Int. J . Cancer: 22, 645-654 (1978)

CANCER AND " CANCER RELATED " COLORECTAL LESIONS IN SAO PAULO, BRAZIL Carlos MARIGO l, Pelayo CORREAand William HAENSZEL Department of Pathology, Faculty of Medical Sciences, Santa Casa Hospital, Siio Paulo, Brazil; Department of Pathology, Louisiana State University Medical Center, New Orleans, La., USA; and Illinois Cancer Council, Chicago, Ill., USA

A series of 832 necropsy specimens were studied grossly with a magnifying lens and all lesions identified were studied microscopically. The age and sexspecific prevalence of adenomatous and hyperplastic polyps i s reported and results are compared with those of other populations. A correlation was made between polyps and cancer of the colon and rectum (407 cases). The data suggest that SILO Paulo i s a community in a transitional stage between intermediate and high risk of cancer of the colon. The epidemiologic characteristics of lower rectum cancer are peculiar to some populations and appear unrelated to colon cancer. The black population of SBo Paulo has a higher prevalencethan that reported for African negroes. The data also implicate adenomatous polyps, diverticulosis and hemorrhoids as being probably related diseases.

The prevalence of colorectal polyps in several populations with varying risks of large-bowel cancer has been described in an effort to investigate the role of polyps in the genesis of colon cancer. Studies in Colombia (Correa et al., 1972), Hawaii (Stemmermann and Yatani, 1973), Japan (Sat0 et al., 1976), Iran (Haghighi et al., 1977) and the USA (Correa et al., 1977), utilizing the same methodology provide the basic data on the geographic pathology of this disease. We report a similar study carried out in the city of Silo Paulo in south-east Brazil, where the incidence of colorectal cancer is intermediate in the international scale. The prevalence of polyps by race and place of birth in Silo Paulo is analyzed and compared with that seen in other countries. In addition, the presentation of polyps is correlated with other pathologic conditions of the colon and rectum and with intestinal metaplasia of the gastric mucosa. MATERIAL AND METHODS

We obtained 832 specimens of large bowel from necropsies performed during the years 1973-1975. The material was obtained from the Santa Casa Central Hospital, SBo Paul0 (620 specimens) which provides care for the population in the low socioeconomic classes of the city and from the MedicoLegal Institute (212 specimens) which covers a wider range of socioeconomic classes and in general represents a population with a higher socioeconomic status than the Santa Casa series. A systematic search for polyps and other lesions was done following published gross and microscopic procedures (Correa et al., 1972) including identical criteria for histologic classification of polyps. All

lesions were localized by exact measurements from the pectinate line. Any distance between 0 and 5 cm from that line was classified as low rectum and any distance between 5.1 and 10 cm from the line was classified as mid-rectum. Two main racial groups were identified : white and black. A person was characterized as black when there was no doubt about the color of the skin. If there was a doubt, the racial characteristics of at least two other features (hair, nose, lips, eyes) were examined. This procedure classified the majority of individuals of mixed race (mulattos) as negroes. All cases with diverticuli showed multiple lesions on gross examination and only a few required microscopic confirmation. We excluded the false diverticuli (Hughes, 1969). The cases of schistosomiasis were diagnosed upon microscopic confirmation of suspect lesions identified by gross examination with the aid of a magnifying lens. The number of cases of schistosomiasis may be underestimated since we could not exclude the presence of microscopic lesions which were not detected grossly. The diagnosis of hemorrhoids was based on gross examination; in doubtful cases the mucosa of the anal,canal was dissected and the veins examined. The diagnosis of appendicitis was always based on microscopic examination. All cases had the same histologic lesions, namely, cicatricial fibrosis, mainly in the distal third of the organ, accompanied in most instances by obliteration of the lumem and absence of the rnucosa (healed obliterating appendicitis). Absence of the appendix and identification of the scar of previous surgery were used to characterize appendectomy. Follicular lymphoid hyperplasia was characterized as multiple sessile nodules measuring no more than 2 mm in diameter, distributed thoroughout the colon and rectum and which upon microscopic examination revealed enlarged lymphoid follicles. The study of intestinal metaplasia of the gastric mucosa followed methods previously described (Correa et al., 1970). RESULTS

Table I shows the prevalence of three types of polyps found in the colon and rectum by age and sex, and provides the corresponding data for individuals with multiple polyps. Hyperplastic polyps were more numerous than adenomatous ones Received: August 31, 1978.

646

MARIGO ET AL. TABLE I AGE- AND SEX-SPECIFIC PREVALENCE (PER 100 SPECIMENS) FOR ADENOMATOUS, HYPERPLASTIC AND JUVENILE POLYPS; SAO PAULO, 1973-1975 Adenomatous Number of specimens

Single and multiple No.

Males, total 0-14 15-44 45-64 65 and over

Females, total 0-14 15-44 45-64 65 and over

52

Rate

12.9

Hyperplastic

Multiple only No.

403 45 175 103 80

-

_

20

5 20 27

2.9 19.4 33.7

2 8 10

429 46 172 121 90

52 1 10 20 21

12.1 2.2 5.8 16.5 23.3

22 3 10 9

_

Single and multiple

Julenile

Multiple only

Rate

No.

Rate

5.0

86 1 26 25 34

21.3 2.2 14.8 24.3 42.5

35 8 12 15

4.6 11.6 18.7

73 1 21 26 25

17.0 2.2 12.2 21.5 27.8

38 6 18 14

8.8 3.5 14.9 15.5

-

1.1 7.8 12.5 5.1

1.7 8.3 10.0

at all ages and in both sexes. Both conditions were more frequent in men and their prevalence increased with age in both sexes. In SBo Paul0 there was no male excess in the prevalence of multiple polyps and in this respect the local experience differs from other reports (Correa et ul., 1977). Review of the data from SBo Paulo, Hawaii, New Orleans, Akita, Miyagi and Cali reveals that the predominance of hyperplastic over adenomatous polyps is limited to SBo Paulo and Hawaii. In Hawaii, as in Sgo Paulo, there was no male excess of multiple adenomatous polyps. Juvenile polyps in SBo Paulo exhibit the same features as noted elsewhere, namely, they are slightly more frequent in men and usually appear in childhood and adolescence, only occasionally being found in adults. N o additional tabulations of them are presented in this paper. The average size of adenomatous polyps increased up to age 65 (Table 11). Only at ages over 65 years were polyps larger than 1 cm in diameter found. This experience is similar to that reported from Cali. The large intestines among persons over 35 years of age in the SBo PauIo series were longer than those

No.

Single and multiple

Multiple only

Rate

No.

Rate

No.

Rate

8.6

9 1 8

2.2 2.2 4.6 -

4 2 2

1.0 2.4 1.1

-

-

9 3

2.1 6.5 2.9 0.8

5

1 -

-

2 2 -

-

0.5

-

1.2 -

reported for Cali. The average length of the large bowel in SBo Paulo men was 165 cm compared to 150 cm in Cali; the corresponding female values were 157 cm and 146 cm. Table I11 compares the length of the colon in polyp-bearing and polyp-free individuals and summarizes the findings in the form of relative risks. It suggests that the risk of developing polyps increases with length of the intestine, especially in men. Corresponding data from other countries were not available for comparison. The number of polyps per positive specimen was greater for hyperplastic than for. adenomatous polyps. The interpopulation comparisons of data on this point are summarized in Table IV, The

TABLE I11 RELATIVE RISK OF ADENOMATOUS A N D HYPERPLASTIC POLYPS BY LENGTH OF LARGE INTESTINE; SAO PAULO, 1973-1975

Males TABLE I1 AVERAGE SIZE (MM.) OF ADENOMATOUS POLYP BY AGE A N D SEX Sex

Males

Age

15-44 45-54 55-64 65 and over

Females 15-44 45-54 55-64 65 and over

Average size

2.5 3.8 4.1 3.7 2.8 3.6 3.8 2.8

100-139 140-179 180+

4 27 16

14 39 24

27 70 31

Average length(cm) 169

165

162

9 25 11

19 36 13

39 71

Average length(cm) 161

155

156

1.00 2.6 3.5

1.00 1.13 1.49

1.00 1.52 1.91

1.00 1.04 1.07

Females 100-139 140-179 180+

25

* The risk of polyps being present in intestines of specified length in terms of unit risk for intestines 100-139 cm in length. See Cornfield and Haenszel (1960) for discussion of concept and method of computation.

647

COLORECTAL CANCER I N SAO PAULO

transverse colon (24 %) than in the ascending colon (2073, but when the surface area for the respective segments is taken into account (40% vs 17%; Haenszel et al., 1979, it is obvious that even in Cali the greatest concentration of polyps occurs in the ascending colon. Hyperplastic polyps which are concentrated in the segments distal to the rectosigmoid junction present an entirely different configuration. In Sgo Paulo the highest proportion of hyperplastic polyps occurred in the rectum ( 5 5 7 3 , which coincides with the findings in New Orleans (50%) and Cali (51%). In Hawaii more hyperplastic polyps were observed in the sigmoid (33 %) than the rectum (29%), but introduction of surface considerations suggests that the rectum has the highest polyp risk per unit area. The small number of hyperplastic polyps reported in Japanese publications precludes examination of these by location. The anatomic localization of polyps by age (see Table VIII) suggests that the concentration of polyps in the proximal segments rises with age among Sgo Paul0 women, a feature not observed in men. This pattern diverges from that of Cali where distal displacement with age was seen for men. Table VI contrasts the prevalence of adenomatous polyps in Sgo Paul0 natives with that of migrants from other parts of Brazil and from foreign countries. The population of greater Sgo Paul0 as of the 1970 census was 7,650,000 and included approximately 950,000 migrants from north-east Brazil and 650,000 from Minas Gerais. The states of Sgo Paulo and Minas Gerais are geographically close but the distant northeast states differ from S g o PauIo in many cultural and ecological characteristics. The results suggest a deficit in adenomatous polyps

TABLE I V AVERAGE NUMBER OF POLYPS PER POSITIVE SPECIMEN INTERNATIONAL COMPARISON Sex

Miyagi

SLo N. Hawaii Paulo Grleans (Japanese)

Cali

Akita

Adenomatous Polyps Both sexes 1.80 Male 2.14 Female 1.46

1.85 2.24 1.46

2.02 2.28 1.77

2.06 2.23 1.90

2.07 2.43 1.73

2.63 2.60 2.67

Hyperplastic Polyps Both sexes Male Female -

1.89 2.16 1.62

-

2.42 2.54 2.31

1.79 1.84 1.75

6.28 7.61 4.96

Hawaii Japanese showed the highest average number of adenomatous and hyperplastic polyps. Sgo Paulo, New Orleans and Akita displayed similar results for adenomatous polyps. For hyperplastic polyps Sgo Paulo was placed second after the Hawaii Japanese, followed by New Orleans and Cali, the two latter populations with significantly fewer polyps. Table V shows the adenomatous polyps in the S g o Paul0 population to be preferentially located in the proximal segments (24%, in the ascending colon) with a secondary peak in the recto-sigmoid segment. This selective localization in the ascending colon was more accentuated in Hawaii (34%), New Orleans (38 %), Akita (42 %) and Miyagi (41 %). In Cali more adenomatous polyps were observed in the

TABLE V NUMBER OF POLYPS BY LOCATION; ShO PAULO, 1973-1975 Hyperplastic

Adenornatous Single

CeCUm

Relative distance from ileocecal valve (per cent)

Absolute distance from ano-rectal line (cm) Total

0-4 5-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-84 85-89 15-22 10-14 6-9 0-5

M

F

M

2 1

1 1 4 6 3 1 1 4 2 -

6 19 7 7 7 8 6

1 3 2 2 1 -

Single

Multiple

2 2 2

3 1 1 3

30

31

4

4 7 3 1

F

5 10 3 1 2

Multiple

M

F

M

F

1 2 2 6 1 6 2 1 3 2

6 3 2 2 1 2 2 1

4 7 6 6 5 1 6 1 3 5 9 12

6 4 3 10 16 6 4

3

-

2 2

4 1 2

4 3 5 10

1 1 6 8

13 33 13 40

3 10 23 42

86

68

51

35

164

138

3

-

-

648

MARIGO ET AL. TABLE VI

AGE-SPECIFIC PREVALENCE (PER 100 SPECIMENS) OF ADENOMATOUS POLYPS A N D DIVERTICULA BY PLACE OF BIRTH; SAO PAULO, 1973-1975 Number With adenomalous POlYPS of specimens No. %

With diverticula

Slo Paulo City 0-29 30-59 60

+

%

No.

~

~~

143 139 94

3 20 24

2.1 14.4 25.5

-

-

14 19

10.1 20.2

61 68 64

2 4 15

3.3 4.1 23.4

3 I2

3.1 18.8

32 71 43

2 10 13

6.3 14.1 30.2

6 5

8.5 11.6

12 29

2 16

16.7 55.2

2 7

16.7 24.1

North-east Brazil 0-29 30-59 60

+

Minas Gerais 0-29 30-59

+

60

Foreign-born 30-59 60

+

limited to persons under age 60, among natives of north-east Brazil. Differences between natives and migrants over age 60 were limited to an elevated prevalence in the small sample of foreign-born studied, most of whom came from Portugal, Italy, Spain and Japan. Within SPo Paulo, whites exhibited a higher prevalence of polyps than did negroes: 15.6% vs 9.4%for adenomatous polyps and 26.0% vs 15.6% for hyperplastic polyps, the white-black differential being most accentuated at age 60 and over. The anatomic localization of polyps also differed by race. Figure 1 depicts a rather uniform distribution of adenomatous polyps by bowel segments in negroes, while in whites they were more concentrated in the proximal 20%. The overall SPo Paulo results on polyp distribution reflect essentially the white experience. The distribution of hyperplastic polyps

(Fig. 2) is similar for both races and displays an obvious concentration in the distal 10% of the large intestine. The available data o n colon cancer incidence assign SPo Paulo to the intermediate-risk category and Table VII places the polyp findings for SPo Paulo in an international perspective. There is a close correspondence in rankings of adenomatous polyps and colon cancer risk. There is no obvious association between hyperplastic polyp prevalence and colon cancer risk. The information on polyp location in relation to the anatomical distribution of bowel cancer within SZo Paulo is reviewed in Table VIII. The cancer cases were obtained from autopsy and surgical records at the Santa Casa Hospital. The most distal segment combines mid- and low-rectum because many cancers in this region involved both areas. The concentration of carcinomas in the rectum coincides with the distribution of hyperplastic polyps. In the proximal large bowel the carcinoma tended to be concentrated in the segments from descending colon to upper rectum as opposed to the greater representation of adenomatous polyps from the cecum to the transverse colon. Several other lesions of the bowel were studied in the SPo Paulo series in an effort to describe their interrelationship. Information on the prevalence of these other lesions is summarized in Table IX. Healed appendicitis was the lesion most frequently encountered (13.1 % of the specimens studied), followed by lymphoid hyperplasia (10.3 %), diverticulosis (9.5%) and hemorrhoids (8.7%). Sex differences in prevalence did not appear to be a dominant characteristic, the largest disparity being noted for lymphoid hyperplasia (62 males vs 24 females) and lipomas (1 1 males vs 25 females). The rise in prevalence with age was obvious for all conditions except schistosomiasis, appendectomy and lymphoid hyperplasia. The age-adjusted prevalence of diverticulosis was as follows: Hawaii Japanese 38 %; SZo Paulo 12 %; Akita (Japan) 10%;Miyagi (Japan) 0.6%(Stemmerman and Yatani, 1973; Sato et al., 1976). The popu-

TABLE VII AGE-ADJUSTED PREVALENCE (PER 100 SPECIMENS) OF ADENOMATOUS AND HYPERPLASTIC POLYPS, INTERNATIONAL COMPARISON Adenornatous polyps (%) Population

Hawaii Japanese New Orleans (Negro) New Orleans (White) Japan (Akita) Slo Paulo (White) SZo Paulo (Negro) Japan (Miyagi) Colombia (Cali)

Colon cancer risk

Very high

High High Intermediate Intermediate Intermediate Low Low

Hyperplastic polyps (%) P

Males

Females

Males

Females

63 37 36 36 20 14 13 11

52 29 20 20 17 13 12 11

73 14 15 2 29 18 3 11

51 8 21 4 25 16 1

7

COLORECTAL CANCER IN, SAO PAUL0

649

ADENOMATOUE POLYPS

BLACKS

WHITES 50

a0

FIGURE1 - The anatomic distribution of adenomatous polyps. The figures indicate relative position as a percentage of the total length of the large bowel. Each point represents one polyp.

lation ranking for diverticulosis corresponded well with that described for polyps and colon cancer. The association in presentation of the several lesions studied within the same individuals are summarized in Table X. The odds ratio has been used to describe the degree of association: when the joint presentation of two lesions in the same specimen observed equals that expected on the basis of chance the odds are 1.0; values greater than 1.0 indicate positive association and values less than 1 .O negative association. Since hyperplastic and adenomatous polyps were positively associated (odds ratio of 2.7) it is not surprising that the other conditions tended to display about the same degree of association with both types of polyp.

Diverticulosis and hemorrhoids were positively associated and both conditions in turn were positively associated with each polyp type. Other evidence supports the positive association of polyps and diverticulosis. There has been a concomitant rise in diverticulosis and adenomatous and hyperplastic polyps (and colon cancer) in the Hawaiian Japanese when compared to the baseline experience in Japan (Stemmermann and Yatani, 1973; Sat0 et al., 1976). The natives from north-east Brazil show a deficit in diverticulosis limited to persons under age 60 (see Table VI). Healed obliterating appendicitis was associated with both types of polyp, and the scant data on appendectomy point very weakly in the same direc-

HYPERPLASTIC POLYPS B lACKS

WHITES

10

FIGURE2 - The anatomic distribution of hyperplastic polyps. The figures indicate relative position as a percentage of the length of the large bowel. Each point represents one polyp.

650

MARIGO ET AL. TABLE VIII PERCENTAGE DISTRIBUTION OF ADENOMATOUS A N D HYPERPLASTIC POLYPS AND CARCINOMA ’, ACCORDING TO LOCATION BY SEX A N D AGE Age 0-54 years

Age 1 5 5 years

Adenomatous Polyps

Hyperplastic Polyps

Carcinoma

Adenomatous Polyps

Hyperplastic Polyps

Carcinoma

32 100.0

72 100.0

102 100.0

85 100.0

140 100.0

98 100.0

59.4

37.4

24.5

69.4

20.7

11.2

40.6 -

32.0 33.3

20.6 54.9

23.5 7.1

47.9 31.4

32.7 56.1

27 100.0

71 100.0

101 100.0

71 100.0

102 100.0

106 100.0

55.6

43.7

19.8

56.3

32.3

32.3

33.3 11.1

18.3 38.0

33.7 46.5

36.6 7.1

16.7 51.0

39.6 37.7

Males Total number Per cent Cecum through transverse colon Descending colon through upper rectum Mid and low rectum Females Total number Per cent Cecum through transverse colon Descending colon through upper rectum Mid and low rectum Data from Santa Casa Hospital.

conclusions on this point. Benign tumors of connective tissue were not associated with polyps. No statistically significant association between schistosomiasis and hyperplastic and adenomatous polyps was uncovered. Study of the lymphoid system showed marked differences between the material from Santa Casa Hospital (2.2 % positive for lymphoid hyperplasia) and the Medico-Legal Institute (34% positive). These differences persisted within all age groups and for both sexes. Our tentative interpretation of the differences’between the two sources is that lymphoid

tion. When appendicitis and appendectomy are combined (assuming that the appendix was removed because of appendicitis) the association with polyps remains positive (odds ratio 2.14 for adenomatous polyps, and 1.9 for hyperplastic polyps). No positive association between appendicitis and diverticulosis and hemorrhoids is suggested when appendectomy and appendicitis are combined (the odds ratio are 0.75 for diverticulosis and 0.59 for hemorrhoids, respectively). Lipomas may be associated with polyps, but the small number of lipomas observed prevents firm

TABLE 1X AGE-SPECIFIC PREVALENCE (%) OF SELECTED LARGE BOWEL, APPENDIX A N D ANAL LESIONS; SAO PAULO, 1973-1975 Diverticula No. of spec.

All ages both sexes 832 403 Males 429 Females 0-20 20-29 30-39 40-49 50-59 60-69 70 f

149 110 112 117 109 114 121

Hemorrhoids

No. pos.

%

No. pos.

79 37 42

9.5 9.2 9.8

72 37 35

-

-

-

-

3 10 15 23 28

2.7 8.5 13.8 20.1 23.1

2 9 11 11 20 19

”/,

8.7 9.2 8.2 1.8 8.0 9.4 10.0 17.5 15.7

Lipoma No. pos.

A

36 11 25

4.3 2.7 5.8

_ _

_

_

-

_

4 8 11 13

3.7 7.3 9.7 10.8

Leiomyoma No. pos.

14 7 7 1

_

2 3 4 1 3

%

Appendicitis Appendectomy

-No. pos.

1.7 109 1.7 57 1.6 52 0.7 3 _ 6 1.8 10 2.6 12 3.7 16 0.9 26 2.5 36

%

13.1

14.1 12.1 2.0 4.0 8.9 10.2 14.7 22.8 29.7

sczir$

No. pos.

%

No. pos.

48 24 24 6 4 6 8

5.8 6.0 5.6 4.0 3.6 5.4 6.8 5.5 6.1 9.1

50 21 29

6

7 11

5

15 11 4 10 3 2

~

~

~

%

No. pon.

%

6.0 5.2 6.8 3.3 13.7 9.8 3.4 9.1 2.7 1.6

86 62 24 36 18 13 12 3 0 4

10.3 15.4 5.6 24.2 16.7 11.6 10.3 2.8 3.3

~

~

?

T

COLORECTAL CANCER IN SAO PAULO TABLE X FREQUENCY OF JOINT PRESENTATION OF SELECTED LESIONS IN THE SAME SPECIMENS AS MEASURED BY THE ODDS RATIO: FREQUENCY GREATER THAN EXPECTED BY CHANCE (ODDS RATIO 1.0) A N D FREQUENCY LESS THAN EXPECTED BY CHANCE (ODDS RATIO 1.0); SAO PAULO, 1973-1975

Adenomatous and hyperplastic polyps Diverticula and adenomatous polyps Diverticula and hyperplastic polyps Diverticula and hemorrhoids Diverticula and appendicitis Diverticula and appendectomy Hemorrhoids and adenomatous polyps Hemorrhoids and hyperplastic polyps Hemorrhoids and appendicitis Hemorrhoids and appendectomy Appendicitis and adenomatous polyps Appendicitis and hyperplastic polyps Appendectomy and adenomatous polyps Appendectomy and hyperplastic polyps Lipoma and adenomatous polyps Lipoma and hyperplastic polyps Other benign tumors and adenomatous polyps Other benign tumors and hyperplastic polyps Schistosomiasis and adenomatous polyps Schistosomiasis and hyperplastic polyps Lymphoid hyperplasia and adenomatous polyps Lymphoid hyperplasia and hyperplastic polyps Intestinal metaplasia and adenomatous polyps

2.7 1.9 2.3 2.9 0.42 1.7 1.45 1.9 0.81 0.21 2.3 2.0 1.43 1.27 1.7

1.43 0.95 1.06 0.43 1.20 0.15

0.46 1.18

Odds ratio differs significantly 1.0 at 5 % level of significan-e.

hyperplasia represents a normally reactive lymphoreticular system rather than a pathological process. One might then anticipate a predominance of positive findings in the Medico-Legal Institute series representing younger and healthier individuals, presumably from higher socioeconomic classes, of better nutritional status at time of death than hospitalized, seriously ill individuals from Santa Casa. In a sub-sample of 473 autopsies a special search for intestinal metaplasia of the gastric mucosa was made. No significant association with adenomatous polyps was demonstrable after adjustment for age. An unusual feature in the SBo Paulo material was the observation that 3.6% of the cases showed dysplastic changes in the squamous epithelium of the anal canal and anus. These will be reported in a separate communication. Atypical findings were obtained with some adenomas and these will be published elsewhere (Cuello et d). DISCUSSION

Several investigators have analyzed morphological and epidemiological data on hyperplastic polyps and concluded that they are probably not related to cancer (Morson, 1962; Lane, 1971 ; Correa, 1972, 1977). Other studies have suggested that adenomatous polyps are probably related t o the cancer process (Helwig, 1947; Burkitt, 1969; Haenszel and Correa, 1971; Correa et al., 1972, 1977; Morson,

65 1

1974). Recent work has described epidemiologic differences between cancer of the colon and rectum, which may prove to be different epidemiologic entities (Haenszel and Correa, 1971 ; Correa, 1975). If there are factors common for cancer and hyperplastic polyps, they should exert their action in the lower rectum. From this point of view the SBo Paulo finding of a statistical association between hyperplastic polyps and colorectal cancer based on the concentration of both entities in the lower rectum are of interest. However, the SBo Paulo results are not supported by inter-population comparisons. Japan, with low polyp prevalence, has a relatively high risk of carcinoma of this segment (Sato et al., 1976). This inconsistency is also illustrated by the data from Cali and New Orleans (Correa, 1975); cancer of the lower rectum is more frequent in Cali than in New Orleans in the presence of a higher frequency of hyperplastic polyps in New Orleans. While, on morphological grounds, we do not consider hyperplastic polyps to be true neoplasias, the Silo Paulo findings cannot be completely dismissed and the possibility of an etiologic factor common to both hyperplastic polyps and low rectal cancer may be entertained. Several types of epidemiologic and pathologic evidence have supported the inference of a n etiological relationship between adenomatous polyps and colon cancer risk (Haenszel and Correa, 1971 ; Morson, 1974). The distinctive features of adenomatous polyps in SBo Paul0 are the minimal sex differences in prevalence, and the frequency in presentation of multiple polyps. These stand in sharp contrast to the male predominance of multiplicity in Cali, Colombia. It may be possible to reconcile these findings with the higher colon cancer incidence in SBo Paulo women (10.8 per 100,OOO) than in men (8.7 per lO0,OOO) (Waterhouse et al., 1976). Table VIII depicted a greater concentration of cancer in the distal colon of older ages, which was not seen for adenomatous polyps. This would suggest that with age the distal polyps have a higher rate of transformation to malignant lesions than the proximal polyps. This is consistent with the findings in Japan (Sato et al., 1976) and Sweden (Ekelund et al., 1974) of higher degrees of atypia in distal polyps as compared to proximal polyps. The SBo Paulo finding of a higher prevalence of polyps in the longest intestines suggests that polyp formation may be a function of surface area at risk. One might, therefore, expect populations with longer intestines on the average to have a higher prevalence of polyps and this factor may account in part for the excess prevalence in SBo Paulo (with longer intestines) compared to Cali. It may also be that nutritional status is independently related to polyps and body size. The observations on prevalence of polyps among migrants to Silo Paulo should be pursued. The intriguing aspect is the low frequency of adenomatous polyps among persons from north-east Brazil under 60 years of age, where the colon cancer risk is low: 1.78 per 10,000 inhabitants (Waterhouse et a[., 1976). After age 60 the polyp experience of migrants from the north-east approaches that of Siio Paulo

652

MARIGO ET AL.

natives. People coming from the neighboring state of Minas Gerais show at all ages the characteristic adenomatous polyps prevalence of Siio Paulo natives. North-east Brazil and Minas Gerais are primarily rural and with diets rich in fiber, typical of populations at low risk for large bowel cancer. While some of the factors that determine the appearance of polyps may have spread from Siio Paul0 to Minas Gerais and other parts of Brazil, the more probable explanation is that immigrants from Minas Gerais and older persons from the north-east had lived for several decades in Siio Paulo prior to death and were exposed for many years to local environmental factors. This explanation would be consistent with observations on migrants to the United States from Europe and Japan who in their life-time acquired the high colon cancer risk of the host population. It also helps explain the high prevalence of adenomatous polyps in the Hawaiian Japanese, which has suggested a role for exposures in late adult life in modulating the expression of bowel lesions (Stemmermann, 1966). Observations on intercountry variation and migrant populations have indicated that race per se does not play a determinant role in polyp prevalence or incidence of colon cancer. Migrants from lowrisk to high-risk countries acquire the high prevalence of polyps and the high incidence of cancers of the host countries as has been proved for Caucasian, Japanese and Negro migrants (Staszewski et al., 1965; Haenszel et al., 1968; Williams et al., 1975; and Correa et al., 1977). The negroes of Brazil apparently have acquired an intermediate risk for adenomatous polyps when compared with the African negroes (Bremmer et al., 1970; Williams et al., 1975). While in our opinion the Siio Paul0 results provide additional support for the proposition that race is not an important determinant, some aspects of the local comparisons warrant comment. In Siio Paulo there is a predominance of polyps in whites, while in New Orleans, there is a slight predominance in negroes. The presence of greater racial variation in polyp prevalence in Siio Paulo than in New Orleans is somewhat puzzling given the greater racial admixture in Brazil. One possibility is that the negroes in Brazil have a lower economic status than whites and that Siio Paulo whites are currently in a transitional phase to a higher prevalence of polyps accompanied by a greater concentration of polyps in the sigmoid and adjacent segments. These changes, linked to socio-economic conditions, have not yet been expressed among Siio Paulo negroes as suggested by the absence of a concentration of adenomatous polyps in the sigmoid and adjacent segments among Siio Paulo whites. This study has described a positive association in the distribution of four entities : adenomatous polyps, hyperplastic polyps, diverticulosis and hemorrhoids. The association between diverticulosis, adenomatous polyps and cancer of the colon was suggested by Burkitt in 1969 as characteristic of developed western community societies where diet is low in fibers and rich in refined carbohydrates, contrary to what is observed in Africa where diver-

ticulosis, adenoma and cancer are rare entities (Bremmer et al., 1970; Williams et al., 1975). Japan has a low incidence of bowel carcinoma and a low prevalence of diverticulosis (Sato, 1976), while the migrant Japanese in Hawaii have acquired the high prevalence of diverticulosis seen in high-risk communities (Stemmermann et al., 1973). Burkitt (1972) extended his comments to include hemorrhoids, varicose veins in the extremities and thrombosis of deep veins as diseases linked to the same etiologic complex. Hemorrhoids are also reported to be rare in Africa (Trowell, 1960; Dodd, 1964) and frequent in western societies. The Siio Paulo findings, showing that these conditions tend to cluster in the same individuals, go along with the Burkitt hypothesis. We were unable to find other references in the literature to the correlation between adenomatous polyps and hemorrhoids in autopsy studies. Healed obliterating appendicitis was associated positively with polyps but negatively with diverticuli and hemorrhoids, so that assignment of this disease to the class of conditions correlated with bowel cancer seems doubtful. Burkitt did classify appendicitis as one of the diseases correlated with bowel cancer, but did not specify whether he meant acute appendicitis or healed obliterative appendicitis. A relation between appendectomy and neoplastic diseases has been sought (McVay, 1964; Howie and Timperley, 1966 ; Gross, 1966; Bierman, 1968 ; Cassimos et al., 1973) in order to test the hypothesis first proposed by Murphy (1926), suggesting that the lymphatic structures of the appendix could represent a defense against malignancies. MacVay (1964) showed a significantly higher incidence of previous appendectomy in patients dying of carcinoma of the colon than in controls. This association has not been confirmed by more recent clinical and experimental investigation (Abeatici et al., 1977). On the basis of known immunologic principles, one may speculate that appendectomy (absence of a probably important amount of lymphoreticular tissue) and lymphoid hyperplasia are inversely related factors. Pursuing this thought, we note that the Siio Paulo data consistently described negative associations of lymphoid hyperplasia with adenomatous polyps, appendectomy, appendicitis, diverticulosis and hemorrhoids (odds ratio respectively of 0.15, 0.17, 0.14, 0.10, 0.10). Therefore, studies of the so-called lymphoid hyperplasia in specimens with and without polyps should be pursued to elaborate the relationships between polyp prevalence and the immunologic status of the host. Since lipomas are more frequent in obese persons, the positive association between lipomas and adenomas of the colon goes along with the correlation between colon cancer and obesity (Burkitt, 1971) and with some conditions related to obesity, such as atherosclerosis, diabetes (Stemmermann, 1970; Wynder ef al., 1969) and high fat ingestion (Wynder, 1975). Schistosomiasis of the bladder has been implicated as a precancerous condition in Egypt (Aboul Nasr et al., 1962). Tntense research in Brazil has tried to establish the role of schistosomiasis in neoplasia and other conditions. Our data do not support

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the suspected precursors. Similar findings have been reported from Costa Rica (Salas, 1977). A probable reason for this outcome is that within a given community the forces governing stomach and colon cancer operate at different points in the life span, stomach being influenced by childhood exposures while colon cancer may respond to events in late adult life. Since intestinal metaplasia presumably does not protect against the later development of adenomatous polyps (which would produce a negative association), the lack of association in autopsy materials may reflect independent host responses to environmental factors.

any etiologic role for schistosomiasis in either adenomatous or hyperplastic polyps. This fact does not support the opinion that the nature of hyperplastic polyps is related to inflammatory stimulation (David, 1940). Arthur (1968) suggests that hyperplastic polyps represent aging changes in the mucosa. Inter-population comparisons of the risk of stomach and colon cancer have depicted the two diseases as being inversely correlated (Segi and Kurihara, 1966; Segi et al., 1969; Waterhouse et al., 1976; Zaldivar, 1977). It is not feasible to observe whether individuals diagnosed as having stomach cancer are subsequently at higher risk to colon cancer, or vice versa. However autopsy studies can investigate whether the simultaneous presence of their suspect precursors-intestinal metaplasia and adenomatous polyps- exceeds the figure expected on the basis of chance alone. Our results have failed to detect an association between

LESIONS COLORECTALES CANCeREUSES O U

ACKNOWLEDGEMENTS

This work was supported by contract NOl-CP53521, Louisiana State University, and National Cancer Institute, N.T.H., US Public Health Service.

“

LIfiES AU CANCER

”

A SAO PAULO (BRESIL)

Une s6rie de 832 spkimens necropsiques ont fait I’objet d’une etude macroscopique B l’aide de lentilles grossissantes et toutes les lesions ainsi identifiks ont 6t6 examin6es au microscope. La prevalence par age et par sexe des polypes ad6nomateux et hyperplasiques est indiquee et les rbultats sont compares B ceux d’autres populations. Des corrtlations ont Btb &tabliesentre polypes et cancer colorectal (407 cas). Les donnees recueillies donnent B penser que la communautt paulienne est dans une phase transitoire ou le risque de cancer du d o n est en train de passer de moyen A 61ev6. Les caracteristiques tpidkmiologiques du cancer du rectum inferieur sont propres B certaines populations et semblent btre sans rapport avec le cancer du ci3lon. Dans la population noire de SBo Paulo, la prevalence est plus 6levCe que celle qui est signalbe chezles Noirs d’Afrique. Selon les donnks recueillies, il y a probablement un lien entre polypes ad6nomateux, diverticuloses, hemorroides, d’une part, et cancer d’autre part.

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