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In past centuries, people feared epidemic diseases, with ghastly symptoms, agonizing death, and sometimes disfigurement for survivors. Today, especially in the developed world, the dread of epidemic contagion has been replaced by the dread of cancer. The basic causes of cancer remain shrouded in mystery.

Cancer is a process whereby uncontrolled cell multiplication produces a tumor that can invade adjacent tissues and metastasize - that is, implant cancerous cells at a noncontiguous site, where abnormal multiplication continues. Cancer in connective tissues (mainly bone or muscle) is called sarcoma; cancer in epithelial tissues (lining tissues and organs) is called carcinoma. Carcinoma is by far more common. In Egypt, tumors have been found in third-millennium B.C. mummies, and ancient physicians there knew and treated different cancers.

The ancient Greeks, too, were familiar with cancers. Hippocrates is credited with naming the disease "cancer" from karcinos (Greek for "crab"), perhaps because some breast cancers appear crablike or perhaps because the pain of cancer resembles the pinching of a crab. The terms neoplasm ("new formation") and oncology ("study of masses") are also derived from Greek, as is the word tumor. Hippocratic medicine attributed tumors - including all sorts of swellings - to abnormal accretion of humors. Galen sought to differentiate cancers from inflammatory lesions and gangrene. Cancer was held to be caused by black bile.

Breast cancer was probably the first to be treated by attempting surgical eradication. Some ancient surgeons performed total mastectomies, and although the healing of these terrible procedures was little reported, Rhazes warned in the ninth century that operating on a cancer generally only caused it to worsen unless it was completely removed. It seems likely, however, that few cancers were treated surgically until relatively modern times. Ambroise Pare wrote toward the end of the sixteenth century that those who pretended to cure cancer surgically only transformed a nonulcer-ous cancer into an ulcerated one. Nevertheless, in the seventeenth century, Wilhelm Fabricius provided adequate descriptions of operations for breast and other cancers.

The discovery of the lymphatic system by Gasparro Aselli in 1622 directed attention toward lymphatic abnormalities in the causation of cancer. Basically, the idea was that cancer was an inflammatory reaction to extravasated lymph. About 150 years later, John Hunter modified the lymph theory by defining "coagulating lymph" (i.e., blood serum). Hunter viewed this substance (when contaminated by "cancerous poison") as the cause of cancer. Quite presciently, he described metastases as "consequent cancers" that traveled via lymphatic channels.

Another hypothesis (advocated particularly by the German Daniel Sennert and the Portuguese Zacutus Lusitanus) early in the seventeenth century was that cancers, at least when ulcerated, were contagious - a popular fear that persisted well into the twentieth century. The first accurate etiologic observation about cancer is attributed to London surgeon Percival Pott, who reported in 1775 that many longtime chimney sweeps suffered scrotal cancer. He linked this observation to the men's chronic contact with soot and thereby identified the first occupational cancer.

The impact of microscopy on cancer research came slowly. Robert Hooke, the pioneering seventeenth century microscopist who coined the term "cell," thought that tissues were composed of fibers - a hypothesis that persisted into the nineteenth century. Not until after 1830, when Joseph J. Lister designed the first achromatic microscope lenses, did progress begin. In 1855,

Rudolph Virchow postulated that neoplasms developed from immature cells. In 1867, Edwin Klebs suggested that most cancers originated in epithelial tissues.

Despite its antiquity, cancer is viewed as largely a modern phenomenon. Along with cardiovascular disease, it is perceived as the greatest health problem facing the developed world. Thus far, the World Health Organization has classified some 100 kinds of cancer according to sites of origin. Estimates indicate that one-third of the inhabitants of the industrialized world will develop some form of cancer. Cancer cures have largely eluded scientific medicine. Nor has Virchow's observation that irritants could summon forth cancerous cells proved very helpful in cancer prevention - although irritants are among the foci of cancer research today.

The concept of autonomy suggests that once a cell has become truly cancerous it is beyond bodily control. This idea was established around the turn of the twentieth century by Arthur Hanau, Leo Loeb, and Carl Jensen, who transplanted cancer cells into healthy animals and plants, subsequently observing the growth of new cancers in the previously healthy hosts. Yet the fact that established cancers can enter a stage of remission - sometimes permanently -argues that the body can retard or even reverse previously uncontrolled cell proliferation.

The next advances were made when cancer was induced experimentally in plants and animals by various chemical, physical, and biological agents. For example, some 150 different viruses caused tumors, and ultraviolet light, X-rays, radium, uranium, coal tars, certain dyes, and other substances also induced cancer. Even natural bodily compounds such as estrogen have caused cancer in experimental animals.

Cancer is predominantly an illness of middle age and, with a few exceptions, is relatively rare in children. Thus, people in the developed world, having escaped famine and epidemic disease, have extended their life expectancy into the ages in which cancer frequency is increasingly high.

The three most common cancers of men -prostate cancer, lung cancer, and colon cancer - comprise about 50 percent of new cases and 55 percent of cancer deaths. The three most common cancers of women - breast cancer, colon cancer, and lung cancer - also comprise about 50 percent of new cases and account for 50 percent of deaths. Cancer deaths in women peak at 41.0 percent in the 35-54 age group. In contrast, men's average age of cancer death peaks at 30.2 percent in the 55-74 age group. This difference is mostly attributable to the difference in age distribution of women with breast cancer and men with prostate cancer.

Survival has improved variably since the 1960s. The greatest improvements have occurred in stomach cancer (both sexes) and female uterine cancer. Lung cancer has increased in incidence in both sexes, as has male prostate cancer. The decrease in stomach-cancer deaths has resulted from a decline in incidence rather than any significant improvement in treatment. Survival generally has been and remains poorer for black than for white patients, a difference often attributed to the black population's poorer access to medical care. However, there are no apparent race-related differences in survival of certain common carcinomas (lung cancer, kidney cancer, and stomach cancer).

The greatest problem of exogenous carcino-genesis today is not exposure to industrial pollutants, as many believe, but rather the use of tobacco products. Cigarette smoke appears to exert the most potent carcinogenic effect, although cigar smoke and chewing tobacco are also implicated. Historically, the possibility that an increase in lung cancer was related to an increase in cigarette smoking was first raised in Germany in the 1920s. In the United States, interest was stimulated by the 1950 publication of three studies showing that lung-cancer patients were likely to be heavy smokers. Resistance to a causal relationship between smoking and lung cancer was based initially on doubt that lung cancer incidence was actually increasing, and then on a failure to appreciate the long preclin-ical phase of the disease.

Cigarette smoking is also associated with neoplasms of other organs (such as bladder cancer), but this does not obscure the clearly quantitative relationship between smoking and increased probability of lung cancer. Nevertheless, lung cancer occurs in only a small minority of even heavy smokers. This may indicate a predisposition that could warn persons at risk, but investigations have thus far failed to yield useful results. Finally, there have been no reproducible experiments showing tobacco smoke to cause lung cancer in experimental animals.

No potent pulmonary carcinogens have as yet been identified in tobacco smoke, but a 1970s finding appears to clinch the causal relationship between smoking and lung cancer: A 20-year investigation showed that the risk diminishes increasingly after smoking has been discontinued for several years, which cannot be ascribed to genetic or psychological factors. However, even 15 years after cessation, the risk among former smokers remained twice that of similar-aged men who had never smoked.

Smoking has now been common among women long enough to be reflected in an alarming increase in lung-cancer incidence, beginning in the mid-1960s and now half that of men in the United States. By 1986, the lung-cancer death rate of U.S. women equaled that for breast cancer.

Of the half-million women worldwide who develop breast cancer annually, half reside in North America and Europe, which contain less than 20 percent of the world's population. But more localized questions arise as well. For example, why is the breast-cancer death rate in Finland and Denmark more than triple the rate in Sweden, and why is the rate in Scotland quintuple that of England?

A daughter or sister of a woman with breast cancer has a nearly three times greater risk of developing it than a woman without such associations. The risk is greater if the relative's cancer appears at an early age, and greater still if both mother and sister have been affected. This suggests a genetic predisposition, as does the increased risk of a second breast cancer.

However, evidence indicates that environmental factors must also be involved. For example, breast-cancer prevalence in Japan is about one-fourth that in Europe or North America. Nevertheless, among Japanese-descended women in North America, the incidence of breast cancer by the second generation matches that of indigenous whites. But what factors are implicated remains unresolved.

Prostate cancer is the second most frequent cancer among U.S. men and the fifth worldwide. It is more prevalent among U.S. blacks than any other population - about 80 percent more common in black than white men in the United States. It is also common in black Caribbean populations, whereas information from Africa indicates much lower prevalence. The incidence of prostate cancer is more highly correlated with increasing age above 50 than any other neoplasm. It is six to seven times more prevalent in the 75-84 than in the 55-64 age group, and the black/white difference diminishes with age. Increased risk is associated with chronic cigarette smoking, and there is an apparent correlation between above-average sexual drive and susceptibility to prostatic carcinoma. This could mean that an alteration in sexual hormones has a predisposing role. Alternatively, a correlation between promiscuity and (male) prostate cancer would suggest an analogy to the better-documented correlation between promiscuity and (female) cervix cancer, and the possibility that a sexually transmitted virus is the patho-genetic agent. None of these hypotheses, however, explains the increased incidence of this disease in the late 1900s.

With regard to possible roles of diet in carcinogenesis, both low-fiber and high-fat diets have been proposed to be pathogenetic for colorectal cancer. The best evidence now indicates a carcinogenic effect of increased fat consumption, particularly in women. The predominant hypothesis for this association is: Higher fat consumption increases excretion of bile acids and growth of colonic bacteria; therefore, the conversion of bile acids into carcinogenic substances by bacterial metabolism is facilitated.

In the United States, colorectal cancer has remained stable in white men and decreased moderately in white women but increased in the black population.

The ultraviolet component of sunlight is a major cause of skin cancer. Susceptibility is related to paleness, poor tanning ability, and chronic exposure. Overall incidence of non-melanoma skin cancers in the white U.S. population is about 165 per 100,000. However, the prevalence in Texas is three times that in Iowa. The incidence of melanoma is only about 4 per 100,000, but 65 percent of skin-cancer deaths are caused by this disease. The lesion occurs twice as often on the legs of white women as on those of white men. It occurs nearly twice as frequently on the male trunk than the female trunk. Melanoma is uncommon in blacks, and its location tends to be on palms or soles and within the mouth - less heavily pigmented areas. Melanoma incidence has been increasing everywhere, and mortality has nearly doubled. Whether the increase is attributable to changes in ultraviolet intensity is unknown.

X-rays and related radiation are estimated to cause no more than 3 percent of cancers. Radon gas exposure is clearly a cause of lung cancer in uranium miners. If the concentration of radon in some homes were found to be sufficiently carcinogenic, presumably the proportion of known cases of radiation-caused cancer would increase substantially. Thyroid cancer results from small-to-moderate radiation exposure to the neck, with a latency period of about a decade. Bone marrow is another radiosensitive organ. Increased risk of leukemia begins as early as 2 years after radiation exposure, reaches peak probability after 6-8 years, and then diminishes.

Suspicion of potential carcinogens in consumer goods led to the 1958 passage of the De-laney amendment to the U.S. Food, Drug, and Cosmetic Act, which bans any food additives that cause cancer in any experimental animals in any dosage. One result has been the forced withdrawal of some products based on dubious and unrealistic experiments.

Worldwide, stomach cancer, now relatively uncommon in the United States, is the most prevalent visceral cancer (second for men, fourth for women). Nevertheless, death rates have declined to about 35 percent of 1930s figures. The decrease has been worldwide and is unexplained. It remains the most prevalent carcinoma in East Asia - the rate in Japan is more than seven times that in the United States, accounting for one-third of all Japanese cancer deaths. Repetitive ingestion of high concentrations of salt has been proposed as a cause of gastric cancer; indeed, the decline in incidence has correlated with the decline in salt preservation of foods. In regions where stomach cancer remains common, salted seafood remains a staple. The incidence of gastric cancer among first-generation Japanese immigrants to the West is similar to that in their homeland, but it declines to the incidence of the Western community where the next generation resides. Because this is not a genetic disease, a generation that is not exposed to salt at a critical age presumably will not suffer inordinately from this neoplasm.

Cervix cancer is apparently related not to geography but to cultural sexual practice. Sexual intercourse during adolescence, multiple partners, or partners who have had numerous partners are all risk factors, as is frequent pregnancy. Thus the disease is rare among nuns and common among prostitutes. A sexually transmitted virus is suspected to be a causative factor. In the United States, cervix cancer occurs twice as frequently among black as white women, whereas uterine cancer occurs two to four times as often in white women.

Liver cancer is much more prevalent in developing countries than in the industrialized world. China alone accounts for 45 percent of cases. The liver is subject to two principal types of cancer: one in liver cells, predisposed by a history of hepatitis B infection; another in bile-duct cells, predisposed by liver flukes and similar infestations. The geographic distribution of such parasites is reflected in the prevalence of this disease.

In summary, the concept of cancer has evolved from the idea of a single illness to one of many diseases with many causes. Most prevalent are carcinomas of the stomach, lungs, breast, cervix, colon and rectum, prostate, and liver. Chief among carcinogens are tobacco, certain metals, radiation, specific chemical compounds, helminthic parasites, and possibly viruses. Various carcinogens constantly bombard everyone, but cancer develops in a minority of people. A few uncommon neoplasms clearly are genetically determined. Resistance to carcinogens also appears to have a genetic basis.

Available treatments are generally drastic, poorly selective, and in many circumstances not curative. Earlier diagnosis improves the cure rate of many but not all cancers. Therefore, public education about cancer and further improvements in diagnostic methods are important. Until our understanding of the fundamental biology of cancer improves, preventive measures, such as minimizing exposure to carcinogens, will constitute the greatest benefit to public health.

Thomas G. Benedek and Kenneth F. Kiple

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