanese/Americans in Hawaii showed a RR of 17.3 (6.7-44.2) in heavy smokers and drinkers compared with those who neither smoked nor drank heavily; in heavy drinking non-smokers, the RR was 8.6 (2.01-36.0) (4). In a population based cohort of 9353 individuals followed up for a mean of 7.7 years after treatment for alcoholism the S.I.R. of oesophageal cancer was 6.8 (4.5-9.9) although confounding by smoking was present (5).
2.1.2 Rare Causes
Rare but significant other causes include previous damage from corrosive ingestion for which the incubation period may be as long as 40 years for squamous carcinoma, and achalasia of the oesophagus. Patients with coeliac disease also have a small but significant elevation of risk. On the other hand there is good evidence for protective dietary factors, deficiency of which may contribute to the incidence of carcinoma associated with alcohol abuse.
Table 1. Population Attributable Risk (%) for oesophageal cancer
Males Females Combined
Smoking 71 32 61
Alcohol 45 10 39
Lowȕ carotene intake 40 29 38
Combined * 90 58 83
* assumption of a multiplicative model
One of the largest studies is an analysis of several data sets of case control studies in Northern Italy examining the dietary pattern of confirmed cases and controls. For the 294 oesophageal cancers, after allowance for various social factors including smoking, a multivariate RR of 0.2 for those in the upper tertile of fruit and vegetable consumption was found.
Interestingly, there were positive benefits for all the epithelial cancers of the
upper aero-digestive tract but no benefit for lymphomas and multiple
myeloma (6). A multicentre French study of 208 cases of oesophageal
squamous cancer made similar findings. After adjustment for alcohol and tobacco use a beneficial effect of fresh fish, fruit and vegetables, vitamin A and vitamin D was found; the benefits of ascorbic acid were confined to heavy drinkers (7).
2.2 Adenocarcinoma
This is largely confined to the lower third of the oesophagus and is considered to arise from columnar epithelium extending up from the cardia (Barrett’s oesophagus). Commoner in males it is increasing in incidence in western societies in parallel with adenocarcinoma of the cardia although distinction from carcinoma arising from the fundus of the stomach may be difficult. Many studies of risk factors do not distinguish it from squamous carcinoma and the significance of the major risk factors for squamous carcinoma, smoking and alcohol, in its production is not certain. It is however, associated with long standing reflux through Barrett’s oesophagus.
In Britain the adenocarcinoma rate for women is among the highest in the world. Multivariate analysis of 74 patients showed an OR for the highest quartile of weight around age 20 of 6.04 (1.28-28.52). For the highest quartile of fruit and vegetable consumption the OR was down to 0.08 (0.01- 0.49). Breast feeding was also protective (OR=0.41) and duration dependent (P for trend 0.0005). The similar PAR for obesity in youth and low fruit intake was 90% to 96% with the breast feeding factor (8).
3. CLINICAL IMPLICATIONS
These are clear; whilst the adverse effect of alcohol has not been demonstrated for up to three drinks per day, beyond this it is clear that alcohol plays a significant role but it is probably exceeded by the effect of heavy smoking with relative risks of up to 6. However the effect of heavy alcohol use is significantly contributed to by the associated poor dietary intake of some of the micronutrients in fresh fruit and vegetables of which vitamin A, D and vitamin C are contributors. Traditionally, spirits have been regarded as being more dangerous than beverages of lower alcohol content but no firm data in support have been found.
The work of Negri’s group (3) suggests that four of five cases of
oesophageal squamous carcinoma may be attributed to the influence of
smoking, heavy alcohol use and a nutritional deficiency in the form of ȕ
carotene deficiency. It is tempting to speculate how much other nutritional
deficiencies contribute to the rest.
4. PREVENTATIVE STRATEGIES
That there is a nutritional aspect to oesophageal carcinoma has been clearly demonstrated in a nationwide Swedish controlled study of 608 cases (9). Fruit and vegetable consumption was inversely related to the risks of both types of oesophageal cancer but, surprisingly, not to adenocarcinoma of the cardia nearby, suggesting different factors for this type of tumour.
Comparison of the highest quartile of intake (4.8 servings / day) with the lowest (1.5 servings) showed a lower risk of adenocarcinoma of 50% and a 40% reduction for squamous carcinoma. It was calculated that 20% of oesophageal squamous and adenocarcinomas were attributable to consuming fewer than three servings of fruit and vegetable per day. However, importantly from a public health point of view, over 25000 individuals would have to increase their fruit and vegetable consumption moderately to prevent one cancer per year. The findings corroborate the findings of the Italian study (3). We may safely conclude that the combination of heavy drinking, smoking and a low fruit and vegetable diet constitute a triad largely responsible for these carcinomas. As the authors point out, modifying the population intake achieves little. However, chemoprevention may have a role. A more recent metaanalysis of nine studies utilising data on aspirin, NSAIDs and both types of oesophageal cancer showed a protective effect of both aspirin and NSAIDs (OR=0.57, CI 0.47-0.71) overall (10). Aspirin was more protective (OR=0.5, CI 0.38-0.66). Dose response curves were noted. Before embarking on a chemoprevention program of aspirin in alcoholics, we need to recognise the life threatening haemorrhage that may follow its use in cirrhotic people.
References
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3. Negri E, La Vecchia C, Franceschi S et al. Attributable risks for oesophageal cancer in Northern Italy. Eur. J. Cancer 28A(6-7),1167-71 (1992).
4. Kato I, Nomura AM, Stemmermann EN, Chyou PH. Prospective study of the association of alcohol with cancers of the upper aerodigestive tract and other sites. Cancer Causes Control 3,145-51 (1992).
5. Adami HO, McLaughlin JK, Hsing AW et al. Alcoholism and cancer risk : a population- based cohort study. Cancer Causes Control 3,419-25 (1992).
6. Negri E, La Vecchia C, Franceschi S, D’Ananzo B, Parazzini F. Vegetable and fruit consumption and cancer risk. Int. J. Cancer 4,350-4 (1991).
7. Launoy G, Milan C, Day NE et al. Diet and squamous-cell carcinoma of the oesophagus.
Int .J. Cancer 76,7-12 (1998).
8. Cheng KK, Sharp L, McKinney PA et al. Risk factors for oesophageal carcinoma in women in Britain. Gastroenterology 118 (Suppl 2), A 36 (2000)
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9. Terry P, Lagergren J, Hansen H, Wolk A, Nyren O. Fruit and vegetable consumption in the prevention of oesophageal and cardia cancer. Eur. J. Cancer Prev. 10,365-9 (2001).
10. Corley DA, Kerlakowske K, Verma R, Buffler P. Protective association of aspirin / NSAIDS and esophageal cancer : a systematic review and meta analysis.
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