[GANN, 65, ; August, 1974] ADENOMATOUS POLYPS OF LARGE INTESTINE IN AUTOPSY AND SURGICAL MATERIALS

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1 [GANN, 65, ; August, 1974] ADENOMATOUS POLYPS OF LARGE INTESTINE IN AUTOPSY AND SURGICAL MATERIAL*1 Eiichi SATO Department of Pathology, Tohoku University School of Medicine*2 A study of the large intestine in 1,000 autopsy subjects yielded 95 patients (9.5%) with 127 adenomas. This frequency was significantly higher than that of hypertrophic mucosal protrusion (3.5%), juvenile-type polyp (0.3%), Peutz-Jeghers type polyp (0.2%), and hyperplasia (metaplasia) (1.1%). Adenoma increased in frequency with advancing age, appearing in 33.3% of octogenarians. The right colon (51.2%) was the most frequent site, followed by the distal transverase and descending colon (23.6%). The adenomas were found in the sigmoid colon or rectum in 18% of subjects. Analysis of the age distribution of 116 surgical patients with 150 adenomas revealed that satellite polyps were most numerous between 60 and 69 years of age, whereas adenomas in noncancerous bowel were most frequently observed in the 40's. Histological atypia was related to the size and location of adenomas. In the autopsy series atypia was most prominent in the lower large bowel. Adenomas of the surgical series, obtained mostly from the lower tract, generally showed advanced atypia. Adenomas with focal malignancy were found in 13.3% of the surgical series but rose to 32.6% in adenomas of over 10mm in diameter. The incidence of focal malignancy in adenomas was 21.4% in females and 14.1% in males. Adenomatous polyps in the large intestine are believed to be related epidemiologically to carcinoma in this portion of the gut.9,13,20,24-27,30) The fact that reports on this subject in Japan have been few to date12,15,18,33,37) probably reflects the generally low incidence of carcinoma in the large intestine.16,28) It is suspected, however, that changes in the living and dietary habits of the Japanese may sooner or later increase the frequency of this carcinoma to the level of that in Western countries.5,29,32,36) Therefore, it is important to determine the incidence of adenomatous polyps in the large intestine in Japan before this event occurs. This survey of adenomatous polyps in autopsy and surgical materials was conducted in order to assess their premalignant potential. MATERIALS AND METHODS Materials were the large intestines obtained from 1,000 consecutive autopsy cases (over 1 year of age) in a 3-year period from 1968 to 1971, and from 170 surgical cases in a 10-year period from 1963 to 1972, at the Department of Pathology, Tohoku University School of Medicine. The surgical cases were divided into two groups; one consisted of those removed as polypoid lesions in the distal portion of the large intestine and the other was composed of satellite polyps which were found in 232 carcinoma cases of the colon and rectum. In the autopsy series, the large intestines were stored in 4% formaldehyde solution and were examined grossly for the presence of mucosal changes. Every observable protrusion was sectioned for histological examination. Paraffin sections were stained with Hematoxylin and Eosin, Gomori's silver impregnation, Alcian Blue-PAS-Masson (Goldner), and Weigert's Elastica-Masson. Tumor and tumor-like lesions were classified according to Morson's criteria into adenoma, hyperplasia (metaplasia), and hamartoma (juvenile type and Peutz Jeghers type). Mucosal hypertrophy35) was distinguished from the above by the normal appearance of the elongated gland and lack of atypism in epithelial components. For further evaluation of the structural atypia of adenoma, a set of criteria for grading into 3 categories of mild, moderate, and severe was adopted (Table I-a) (Photos 1-6). Cytological atypism was classified into 4 categories (0, I, II, III) according to criteria (Table I-b). Invasive growth in the level of the mucosa was evaluated as a sign of focal malignancy (Photos 7-10). In the tabulation for topographic comparison, the lesions were grouped by their location into three major regions of the right colon, left colon, and the sigmoid colon and rectum. The right colon included *1 This study was supported in part by Public Health Service Contract PH , U.S.A., and in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Japan.

2 E. SATO the cecum, ascending colon, and the proximal half of the transverse colon. The left colon consisted of the distal half of the transverse colon and the descending colon. Nine adenomas in the narrow transitional segment between the right and left colon were excluded from the analysis. Table I. Criteria for Evaluation of Histolygy of Adenoma RESULTS Age Distribution The autopsy study yielded 127 adenomas in 95 large intestines, and 150 adenomas were seen in 116 surgical materials. Adenomas were much more frequent than other types of polyp (Tables II and III). Among the latter, hypertrophic and hyperplastic polyps predominated in autopsy materials, while juvenile and Peutz-Jeghers type polyps were rather frequent in the surgical cases (Tables II and III). In the autopsy series adenomas increased with advancing age (Fig. 1) but, in surgical material, adenomas were evenly distributed in the 5th, 6th, and 7th decades. Non-adenomatous polyps showed no distinct age distribution. Table II. Age Distribution of Various Types of Polyps of the Large Bowel in 1,000 Autopsy Cases Table III. Age Distribution of Various Types of Polyps of the Large Bowel in 170 Surgical Cases Figures in parentheses represent No. of patients with adenomas in association with cancer (satellite polyps). 296 GANN

3 ADENOMA OF LARGE INTESTINE Fig. 1. Frequency of adenoma by age and sex in autopsy material Fig. 2. Age distribution of adenoma and carcinoma of the large bowel in surgical cases Satellite adenomas9) were found in 38 (16.4%) out of 232 patients with carcinoma of the colon and rectum. The age distribution of these adenomas was the same as that for all 232 carcinoma cases and peaked in the 60's (Fig. 2). The age distribution of adenoma in 78 noncarcinoma cases, had a peak in the 40's. The juvenile type polyps were prevalent in the age group below 40 years (Table III). 65(4)

4 E. SATO Fig. 3. Table IV. Size and Location of Adenomas In the autopsy series, adenomas were most frequently observed in the ascending colon; 65 (51.2%) were located in the right colon, 30 (23.6%) in the left colon, and 23 (18.1%) in the sigmoid colon and rectum (Fig. 3). Of the 170 surgical materials, 145 out of 150 adenomas were located in the rectum and sigmoid colon, while only 3 satellite adenomas were found in the ascending colon and 2 in the descending colon. Adenomas were classified into three types according to their diameter; small (less than 4.9mm), medium (5-9.9mm), and large (more than 10mm). The autopsy series had 88 small (69.3%), 33 medium (26%), and 6 large adenomas (4.7%), while surgical cases had 52 small (34.7%), 55 medium (36.7%), and 43 large (28.7%) (Table IV). In the autopsy series, adenomas of medium or large size were seemingly more frequently found in the left colon, but in general, the size of tumors was not related to their site (Table V). Signs of Proliferative Activities of Adenoma a) Relation of Histological Atypia to the Location: In the autopsy material, adenomas with moderate degree of structural atypia were found almost the same in both the right (10.8%) and the left colon (10.0%) (Fig. 4). Adenomas with severe atypia, however, appeared more frequently in the left colon (6.7%) than in the right (1.5%). Among adenomas in the sigmoid colon and rectum, 17.4% showed a moderate degree of structural atypism and atypism was severe in 8.7%. The incidence of cytological atypism of grades II and III was 9.2% and 0% in the right colon, 13.3% and 0% in the left colon, and 13.0% and 13.0% in the sigmoid colon and rectum. b) Relation of Histological Atypia to Age: Structural atypia increased in severity according to age in the autopsy series (Fig. 5), but was uniformly distributed among all age groups in the surgical cases (Fig. 6). The degree of cytological atypia also increased slightly with age in the autopsy series; while in the surgical cases epithelial atypia was far more prominent in younger age groups. Distribution of adenoma (autopsy) Size of Adenoma in Autopsy and Surgical Cases Percentage in parentheses Table V. Percentage Location and Size of Adenoma (Autopsy) in parentheses 298 GANN

5 ADENOMA OF LARGE INTESTINE Fig. 4. Atypism in adenomas according to location Fig. 5. Histological grading of adenoma (autopsy) 65(4)

6 E. SATO Fig. 6. Histological grading of adenoma (surgical) c) Relation of Histological Atypia to Size of Adenomas: As indicated in Tables VI and VII, large adenomas showed more severe degrees of histological and cytological atypism in both autopsy and surgical cases. Medium-sized adenomas, 5-9.9mm in diameter, were found in 33 and 55 in the autopsy and surgical cases, respectively, and they provided materials for histological comparison between the two series of the same size. Severe and moderate structural atypism was noted in 9.1% and 24.2% in the autopsy series, and in 16.4% and 41.8% Table VI. Grade of Histological Atypism of Adenoma According to Size in Autopsy Materials Percentage in parentheses Table VII. Grade of Histological Atypism of Adenoma According to Size in Surgical Cases Percentage in parentheses 300 GANN

7 ADENOMA OF LARGE INTESTINE in the surgical series, respectively. Grade III and grade II cytological atypism were noted in 3.0% and 24.2% in the autopsy series, and in 29.1% and 27.3% in the surgical series. The surgical series showed far advanced histological atypia. As will be stated below, the frequency of focal malignancy increased with the size of adenoma in the surgical cases and adenomas measuring over 10mm in diameter showed a high incidence of focal invasion (32.6%) Table VIII. Relation of Focal Malignancy to Size of Adenoma in Surgical Cases Ferquency of focal malignancy in the group of larger adenoma of over 10mm in diameter is 14/43 =32.6%. (Table VIII). d) Malignant Changes of Adenoma (Table IX): None of the adenomas found at autopsy had signs of invasion and only one case showed carcinoma in situ in the strictest sense of the term. In surgical material, focal malignancy was detected in 6 satellite adenomas (15.8%) and 14 simple adenomas (17.9%). The incidence of malignancy was higher in females than in males, with the ratio of 21.4% to 14.9%. One tumor showed infiltration beyond the muscularis mucosae (Photos 11 and 12). Carcinoma in situ was confirmed in 9 satellite and 4 simple adenomas (Photos 5 and 6). Satellite adenoma showed a little severer cytological atypism than simple adenoma, but no other essential differences were observed between the two types of adenoma. Table IX. Age and Sex Distribution of Focally Malignant Adenomas in Surgical Materials DISCUSSION For identification of correct incidence of intestinal polyps, a comprehensive survey of autopsy cases is required. In Western countries with generally high incidence of intestinal carcinoma, there have been a great number of papers reporting intestinal polyps in surgical and autopsy materials.1,8,10,11,14,21) The incidence of adenomas, however, varied considerably with individual authors, ranging from 0% to 69%2) in the autopsy cases. Bremner and Ackerman,3) who examined 14,000 autopsy cases of the South African Bantus, reported no occurrence of adenoma and a very low incidence of carcinoma of the large intestine. This variability in incidence may be due to the diversity in age of cases examined, different methods for 65(4)

8 E. SATO examination, and racial or geographical differences.7) Martin and Sutton,24) introducing several reports on the incidence of adenoma ranging from 2.8% to 21.5%, stated that the mean of these data was 10%, which fairly agreed with the result of our present study. In Japan, there have been very few studies made on the relationship of polyps in the large intestine to carcinoma. Hara14) made a careful examination on the large intestine of 500 consecutive autopsy cases of over 50 years of age and found adenomatous and hyperplastic polyps in 30.4%. He also reported the presence of 3 cases of invasive carcinoma and 1 case of carcinoma in situ which were all presumably regarded as a sequence of malignant transformation of adenomas. On the other hand, Kikkawa et al.19) stated that the possibility of cancer induction from adenoma in the clinical setting was only speculative, and could not be confirmed by the analysis of experimental colonic tumors. Their conclusion agrees with the view of Castleman and Crickstein,6) and that of Spratt and Ackerman.31) In discussing the concept for malignant transformation of the adenoma of large intestine, histological criteria for carcinoma in situ and for the precancerous atypical proliferation of epithelium should be established.4) Detailed analysis of adenomas revealed that the degree of structural atypia is not always consistent with cytological atypism. In some instances, insignificant proliferation of the glandular epithelium may accompany a localized malignancy.21) In the analysis of the biological characteristics of adenomas, therefore, these two items were investigated individually in the present work. Adenomas of the lower large intestine were observed infrequently in the autopsy cases, but showed more advanced histological and cytological atypism. Adenomas of surgical material, mostly obtained from the distal part of the large intestine, were generally large, and atypia was generally severer than those from the same site of autopsy material. These findings suggest that adenomas in the lower large intestine may make an irregular and intensive growth, eventually more likely to develop clinical symptoms, than those originating in the upper region. This may account for the fact that the majority of the carcinoma of the large intestine reported in Japan has been observed in this lower region.16,22,23) Focal carcinoma within adenomatous tissue has been repeatedly emphasized as evidence of malignant potentiality of adenoma, though its incidence ranges widely from 1% to 32.6%.10) Generally speaking, the incidence based on autopsy materials was lower. The development of colonofiberscope has made it possible to examine the large intestine along its entire length. Wolff and Shinya34) discovered 6.8% of "malignancy" in 499 adenomas by this method. In the present investigation, focal maligancy was seen in 20 cases (13.3%) out of 150 surgical adenomas, in which the great majority were located in the sigmoid colon and rectum. Silverberg30) claimed that the incidence of focal malignancy differed according to the location of adenoma and was the highest in the sigmoid colon. In conclusion, adenomas located in the lower portion of the large intestine and measuring over 10mm in diameter may have high potentiality for malignant transformation. The author expresses his sincere gratitude to Prof. Sasano and to Dr. Stemmermann, Kuakini Hospital, Hawaii, for their critical review of the manuscript. (Received March 6, 1974) REFERENCES 1) Arminski, T. C., McLean, D. W., Dis. Colon Rectum, 7, 249 (1964). 2) Atwater, J., Bargen, J. A., Gastroenterology, 4, 395 (1945). 3) Bremner, C. G., Ackerman, L. V., Cancer, 26, 991 (1970). 4) Buntain, W. L., ReMine, W. H., Farrow, G. M., Surg. Gynecol. Obstet., 134, 499 (1972). 5) Burkitt, D. P., Cancer, 28, 3 (1971). 6) Castleman, B., Krickstein, H. I., New Engl. J. Med., 267, 469 (1962). 302 GANN

9 ADENOMA OF LARGE INTESTINE 7) Chapman, I., Ann. Surg., 157, 223 (1963). 8) Correa, P., Duque, E., Cuello, C., Haenszel, W., Int. J. Cancer, 9, 86 (1972). 9) Culp, C. E., Surg. Clin. North Am., 47, 955 (1967). 10) Eichhorn, R. D., Dentlif, P. S., Kelsey, J. R., Am. J. Dig. Dis., 16, 433 (1971). 11) Ekelund, G., Acta Pathol. Microbiol. Scand., 59, 165 (1963). 12) Enjoji, M., Ikawa, M., Kato, M., Kagoshima Igaku Zasshi, 22, 253 (1970). 13) Enterline, H. T., Evans, G. W., Mercudo-Lugo, R., Miller, L., Fitts, T. W., J. Am. Med. Assoc., 179, 322 (1962). 14) Feyrter, F., Beitr. Pathol. Anat., 86, 663 (1931). 15) Hara, K., Nippon Gekagakkaishi, 74, 18 (1973). 16) Haenszel, W., Correa, P., Cancer, 28, 14 (1971). 17) Helwig, E. B., Surg. Gynecol. Obstet., 84, 36 (1947). 18) Hino, T., Gann, 36, 441 (1942). 19) Kikkawa, N., Yasutomi, M., Hirose, S., Jinnai, D., I-to-Cho, 8, 1519 (1973). 20) Knoerrenschild, H. E., Surg. Forum, 14, 137 (1963). 21) Lane, N., Kaplan, H., Pascal, R. R., Gastroenterology, 60, 537 (1971). 22) Majima, S., Karube, K., Narisawa, T., Yamaguchi, G., Yoshida, K., Teshima, T., Gan-no-Rinsho, 13, 861 (1967). 23) Majima, S., Karube, K., Narisawa, T., Hoshi, H., Hiroki, T., Gan-no-Rinsho, 13, 1088 (1967). 24) Martin, J. D., Sutton, G., Am. Surgeon, 31, 551 (1965). 25) Morson, B. C., Brit. J. Surg., 55, 725 (1968). 26) Morson, B. C., Bussey, H. J. R., "Predisposing Causes of Intestinal Cancer," p. 19 (1970). Year Book Medical Publishers Inc., Chicago. 27) Potet, F., Soullard, J., Gut, 13, 468 (1971). 28) Segi, M., Kurihara, M., "Age-adjusted Death Rates for Malignant Neoplasms for Selected Sites, by Sex, in 24 Countries" (1966). Dept. Public Health, Tohoku University School of Medicine, Sendai. 29) Segi, M., Kurihara, M., "Cancer Mortality for Selected Sites in 24 Countries, No. 6 ( )" (1972). Japan Cancer Society, Tokyo. 30) Silverberg, S. G., Surg. Gynecol. Obstet., 131, 103 (1970). 31) Spratt, J. S., Ackerman, L. V., J. Am. Med. Assoc., 179, 337 (1962). 32) Stemmermann, G. N., Yatani, R., Cancer, 31, 1260 (1973). 33) Watanabe, H., Narasaka, T., Kamiesu, J., Imai, D., Rinsho Geka, 28, 19 (1973). 34) Wolf, W., Shinya, H., Ann. Surg., 178, 367 (1973). 35) Wychulis, A. W., Dockerty, M. B., Jackman, R. J., Beahrs, O. H., Surg. Gynecol. Obstet., 124, 87 (1967). 36) Wynder, E. L., Kajitani, T., Ishikawa, S., Dodo, H., Takano, A., Cancer, 23, 1210 (1969). 37) Yamagata, S., Watanabe, H., Takebe, T., Narasaka, T., "Progress in Proctology", ed. J. Hoferichter, p. 110 (1969). Springer Verlag, Heidelberg. EXPLANATION OF PLATES Photo 1. Usual histological pattern of diminutive adenoma in autopsy case. Note mild gland epithelial proliferation and very little disarrangement of nuclei (mild, grade I). Photo 2. Small adenoma with remarkable findings of fusion and frond-like elongation of glands. Polarity is well preserved (moderate, grade 0). Photo 3. An example of "severe" gland-epithelial proliferation. Photo 4. Medium magnification of Photo 3. Note diffuse dispolarity of nuclei (grade III). Photos 5 and 6. Features of nuclear plumping, hyperchromasia, and disarrangement are remarkable without evidence of invasive growth. These figures were not handled as focally malignant adenoma. Photos 7 and 8. Satellite adenoma with moderate glandular proliferation. In the small portion of the square mark, an obvious pattern of invasive growth can be observed. Photos 9 and 10. Irregularity in growth direction of the glandular epithelium is prominent. A much wider area than in the Photos 7 and 8 composed of the strikingly atypical epithelium without basement membrane. Photos 11 and 12. In the center of this tumor, invasion beyond the muscularis mucosae is distinct. The adenoma-like epithelia still remain in the margin and surface. This is carcinoma and excluded from "focally malignant" adenoma. 65(4)

10 ADENOMA OF LARGE INTESTINE 65(4)

11 E. SATO 306 GANN