Epidemiology of Cancer: Spatial-Temporal Aggregation

MICHAEL B. SHIMKIN Feis Research Institute, Temple University School of Medicine, Philadelphia, Pennsylvania

SUM1\IARY Studies of spatial and temporal distribution patterns of cancer in man and in ani mals have yielded much information and have identified many topics for more in tensive, more rigidly designed epidemiologic investigations. In fact, the wealth of such leads makes the determination of priority and the logistics of the research inn portant considerations. In addition to specific investigations, long-term ecologic observations of cancer in human and animal populations are to be encouraged. There are also unexploited opportunities in experimental cancer epidemiology that deserve biometrically con trolled studies.

AIMS AND PURPOSES Functional judgment then has to be made regarding the During my salad days, when I was more daring about priority of the projected investigations, relative not only being bloodied by the spur of the moment, I once wrote, to similar investigations but to a wider spectrum of bio â€œThe wearing of skirts would undoubtedly correlate medical research. The scientists should involve them strongly with the occurrence of mammary cancer, yet has selves in these judgments, or they will be made for them no possible direct significance in the etiologyâ€• (64). by their financial sponsors. Here Weinberg's (102) criterion Twenty years later, my plea for clemency is based solely is appealing: â€œThat field has the most scientific merit on the word â€œdirect.â€•I prefer now to begin with the which contributes most heavily to and illuminates most thought that in this infinite universe, there are no com brightly its neighboring scientific disciplines.â€• pletely unrelated or independent entities and events. This cursory presentation of spatial and temporal This approach is appropriate to my assignment of dis aggregations of cancer in human and animal populations cussing spatial and temporal aggregation of cancer. â€œAg has 3 purposes. The 1st is descriptive : to indicate some gregationâ€• means the entire number, the sum, the total. examples of epidemiologic excursions into neoplastic In the total, all units of an entity must be considered. disease. The 2nd is evaluative : to suggest the type and Spatial amalgamations, or areas of greater density, are design of further studies that seem fruitful. The 3rd is apparent because they contrast with areas of lesser density. to provide material for deliberations regarding scientific Thus, the rarity of units in some areas may be as impor priority and the illuminative capacity of epidemiology. tant as their frequency elsewhere. Temporal changes of The topic is discussed according to the outline indicated increment or decrement attract our attention, but steady in Table 1, which starts with the broadest stage available states may be equally significant. to man until he plants his feet on other planets, focuses In the investigation of the complex patterns that must down to the smallest epidemiologic units, and then be involved in the disease processes we call cancer, the widens the field to ecology and experimental epidemiology. science of epidemiology has a key role. But it cannot The preceding sessions, devoted to viral, physicochemical, stand alone. It must relate to pathology and statistics, and genetic factors, allow this portion of the conference and, in this age, to genetics, chemistry, virology, and to serve as a correlative summary. molecular biology. These relationships must be continual and intimate, and they must flow in both directions. THE PROBLEM OF IDENTITY Such generalizations have meaning, of course, only as Two assumptions regarding cancer appear to be sound. frameworks for functional decisions regarding what kind The 1st is that cancer is a great group of diseases and not of and which specific investigations are to be undertaken. one disease. The 2nd is that cancer occurs in all human In these decisions, as in all science, it is not enough to and animal populations, although the types of cancers outline broad problems. Rather, having specffied the and the frequencies of occurrence differ widely. question, one must determine whether the requisite Since cancer is a group of diseases, a basic requirement methods and materials are at hand and whether the is the correct identification of separate entities that cancer experimental design is likely to yield convincing results. encompasses. Up to now, our foundation for such identi Among the irreplaceable requirements are the interest fication has been descriptive morphologic pathology. and the availability of competent investigators. This has served us well, but the day may not be too distant

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TABLE 1 SPATIAL-TEMPORAL STUDIES OF CANCER

ApproachMaterialsMethodsGeneral

epidemiologyGlobalTotal populations National features Census, vital statistics Case recordsDescriptive and corn demographicRegionalPopulation parative groups Geographic regions Census, vital statistics Case records SurveysstatisticsSpecific

epidemiologyClass and groupOccupational, social, other subgroups Disease states retrospec Physiologic featuresCase-control tive studies studiesMicro Prospective Family records ClustersEcologyDefined

populations, human and animal laboratory

studiesExperimental Defined environmentRelated .

epidemiologyIdentified groups trials Purposeful modificationsField

when we may be able to place its limitations in the archives velopment of vital statistics, the census, central tumor of history. It is no longer a flight of imagination, for registries, along with continual improvements in diagnosis example, to predict that some forms of leukemia and and in records have placed such data on a more reliable mongolism may be reclassified as reactions to a viral footing. Segi's (79, 80) collection and analysis of cancer invasion of the ovum, rather than as separate, unrelated mortality rates in 24 countries is a useful baseline for these diseases. An analogy is afforded by tabes dorsalis and considerations. some forms of aortic aneurism, unified as 2 reactions to Tables 2A and 2B summarize the data, using the United infection with Spirochaeta pallida. States white population as a reference figure, and the In 1919 James Ewing (25) prophetically wrote: â€œNo highest and lowest rates for comparison. Some striking one would think of confusing lobar pneumonia with features immediately attract attention. The first is that pneumonic plague, although both are examples of acute the total mortality differs within a factor of 2, whereas exudative pneumonitis, but it is quite the rule to identify for a number of sites such as esophagus, stomach, larynx, for statistical studies several equally different forms of prostate, bladder, and breast the differentials between the

. . . cancer.â€• highest and the lowest rates are 5- to 10-fold. Secondly, The corollary to the requirement of correct identifica the male rates exceed the female rates in all countries tion of separate entities is that entities seemingly distinct except Israel and for all sites common to both sexes, with by one set of criteria may be closely related in regard to the exception of thyroid and possibly liver. Also, the other characteristics. We could miss entirely some im differences by countries and by sites are more pronounced portant relationships of cancer either by the dilution among males than among females. This point is reiterated effect of grouping diverse entities, or by overisolating by considering the male-female ratios, as indicated in such entities from presumably different but really asso Table 3. ciated conditions. Investigations of cancer are impossible It is important to emphasize the gross and limited without appropriate attention to morphologic pathology, nature of these data. The 24 countries represented but also they may be seriously weakened by limiting our include Australia, Austria, Belgium, Canada, Chile, attention to situations that meet its present definitions. Denmark, England and Wales, Finland, France, Germany, Ireland, Israel, Italy, Japan, the Netherlands, New Zea WORLD DISTRIBUTION OF CANCER IN MAN land, Northern Ireland, Norway, Portugal, Scotland, A century ago, August Hirsch (39) accumulated some Sweden, Switzerland, the Union of South Africa, and the data on the frequency of cancer in a few countries of the United States, the last being divided by its white and world. In 1915, Frederick Hoffman's (40) compilation of nonwhite populations. The total population encompassed @ cancer mortality throughout the world revealed some of is approximately 567 million, or of the peoples of the the major patterns of occurrence. Since then, the do earth. Perhaps the recent statistics from the Soviet

TABLE 2A CANCER MORTALITYIN 24 COUNTRIES: MALES

100,000U. AGE-ADJUSTEDRATESPER

(white)HighestLowestAll S.

neoplasms (189.8) (97.7) Buccal cavity 4.7 France (7.7) Israel (1.2) Esophagus 3.4 France (12.0) Sweden (2.2) Stomach 12.7 Japan (70.6) (U. S.) Rectum 6.4 Denmark (12.6) Portugal (3.6) Liver 4.6 Japan (14.7) Norway (2.8) Pancreas 7.7 U. S. (nonwhite) (9.0) Japan (2.5) Larynx 2.0 France (9.0) Norway (0.4) Lung 29.4 Scotland (61.9) Portugal (7.9) Prostate 13.9 U. S. (nonwhite) (20.6) Japan (0.8) Bladder 5.3 South Africa (7.9) Japan (0.9) Skin 2.5 Australia (3.9) Japan (1.0) Thyroid 0.4 Switzerland (1.5) Japan (0.2) (3.1)a Leukemia139.7 7.8Austria Denmark (8.2)Portugal Japan

From Segi and Kurihara (80).

TABLE 2B CANCERMORTALITYIN 24FEMALESAGE-ADJUSTED COUNTRIES:

100,000U. RATES PER

(white)HighestLowestAll S.

neoplasms (141.2) (76.7) Buccal cavity 1.2 Ireland (2.4) Israel (1.1) Esophagus 0.8 Finland (5.7) Norway (0.7) Stomach 6.5 Japan (37.1) (U. S.) Rectum 4.1 Denmark (7.2) Portugal (2.5) Liver 4.6 Germany (11.8) Norway (3.4) Pancreas 4.6 U. S. (nonwhite) (5.4) Japan (1.8) Larynx 0.2 Ireland (1.2) Norway (0.1) Lung 4.4 Scotland (9.0) Portugal (2.1) Breast 21 .3 Denmark (23.8) Japan (3.9) Uterus 12.3 U. S. (nonwhite) (28.9) Israel (7.7) Ovary 7.4 Denmark (10.4) Japan (1.4) Bladder 1.9 U. S. (nonwhite) (2.7) Japan (0.9) Skin 1.6 Australia (2.3) Japan (0.7) Thyroid 0.6 Switzerland (1.8) Japan (04) Leukemia108.5 5. 1Denmark Israel (6.1)Portugal Japan (2.4)

a From Segi and Kurihara (80).

Union (57) will add another 200 million to the total, but tion. We have learned through hard experience that, in @ that would still represent only of the human popula cancer, differences of less than 2-fold are usually unreward tion, with all of Africa, and most of Asia and South ing to pursue. This still leaves the intriguing questions America, not included. of the factors that may be associated with the high occur The division of cancer mortality by nations is artificial rence of esophageal and laryngeal cancer among French and misleading. Cancer has no political boundaries; males, the high occurrence of stomach cancer in Japan, registration systems do. In Segi's books (79â€”81) there and the low frequency of cancer of the prostate, bladder, are included as items a whole continent, Australia, and and breast in Japan. countries of the size of Denmark. Population units In addition to these national patterns of cancer distribu range from 154 million white inhabitants of the United tion in the world, further insight is derived from con States to 1.4 million of Northern Ireland. sideration of the temporal changes in mortality for specific The limitations of cancer diagnosis, of death registra sites. Segi and Kurihara (81) have performed this tions and many other factors also make mortality rates service also, indicating the changes that have occurred in hazardous as a basis for further investigation. Certainly the 24 countries during the decade 1950â€”1959. For all only the largest differences should attract serious atten neoplasms, there has been an increase of 5â€”30% among

TABLE 3 SEX RAT1OS@

RATIOU. MALE/FEMALE

@ HighestLowestAll S. (white)

(1.0)Buccalneoplasms1.3Finland (1.7)Israel (1.2)Esophagus4cavity4.0France (9.8)Israel (1.2)Stomach2.0U. . 1France (10.8)Finland (1.6)Rectum1.5N. S. (nonwhite) (2.2)Israel (1.3)Liver0.9N. Ireland (2.1)Japan (0.7)Pancreas1 Ireland (1.1)Israel (1.2)Larynx10.0Israel .7New Zealand (2.4)Ireland (1.7)Lung6.7Finland (38.1)N. Ireland (2.3)Bladder2.8South (13.5)Israel (nonwhite)(1.6)Skin1.6Australia Africa (4.6)U. S. (0.8)Thyroid0.6Switzerland (1.7)Israel (0.2)Leukemia1.5Denmark (0.8)Israel (1.7)Israel (1.1)

a From Segi and Kurihara (80).

males in all countries except Norway ; among females, pleura in South African areas noted for asbestos produc there is recorded an increase of up to 10 % in Ireland and tion (99), and perhaps the frequent occurrence of salivary Japan, and a decrease of 5â€”10% in the United States, gland carcinoma among Eskimos (101). Australia, Norway, and the Netherlands. The most In the logistics of many of these situations, however, consistent trends are seen in the continued increase in unless some specific investigations can be planned and cancer of the lung and a decrease in cancer of the stomach. undertaken, the mere reiteration of the observations is The recorded mortality from cancer of the pancreas and hardly a rewarding aim and may indeed perpetrate prostate and from leukemia has increased in many coun erroneous impressions. It is not an appropriate charge tries and decreased in none. A decreased mortality is to cancer research to establish national census and vital reported in at least 5 countries each for cancer of the statistics, especially since this in turn depends upon buccal cavity, esophagus, and uterus. improvements in the general medical care of the region. It would be useful and instructive if similar data were An excellent example of global epidemiology is the available for many more countries and regions of the well-designed investigation under the leadership of the world. From clinical reports, pathology, and hospital National Cancer Institute of the United States and tabulations (cf. Refs. 97, 105), we do have considerably Tohoku University of Sendai, Japan, in which gastric more additional information of importance. The quality and pulmonary cancer are being compared in populations of these data could be greatly improved by some rather of Japanese in Japan, Hawaii, and California. This simple considerations of the age and sex of the cancer should be a model for similar studies between regions of cases and of the patients of the institutions from which the world where differences in cancer occurrence are well they are drawn (21). Gilliam's (28) criticism of the early established. reports on the excess of liver cancer among the Bantus is Two studies on lung cancer under the auspices of the an excellent example of the pitfalls resultant from confus World Health Organization (10) also exemplify careful ing relative distributions and rates, leading to exaggerated biometric design. In one, Finland, with a high pulmonary or erroneous conclusions. A similar situation obtains in cancer rate, is being compared with Norway, with a low the purported low occurrence of bladder cancer in West rate of the disease. In the other, Dublin and Belfast are Africa despite the presence of bladder flukes. Actually, being compared because of the pronounced difference in an adjustment of the age distribution showed that bladder air pollution in these 2 cities. cancer was considerably more frequent in that area than Inspection of the design of these investigations quickly in Europe or the United States (63). The anecdotal reveals that the world's resources of technical personnel rarity of carcinoma in African Negroes and many other can support only a limited number of such studies at any traditional clinical tales evaporate when more intensive one time. analyses and investigations of populations are undertaken The opportunities in cancer epidemiology are extensive, (15, 37). as indicated by a recent bibliography of 2671 items com Nevertheless, there still remain many unusual situations piled by the World Health Organization (105) by pro that deserve consideration independent of better determi ceedings of international meetings (97), and by evaluations nations of rates. Among these are some old friends such by Stocks (91), Lombard (53), and others (6, 19, 83, 84). as the bilharzial bladder cancer in Egypt (63). There Considerations of priority, in regard to scientific impor are also the new attractions, such as the Burkitt lympho tance, timeliness, and professional interest, again confront sarcoma of African children (8), mesothelioma of the us.

REGIONAL DISTRIBUTION OF CANCER The seasonal occurrence of cancer, or of specific cancer The determination of cancer rates on national dimen entities, has been described in the literature (35), but sions represents but the first crude approximation. It is, the data are neither consistent nor convincing. For one indeed, surprising that so many definite differences can thing, the date of clinical onset or of diagnosis bears but be elicited by these milestones. The next measuring dubious relationship to the â€œtrueâ€•onset of the disease. device, an epidemiologic yardstick, divides the popula However, an important lead may be eluding us in Dyks tions into a series of subpopulations according to smaller tra's (18) observation that there is a peak in March as geographic areas, urban or rural residence, economic and the birth date among patients with lung cancer. Another social status, and other broad demographic features. interesting temporal change, in the sex ratio of children For these studies it is desirable to have more refined with leukemia, recently noted in the United States (27), data on morbidity as well as mortality, based upon also defies an easily acceptable explanation. defined populations. Such statistics, covering the past 25 Studies in Connecticut, Iowa, and New York, as well as years, are available from the states of Connecticut (30) in England and in Denmark, show that the cancer mci and New York (26), as well as from the 4 Scandinavian dence and mortality rates for urban residents are 15â€”40% countries (12, 66, 71, 76) and England (70). The perusal higher than those for rural areas. As indicated in the of the publications provides many ideas for further investi Iowa data (33) given in Table 4, the urban excess is more gations, as well as their limitations. It is unfortunately marked among males than among females and is most true that these reports are not well known to the labora evident for neoplasms of the respiratory system among tory investigators. males. This urban factor cannot be totally accounted In the United States, the incidence and mortality for by differences in smoking habits and probably reflects trends in cancer are rather similar in Connecticut and the effects of other sources of atmospheric pollution. New York, and these in turn agree in general with figures Interesting gradients in cancer rates are elicited when a derived from the 10-city surveys of 1937 and 1947 con population is divided by social-economic classes. Such ducted by Dorn (20) and the national mortality statistics analyses are available from the United States, Great (29). The age-adjusted rates for some sites are indicated Britain, and Denmark. Some of the ratios from the in Tables 2A and 2B. The major temporal changes are United States 10-city survey (20) are given in Table 5. in the increase of lung cancer and decrease in gastric The total cancer rates are higher among the less-fortunate cancer. categories, a commentary on cancer not as a disease of For environmental relationships, the physical area of civilization but, like many other diseases, of unequal residence can be described by such physical features as distribution of civilization's benefits. The differentials climate, elevation, water supply, type of soil, etc. Here along social-economic gradients are, again, more pro the investigator is confronted with the difficulties of nounced among males then among females. Among defining the environmental feature to be considered, the males, the differences are most consistent and striking for mobility of human populations, and, finally, the small cancer of the esophagus, stomach, larynx, and lung. They numbers of people that can be truly related to the environ are not recorded for rectum, skin, kidney, or prostate. mental characteristic. With the continual homogenation Among females, cancer of the uterine cervix stands out, of life, the differentials become further obscured because with the rates among the poorest being twice those among food, clothing, and building materials in one area may be the highest income class. The reverse relationships, of imported from distant and unidentifiable sources. Com somewhat higher rates in the higher economic classes, parisons of extreme differences, such as areas with high have been described for cancer of the breast in women radiation versus low radiation, are often made invalid and for leukemia. because the populations at risk differ even more strikingly In regard to diet, I am impressed with the paucity of in regard to other obvious features. convincing data that have become available. Even the There is definite information that skin cancer is related purported increase in cancer mortality among overweight to the intensity of environmental exposure to ultraviolet people, which led to Tannenbaum's (92) work on the radiation, and this pattern is as evident between the effect of diet on the development of tumors in mice, has northern and southern regions of the United States (20) not stood up. Review of the original reports reveals that as it is between Australia and England (79). The in the relationships were not as definite as the conclusions formation on the relationship of goiter to iodine-deficient that were derived and reiterated. The same can be said waters is also firm, but the relationship of goiter to thyroid of the suggested association of protein- and vitamin cancer is quite indefinite (67, 89). The higher occurrence deficient diets with cancer of the oral cavity, pharynx, of leukemia in southern England (90) and the higher esophagus, and liver. We suspect that gastric cancer occurrence of gastric cancer in the northern United States should be influenced in some way by the dietary history, (29) represent relatively minor differences that do not yet the best investigations available to us fail to reveal seem to be accountable to the geography of the environ any convincing information on this point. The recent ment. Nevertheless, overlay maps in which various studies on trace metals and other constituents of the soil geographic and social features are related to the occurrence and gastric cancer (98) are equally tenuous. It would of disease continue to be interesting as leads for further appear that either diet in the range compatible with investigation. Howe's (41) recent atlas of disease mor survival is not an important factor for most neoplasms of tality in the United Kingdom is a thought-provoking man, or that our methods of inquiry, so often limited to addition to such exercises. retrospective recall, are inadequate.

TABLE 4 this will have no effect on neoplastic diseases, and may URBAN-RURAL RATIOS OF AGE-ADJUSTED CANCER INCIDENCE indeed reduce the incidence of cervical cancer, is not RATES, IowA 1950'@ tenable without much longer experience. It would seem prudent, as well as instructive, to plan and to carry out MaleFemaleAll designed observations in order to have the necessary sites1.401.34Buccal data at the earliest possible time rather than to leave cavity1.331.76Stomach1.000.93Rectum1.310.91Lung2.841.47Larynx2.07Bladder1.562.21Skin1.381.82Uterinethese to chance.

GROUP AND CLASS DISTRIBUTION OF CANCER The next smaller units for epidemiologic concern are the special groups or classes of the population that can be characterized by features of their external or internal cervix1.77Uterine environment. corpus1.23Breast1.25 The most important of such units are the occupational groups, which have yielded important information on carcinogenesis since the days of Percivall Pott in 1775. a From Haenszel et al. (33). This field has been reviewed currently by Hueper (44, 45), who draws a sobering picture of the possibilities of indus TABLE 5 trial and other environmental chemical hazards. Without LOWEST-HIGHEST INCOMECLASS RATIOS OF AGE-ADJUSTED necessarily agreeing with all his interpretations, it is CANCER INCIDENCERATES IN 10 U. S. CITIES, 1947a certainly true that new industrial, medicinal, pesticidal, MaleFemaleAll and a galaxy of other chemical agents are being introduced into our environment without adequate knowledge of sites1.281.17Buccal their chronic potentials. Such hazards are not limited to cavity1.72Esophagus2.501.47Stomach1.75141Rectum1.051.08Liver1.030.80Pancreas1.181.92Larynx1.65Lung2.001.29Prostate1.27Bladder0.891.00Cervixindustrial workers, as Kennaway (47) showed for scrotal cancer, but involve much wider surrounding populations. There is great need to get on top of the problem of identi fication and reduction of environmental carcinogens by laboratory studies and by long-term epidemiologic ob servations of workers exposed to industrial processes. For the latter, centralized health records and long follow-ups should become available for analysis. This requires the cooperation of industrial management and of employee uteri2.00Corpus unions, despite possible medicolegal complications. The uteri1.05Breast0.95 same considerations apply to new products that are intended for continual, wide use. The clarion call of Rachel Carson (9) should not be allowed to fade out. Yet a From Dorn and Cutler (20). the warnings must be placed in focus with the inherent risks we incur just by being alive, and by the needs of In contrast, a number of habits have been established industry, economy, and something we call progress. as of significant import in the occurrence of several types Another large and attractive area for further research of neoplastic disease. These habits are not limited to is the study of possible relationships between various exotic practices such as those that led to the Kangri or disease states and cancer (83). The confusing literature the Chutta cancers. The smoking of tobacco is now well on this topic reveals the limitations and pitfalls of retro established as the primary culprit in the global lung spective collections of clinical cases, which are usually cancer epidemic (17). It cries out for research in sociol devoid of comparative controls. Tuberculosis does not ogy, economics, and education to yield assistance to the seem to be associated with an increased or decreased risk reversal of this addiction. The role of alcohol in cancer to cancer, but the demonstration (5) that isoniazid invokes of the esophagus and of the oral cavity deserves further pulmonary tumors in mice forces a new consideration. study. We have no information regarding the effects of Diabetes mellitus does not have much demonstrable opium upon the occurrence of cancer, to mention another influence upon the development of neoplastic disease (46). important habit of man. The incidence of cancer is about the same among psy The relationships of sexual habits to cancer of the chotics as in the general population (24). On the other uterine cervix (31, 73, 93), and to penile cancer (72), are hand, the associations between leukemia and mongolism becoming rather well defined. It seems probable that (50) and of acanthosis nigricans (14) and dermatomyositis these may be of importance in cancer of the prostate and (82) with carcinoma provide important opportunities for of the testis as well, but no such investigations have been further clinical and laboratory research. reported. We are rapidly acquiring a â€œhabitâ€•ofnational In the studies on the effect of other disease states upon proportions in the use of physiologically potent progesto the development of cancer, perhaps the most difficult gens for contraceptive purposes. The assumption that methodologic feature is the selection of appropriate control

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1965 American Association for Cancer Research. SHIMKINâ€”Spatial-temporal Aggregation 1369 groups for comparison. Stratification of cases by severity whether the method will detect biologically earlier breast of the disease may provide additional information. In cancers, but may allow the identification of breast patterns some disease states the opposing ends of the scale, such as that are related to increased risk to neopla.stic develop adrenal hypo- and hyperfunction, or acromegaly and ment. hypopituitarism (62), can be usefully compared. A In regard to cervical cancer, we have in the Papanicolaou recent report (52) indicates that hypothyroids developed smear technic an excellent detection tool, and much has twice as many neoplasms, and hyperthyroids half as many been said about the need for its more universal application. neoplasms, as compared with euthyroid individuals. The literature is replete with discussions regarding cellular An unexplored field of cancer epidemiology is the criteria of malignancy, leading to the conclusion that in search for physiologic and biochemical attributes of this continuum of tissue reactions there is a broad â€œgrayâ€• individuals for possible relationship to greater or lesser zone in which definite diagnosis is not feasible. Perhaps susceptibility to cancer. If the rate of cancer occurrence we are neglecting leads provided by nonspecific manifesta is influenced by cell number, individuals who weigh over tions of cellular reactions by our natural emphasis upon 200 lb should develop more neoplasms than individuals of the diagnostic target. Many positive vaginal smears half that mass. Children with unusual spurts of growth have abundant leukocytes, which are looked upon as inter may demonstrate different patterns of neoplastic occur fering elements in cytodiagnosis. One wonders whether rence than children with more uniform somatic growth. their presence could be exploited to advantage. Perhaps Case-control types of retrospective studies (55), in a total cell count, or pH or alkaline phosphatase of the which index cases of cancer are matched for various vaginal contents could define the high-risk group for more suspected factors in their history with similar patients or detailed cytodiagnostic procedures. other controls, still represent a useful approach in epi demiology. Lane-Claypon's (51) study of breast cancer 1@IICROEPIDEMIOLOGY in 1924 remains an excellent example of such an investiga Alexander Langmuir introduced me to the term â€œmicro tion. Recently Wynder (106â€”108) has made definite epidemicâ€• during our mutual concern with a cluster of contributions in the application of the technic on an inter leukemia cases in Niles, Illinois. It is an expressive national scale in cancer of the breast, stomach, and description of seemingly unusual concentrations of neo bladder. Haenszel et al. (32) made another methodologic plastic disease in small units of geography, in families, extension by using a sample of annual cancer deaths in and in other limited settings of time and place. the United States. The potentials of the method are far The interest in the study of such occurrences is, of from exhausted and are particularly applicable to rela course, closely related to the return of attention toward tively rare neoplastic entities in which a very large base the possibilities of contagion in neoplastic disease, stimu population is needed as a source, such as breast cancer lated anew by the optimistic discoveries in virus research in males (77). on cancer. Our enthusiasms in this direction have to be However, the time is ripe to add considerations of tempered by the inadequate facts available to us, by our clinical laboratory procedures to the retrospective ques memory Of the history of the earlier investigations of tionnaire studies. For example, the distribution of cancer houses and of cancer families, and by the present hemoglobin values in presumably normal individuals is technologic limitations to our abilities to separate con rather well standardized (58), although more study is tagion from shared genetic and environmental factors. needed to provide additional data on how constant the The possible genetic patterns that may be related to values remain for different individuals. If, however, the specific neoplasms have been discussed earlier at this individual level of hemoglobin is a rather constant charac conference. To reiterate, clearly defined genetic factors teristic, it would be of interest to determine in prospective are known for a few rare neoplastic entities, such as studies whether individuals characterized by lower hemo retinoblastoma, xerodemma pigmentosum, and multiple globin values have more or less subsequent hematologic polyposis of the colon. For the more common neoplasms, and other diseases than those in the upper end of the scale. we are confronted with polygenic systems with phenotypic Furthermore, are there disease differences between mdi effects that are difficult to discern (48). Information on viduals who demonstrate decreases, increments, or flue twins thus far has been rather unimpressive (34).' The tuations of hemoglobin, but still within the presumed revolutionary progress in molecular biology may well â€œnormalâ€•range? The application of this line of thought to empower us eventually to unravel these complex situa other laboratory procedures, such as hormonal levels, may tions. Meanwhile, pedigree studies of families in different generate leads toward the identification of cancer-sus settings continue to yield suggestive data and may provide ceptible groups in the population (95). These studies are us with leads that may be of application long before we becoming increasingly feasible with the organization of can manipulate genetic codes. After all, one of the chief large health systems with preventive medical aims as im yields of the extensive genetic work on inbred mice in portant components, such as the Health Insurance Plan cancer research was the discovery of an extrachromo of New York and the Kaiser scheme in California, and somal factor, the Bittner virus. with the availability of statistical personnel and computer In an analysis of family units in Washington County, analytic devices (103). The large contract for the deter Maryland, it was found (11) that sister-sister and brother mination of the use of X-ray mammography for breast brother pairs showed an excess of cancer, but of possibly cancer (85), developed between the National Cancer even more significance, so did husband-wife pairings. A

Institute and the Health Insurance Plan, is a step in this 1 Recent description of leukemia in twins requires modification direction, since the prospective study may reveal not only of this statment.

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1965 American Association for Cancer Research. 1370 Cancer Research Vol.25,September1965 common environment, or a transmission of something DISTRIBUTION OF CANCER IN ANIMALS appears to be a more attractive hypothesis than heredity Cancer research can be appropriately symbolized by a per se. The association of noncircumcision and cervical mouse. For a few laboratory rodents there are available cancer and the role of early initial sexual intercourse (73) extensive pedigrees, careful observations over many suggest the presence of a transmissible factor. It would generations, and other basic information that has made be instructive to determine whether only certain males these animals invaluable. harbor this factor, as may be possible by studies of mul For most animal species, however, all the limitations of tiple marriages, either simultaneous or in seriatim. Inci data regarding the distribution of cancer in man apply dentally, if such carriers can be identified, it would still be with the force of several greater orders of magnitude. unjustified to invoke a viral agent. Using the cocarcino There are no systematic vital statistics, no tumor regis genesis model of Berenbium (4), a single cervical â€œpaint tries beyond collections of museum specimens, and few ingâ€• with a potent carcinogenic chemical can evoke representative populations of animals yielding the date of cancer following applications of a noncarcinogenic irritant birth, a full life-span, and a careful autopsy. at a much later time. Despite these handicaps, we do possess considerable To return to the Niles cluster of 8 pediatric cases of knowledge about some interesting neoplastic situations in leukemia, Heath and Hasterlik (36) have published the animals. A recent conference on epizootiology (56) details of the investigation and found further association described many of these situations and research on the of this occurrence with congenital heart disease and a problems. The published proceedings are instructive â€˜â€˜rheumatic-likeâ€• illness among the population. Schwartz reading for all serious investigators of cancer. et al. (78), using various immunologic technics with what Neoplastic diseases are to be found in all multicellular they consider as leukemia antigens, reported reactors in animals, and plants also develop cellular aberrations that 1â€”3members of each of the affected families, whereas no meet the morphologic criteria of neoplasia (87). Tumors reactions were elicited in controls or in patients with in animals are of particular interest because they may leukemia. demonstrate environmental hazards shared by man and Taken at face value, the findings are compatible with a because of the possibility that some animal species may reaction to an infectious, antigenic agent. Further be vectors or transmitters of viruses that may be involved support for such a conclusion can be mobilized by Pinkel's in human neoplasms. (68, 69) studies in Buffalo, where some degree of spatial In 1961, attention was sharply focused on an outbreak and temporal association between cases of acute leukemia of hepatoma in epidemic proportions in the most popular was deduced, and Mustaccbi's (61) observations in San game fish of the United States, the rainbow trout (16, 104). Francisco that indicate a nonrandom pattern and a weak In some fisheries well over 50 % of the fish over 2 years of relationship to previous occurrences of leukemia in the age were found to have hepatomas. A series of investiga same geographic units. Further evidence is provided by tions was initiated and it was soon established that the the now well-known relationship between acute leukemia occurrence of the neoplasms was related to certain brands and mongolism (50) and the recent data of Miller (59), of commercial fish food. During the last decade, practices indicating an association of acute leukemia and congenital of raising game fish on high protein meat scraps have been malfommat ions. replaced by the use of more convenient pellets composed At an early stage of the Niles surveys, the National of fish meal, meat scraps meal, cottonseed meal, meat Cancer Institute attempted to identify other clusters of shorts, dry milk, distiller's solubles, and yeast. The leukemia. Reports of such were received at frequent carcinogenic factors appear to be in the fat fractions of intervals, but even cursory examinations failed to confirm the diet, and it is suspected that they are formed during the occurrences. A systematic analysis of data on child the manufacturing process, perhaps by overheating (49). hood leukemia in Connecticut failed to detect any tendency An additional and possibly not too unrelated topic in toward clustering (23). And the associations in Buffalo the field of carcinogenic factors in foods contaminated by and in San Francisco were of low magnitude, requiring processing concerns certain fungal metabolites (49). A special statistical procedures for analysis. We are left in virulent hepatotoxic lactone, aflatoxin, is a metabolite of the insecure position of having to consider the Niles some strains of Aspergillus flavus, which grows on damp occurrence as a rare happenstance, or the biologic equiva peanuts and corn. Aflatoxin produces hepatomas in rats, lent of a bridge hand of 13 spades. and it was recently found that it could also evoke hepa Discussions were held on the desirability of making toma in rainbow trout. These facts may well be directly acute leukemia a reportable disease and of creating a relevant to the high frequency of primary liver carcinoma special network for the early identification and study of in the African and Indonesian populations of man and reported cases. The logistics were decided to be too certainly serve to alert us to wider possibilities of import. formidable, and the possible alarm and repercussions from Adenocarcinoma of the kidney in frogs (Rana pipiens), the public had to be weighed against the sad fact that no described by LuckÃ©(54) in 1934, has attracted relatively preventive or therapeutic measures could be offered to little interest. A conference (22) on this subject was justify the effort. Perhaps a number of larger cities, with active collaboration between the medical profession and held in 1961, and a bibliography listed only 64 references. the departments of public health, could make a signal This is presumably a transmissible neoplasm, but the role contribution by a rapid reporting and epidemiologic of a virus cannot be considered as established. We do investigation of all cases of acute leukemia, congenital not know the geographic distribution of the disease or defects, and mongolism in their localities. factors related to its occurrence. The close ecologic rela

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1965 American Association for Cancer Research. SHIMciNâ€”Spatial-temporal Aggregation 1371 tion of frogs to insects should indicate the exploration of In a relatively short time and economically, we could possible insect vectors. Insect vectors may be significant obtain invaluable information on the comparative pa not only for other animal tumors, such as the Shope thology of some fish, amphibians, reptiles, birds, marsu rabbit papiloma (86), but perhaps for some human neo pials, and other mammals, including primates. Such plasms (8) as well. studies should be encouraged, developed, and system The story of the virus-induced neoplasms of chickens, atically planned. They require laboratory facilities for opened by the monumental discovery of Rous (74) in long-term observations and the collaboration of patholo 1911, is well detailed and defined in reports of Beard (3) gists. They are unlikely to be derived from usual zoologic and of Rubin (75) . These investigations are no longer to park collections or experimental institutions unless the be considered as convenient laboratory models or of purposes and the methods are spelled out and diligently practical importance only to the chicken farmers. followed. The distribution and transmission of the ribonucleic Another area for relatively small programmatic de acid-cytoplasmic virus entities that are established to be velopment is the use of animals as an index of environ involved in the occurrence of leukemia and lymphoma in mental hazards. In the wide studies on air pollution, for fowl, mice, and rats, and are suspected in cattle, swine, example, the usual practice is to collect the suspected sheep, dogs, cats, and man, present us with one of the agents and to bring these to the laboratory. It would be most challenging and fruitful approaches toward the an obvious corollary to place mice in the environment solution of a significant section of the cancer problem. itself and to observe the effects. Colonies of inbred mice Huebner's (42, 43) postulation of a grain-centered ecology placed on highways or in industrial plants, may be useful of this group of diseases is intriguing, and we certainly for the detection and prevention of neoplastic hazards. can accept his conclusion that, â€œInsome instances at least human and animal cancers must have similar causes; ECOLOGY AND EXPERIMENTAL to think otherwise in a biological sense is nonsense.â€• EPIDEMIOLOGY Man's position relative to other animal species, in terms In the foregoing discussions, the essential research of numbers, is not unusual particularly if the more rapid approach involves the identification of specific groups of biologic turnover of most other species is taken into animals or human beings and specific environmental consideration (13). To dissociate man from his animal situations as the investigational materials. The essential relatives is no more possible for neoplastic than for any purposes are either to uncover new or suspected relation other diseases (84). ships of etiologic significance in cancer, or to test hypoth Again, as with epidemiology, the opportunities for eses founded on laboratory and clinical observations. outstanding contributions from the study of animal For the appropriate evaluation of these studies, 2 cancers are so numerous that the matter of correct, newer technics or approaches are ready for development. effective choice becomes a major consideration, at least One is ecology, the multifactorial study of complex inter for projects requiring large expenditures of time and relationships, and the other is experimental epidemiology, effort by competent investigators. The problem of the purposeful modification of environmental or other lymphoma in cattle is receiving the emphasis it deserves, factors in human or animal populations. with special herds being maintained in Pennsylvania, The appropriate investigational material for ecology is California, and Denmark (56). To the bovine neoplasms a defined population in a defined geographic area, a of greatest interest perhaps should be added the enzootic situation which has acquired the name of â€œhuman popula hematuria and cancer of the bladder related to a fibro tion laboratory.â€• In the field of oncology, the relevant papilloma agent (65). subjects of study would include the demographic, social, The dog has as large and as varied a spectrum of neo clinical, physiologic, biochemical, and immunologic plasms as man, and the dog shares man's environment measurements of the human population; similar measure more intimately than any other domestic animal. De ments of the animal and plant populations, including signed epizootiologic studies in dogs appear to have many insects, of the area ; the geography; the climatology ; air, attractive features (60, 94). water, and soil determinations; and surveys of the in In addition to these large enterprises that require care dustry, habitations, commerce, and other features of the ful planning, cooperation, and large investments, a wide man-made environment. The observations must be expansion of smaller investigations in comparative pa made repeatedly over a considerable period of time, cer thology would be most informative and could lead to tainly not less than a decade, and the point of emphasis some interesting observations. would be to adduce the patterns and interrelationships Recently Andervont and Dunn (1) completed their between the various factors and their distribution in time study of tumors and other diseases among 240 wild house mice bred and raised in captivity. Over 40 % of the mice and space. One of the serious logistic problems for such endeavors developed a wide variety of tumors. It would be useful to in oncology is the large population that has to be encom extend this approach to many species of smaller animals, passed if meaningful numbers of specific cancers are to be particularly in areas indigenous for the species. Starting derived during a reasonable period of time. These with a few specimens, several generations of identified descendants would be maintained for the duration of the considerations indicate that a population of 500,000 natural life-span, and careful autopsies performed. should be available. This immediately leads to experi Some of the animals could be set aside to determine their mental plans of sample surveys, with concurrent case response to a few carcinogenic chemicals. control designs, and again the hard choice of a restricted

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1965 American Association for Cancer Research. 1372 Cancer Research Vol. 25, September 1965 number of specific studies in depth to avoid unrewarding The same approaches are due, and overdue, to clarify the dilution. preneoplastic role, if any, of rectal polyps, of breast Obviously the very dimension of such studies, which irregularities, and of thyroid nodules. Here scientific are being developed in Alameda County by the California merit joins hands with direct practical application. And Department of Health, must 011 the one hand include here medicine may find areas in which prevention will be considerations and measurements of many features that considered truly as important as treatment. may appear quite distant from cancer and, on the other, REFERENCES must be related to more direct epidemiologic studies that 1. Andervont, H. B., and Dunn, T. B. 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Michael B. Shimkin

Cancer Res 1965;25:1363-1374.

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