World J. Surg. 15, 3-6, 1991
World Journal of Surgery 9 1991 by the Soci6t6 lnternationale de Chirurgie
Natural History of Adenomas Tor J. Eide, M.D. Department of Morphology II, Institute of Medical Biology, University of Tromsr Tromsr Norway One-third of individuals over the age of 55 years have single or multiple colorectal adenomas. During a subsequent period of 10 years, 3-5% of adenoma-bearing individuals will probably develop a carcinoma. The rather low conversion rate from benign to malignant disease indicates that most individuals with adenomas will never develop colorectal carcinoma. More knowledge is required to predict the outcome of the individual adenoma in a given patient. This will probably be obtained by increasing progress within gene technology and through large prospective follow-up studies of adenoma-bearing patients.
adenoma for becoming malignant? and 2) Can one variable or a set of Variables accurateiy predict the risk of subsequent malignancy for the individual adenoma/patient? Thus, the study of adenomas not only plays a role in clarification of carcinogenesis, but also has an important practical implication in the prevention of colorectal malignancy [10]. Epidemiology
The incidence of col0rectal cancer has been steadily increasing, particularly among those populations that have adopted a Western way of life. In many of these countries, colorectal cancer is among the 2 or 3 most frequent types of cancers. The surgical cure rate has improved to some extent during recent decades, but additional new therapy has been shown to have limited value (unpublished data, Cancer Registry of Norway). These facts make the study of precursors of cancer of the large intestine very important because the clarification of precancerous states provides the best hope for cancer prevention [1]. The diseases which are known to predispose to colorectal cancer are hereditary adenomatous polyposis, chronic colitis, and adenomas. Since the 2 former diseases are fairly rare or can adequately be cured before malignancy develops, they contribute very little to the total colorectal cancer burden. Since the study of Schmieden and Westhues, published in 1927 [2], there is accumulating scientific evidence that adenomas play an important role in the pathogenesis of colorectal cancer; however, there are still details concerning the relationship between the 2 types of lesions which are not clarified. Although the "adenoma-carcinoma sequence" theory has been favored by most [1, 3-5] as the main pathogenesis of colorectal cancer, the "de novo" origin of cancer has received more attention in recent years as an alternative pathway in some of the cases [6--8]. Due to the high prevalence of adenomas and the relatively far less frequent incidence of carcinomas, only a small proportion of adenomas give rise to carcinomas [9]. Therefore, important questions to be asked are: 1) What is the essential marker of an Reprint requests: Tor J. Eide, M.D., Department of Morphology II, Institute of Medical BiOlogy, University of Tromsr P.O. Box 977, 9001 Tromsr Norway.
Important evidence of a precursor role of adenomas has been derived from studies demonstrating an association between the frequencies by which adenomas and carcinomas (Fig. 1) occur in different populations [11-18]. Since data based on clinical recording of adenomas may be biased due to selection of patients and diagnostic methods, most accurate epidemiological data on adenomas are obtained through autopsy studies. In a multicenter autopsy study emphasizing the relationship between the prevalence of adenomas and the total incidence of large bowel cancer, the highest proportion of autopsies with adenomas was observed in the population of Aberdeen, Scotland, which has a high incidence of carcinomas [19]. Correspondingly, the autopsy population of Kuopio, Finland had both the lowest prevalence of adenomas and the lowest incidence of colorectal carcinomas, whereas Tromsr Norway showed intermediate figures for both types of lesions. In the same study, the segmental distribution of adenomas within the colon was found to be similar to the subsite distribution of carcinomas, with some modifications [19]. A more detailed analysis of the distribution of the 2 types of lesions in the Tromsr population showed a change in the predilection site of adenomas from the distal part of the colon in younger patients to the proximal part in older patients of both sexes [20]. A similar change in the subsite distribution was also found for carcinomas, but only in males and this occurred 10 years later than for adenomas. Although the segmental distribution of adenomas in autopsy studies is in accordance with the cancer incidence in the different colonic segments, this is not the case for the rectum. The lowest proportion of adenomas is found in the rectum, the segment in which cancer is most frequent [19]. The latter finding suggests that the adenoma-carcinoma sequence is either less important in this part of the bowel or that more rectal than colonic adenomas become malignant. More important, perhaps,
4 Q O
o
World J. Surg. Voi. 15, No. 1, Jan./Feb. 1991 100Y.-..~
Males
5040-
C L13 0
ca C o_ U _r
Incidence, Males
....
Aberdeen, Scotland
Q
o
Accumulating
9
3020-
eTromsr
9
Japanese
Norway
Kuopio, Sao Paulo, Brazil 9 Finland 9 9 Miyagi, Japan
109 Call, Columbia I 10
I 20
I 30
I 40
I 50
I 60
|
70
I
40
/
80
Prevalence of adenomas in per cent
Fig. 1. Prevalence of adenomas and incidence of carcinomas in different populations.
is that these discrepancies can be ascribed to regression and disappearance of adenomas [21]. It is likely that this happens more frequently in pedunculated than in sessile lesions. Pedunculated adenomas occur in the sigmoid colon and rectum more often than in other segments of the large intestine [15, 22]. It is, therefore, reasonable to suggest that more rectal than colonic adenomas regress because of the shape of the lesion and the more pronounced mechanical forces of the fecal bulk in this part of the bowel. More direct evidence of the high proportion of regression of rectal adenomas was observed by Hoff and associates [23] who found regression of adenomas in the distal 10 cm of the large intestine more often among unresected polyps than for the average colonic segment. The frequencies of both adenomas and carcinomas increase with increasing age in both sexes [19]. The accumulated incidence curve of adenomas based on data from the Norwegian Cancer Registry precede the corresponding incidence curve of carcinomas by about 5 years (Fig. 2), which is additional evidence of a precursor role of adenomas. It should be kept in mind, however, that many adenomas are first diagnosed and reported to the Cancer Registry simultaneously with the diagnosis of colorectal carcinoma, indicating a longer timespan between the 2 types of lesions than these curves indicate. Most autopsy and clinical studies have shown a predominance of adenomas in males [13, 14, 19, 22, 24] whereas the incidence of colorectal cancer is more evenly distributed between the 2 sexes [25]; however, if these data are related to age, it seems that adenomas are more prevalent among younger females than in younger males, which corresponds to a higher cancer incidence in younger females [20]. On the other hand, older males have higher frequencies of both adenomas and carcinomas than females. As previously commented, there are some segments relative to others within the large intestine which more often give rise to adenomas and carcinomas. In addition, there is a weak but significant effect of clustering of adenomas [26] within the individual patient. This implies that when multiple adenomas occur, they tend to group within areas of the large intestine. Similarly, synchronous carcinomas occur more often within the same segment than can be expected by chance [27]. Also, adenomas and carcinomas, when they occur in the same bowel,
20
14
25-34
45-54
65-74
85+ age
Fig. 2. Accumulating incidence of colorectal adenomas and carcinomas recorded in the Norwegian Cancer Registry in the period 1983-1985.
tend to cluster [28]. Thus, there seem to be areas specific to each individual patient which are more prone for both benign and malignant neoplastic development than others. This effect comes in addition to the site-specific occurrence in the large intestine of adenomas and carcinomas within each age and sex group. Morphology
Because most adenomas never become malignant, it is important to be aware of particular morphological features of adenomas that may be associated with an increased risk of malignancy. The presence of villi and severe grade of dysplasia, in addition to large size, are all associated with increased frequency of focal malignancy in adenomas [29, 30]. Since these morphological features frequently occur in the same adenomas, they are highly correlated and one of these features may merely be the result of 1 or 2 of the others. Since it is reasonable to suggest that morphological features associated with malignancy occur more frequently in cancer patients, adenomas occurring in the general autopsy population have been compared with adenomas occurring in colorectal cancer patients [31]. From these data, it can be derived that factors which initiate the growth of adenomas and factors which promote the growth of the individual adenoma to large sizes seem to be more prevalent in patients with colorectal cancer than in those without cancer. Factors initiating villous structures and advanced grade of dysplasia in adenomas seem not to be significantly more prevalent in individuals with cancer than in those without cancer. The frequently repeated demonstration of loci of invasive cancer in adenomas provides the strongest evidence of their premalignant nature [29, 30]. Another way of determining the precursor role of colorectal adenomas is to histologically exam-
T.J. Eide: Colorectal Polyps: Natural History
ine carcinomas for remnants of adenomas. This has been found to occur in 14-23% of all colorectal carcinomas. When related to the stage of carcinoma, remnants of adenomas have been found in close to 60% of carcinomas limited to the submucosal layer [4, 29]. The high proportion of adenomatous remnants in carcinomas in a very early stage of the disease has been taken to indicate that most colorectal cancer develops through a stage of benign disease; h o w e v e r , dysplastic epithelium has been observed in flat mucosa [32] and this can probably lead to immediate infiltration [8]. Thus. this could be regarded as a " d e n o v o " pathway of malignancy, which is a term applied to small carcinomas, 5-15 mm in diameter, in which no residual adenomatous tissue can be identified [5]. The fact that patients with carcinomas containing remnants of adenomas have been observed to have coexisting adenomas in the same resected specimen more frequently than patients with carcinomas m which no adenomatous remnants can be detected [4], may indicate 2 alternative pathways in the development of colorectal cancer: one in which the patient develops malignancy through a stage of benign polypoid growth (the "adenoma-carcinoma sequence") and one in which the patient develops dysplastic epithelium which has the property to grow invasively directly from fiat mucosa C'de novo"). Does morphology of the resected adenoma provide any information regarding the risk of subsequent adenomas or carcinomas? Kronborg and colleagues [33] found a higher recurrence rate among patients with adenomas larger than 2 cm and with villous adenomas. The risk was not related to severity of dysplasia. Jensen [34] found (among 479 adenoma patients) 14 subsequent colorectal carcinomas, which was significantly different from the expected number of 6.5. Grade of dysplasia and size of adenomas were variables which significantly contributed to the risk of carcinoma. Genetics and Inheritance
Beside the inheritance of familial adenomatous polyposis and other rare polyposis syndromes, the contribution of heritable factors to the genesis of colorectal cancer and adenomas is in its embryonic stage of knowledge. First-degree relatives of patients with colorectal cancer generally have a 2 or 3-fold increased risk of colorectal cancer [35, 36]. Systematic proctosigmoidoscopy screening for adenomas in pedigree members of colorectal cancer patients and spouse controls revealed in one study [36] a detection rate of adenomas of 21%, compared to only 9% in controls. The results were taken to indicate an autosomal dominant pattern of inheritance. A broader screening for polyps was performed in an additional study of 670 persons in 34 Utah kindereds [37]. Likelihood analysis strongly supported the dominant inheritance of a susceptibility to colorectal adenomas and cancers with a gene frequency of 19%. According to the most likely genetic model, the authors conclude that polyps and colorectal cancers occur only in genetically susceptible persons. In a study looking for genetic alteration, ras-gene mutation occurred in 58% of adenomas larger than 1 cm, but in only 9% of adenomas under 1 cm in size [38]. Sequences on chromosome 5 were lost in 29% and 35% of adenomas and carcinomas, respectively. A specific region of chromosome 18 was deleted frequently in carcinomas (73%) and in advanced adenomas
5
(47%), but only occasionally in earlier-stage adenomas. The results have been taken to indicate a model of colorectal carcinogenesis in which the steps required for the development of cancer often involve the mutational activation of an oncogene coupled with the loss of several genes that normally suppress tumorigenesis. During progression from adenoma to carcinoma, ras-gene mutations and 5 q allelic deletions are likely to be earlier events whereas allelic losses from chromosomes 17 p and 18 q seem to occur more often in advanced tumors [39]. R6sum6
A partir de 55 ans, on voit se d6velopper chez un tiers de la population un ou plusieurs ad6nomes colorectaux. Dans les 10 arts ~t venir, 3 ~ 5% de ces patients ad6nomateux deviendront cancereux. Le taux plut6t bas de passage de l'ad6nome au cancer signifie que la plupart des individus ayant des ad6nomes n'auront jamais de cancer col0rectal. I1 faut 6]argir nos connaissances pour pr6voir le devenir de chaque patient ad6nomateux. On y parviendra probablement grfice au progr~s constant dans la technologie des g~nes et grglce aux grandes 6tudes prospectives de suivi des patients h ad6nome. Resumen
Una tercera parte de los individuos mayores de 55 afios poseen adenomas fmicos o mt~ltiples de la regi6n colorrectal. En el curso d e l siguiente decenio, 3-5% de las personas con adenomas tienen la probabilidad de desarrollar un carcinoma. L a relativamente baja tasa de conversi6n del adenoma benigno a neoplasia maligna indica que la mayorfa de aquel!as que tienen un adenoma jam~is habr~in de desarrollar carcinoma colorrectal. Se requiere mayores conocimientos para lograr predecir la evoluci6n final del paciente con adenoma. Tales conocimientos probablemente ser~in obtenidos mediante e! progreso en la tecnologia gen6tica y a trav6s de amplios estudios prospectivos de Seguimiento de los pacientes con adenomas. References
1. Morson, B.C.: The pathogenesis of colorectal cancer. Major Prob Pathol. 10:1, 1978 2. Schmieden, V., Westhues, H.: Zur Klinik und Pathologie der Dickdarmpolypen und deren Klinischen und pathologisch-anatomischen Beziehungen zum Dickdarmkarzinom. Deut. Zeitschr. Chir. 202:1, 1927 3. Enterline, H.T.: polyps and cancer of the large bowel. Curr. Topics Pathol. 63:95, 1976 4. Eide, T.J.: Remnants of adenomas in colorectal carcinomas. Cancer 51:1866, 1983 5. Jass, J.R.: Do all colorectal carcinomas arise in preexisting adenomas? World J. Surg. 13:45, 1989 6. Maskens, A.P.: Adenomas and carcinomas of the large bowel. Distinct diseases possibly sharing common etiologic factors? Acta Gastroenterol. Belg. 45!158, 1982 7. Desigan, G., Wang, M., Alberti-Flor, J., Dunn, D., Halter, S., Vaughan, S.: De novo carcinoma of the rectum: A case report. Am. J. Gastroenterol. 80:553, 1985 8. Shamsuddin, A.M., Kato, Y., Kunishima, N., Sugamo, H., Trump, B.F.: Carcinoma in situ in nonpolypoid mucosa of the large intestine. Report of a case with significance in strategies for early detection. Cancer 56:2849, 1985
6 9. Eide, T,J.: Risk of colorectal cancer in adenoma-bearing individuals within a defined population. Int. J. Cancer 38:173, 1986 10. Gilbertsen, V.A.: Proctosigmoidoscopy and polypectomy in reducing the incidence of rectal cancer. Cancer 34:936, 1974 11. Bremner, C.G., Ackerman, C.V.: Polyps and carcinoma of the large bowel in the South African Bantu. Cancer 26:991, 1970 12. Correa, P., Duque, E., Cuello, C., Haenszel, W.: Polyps of the colon and rectum in Call, Columbia. Int. J. Cancer 9:96, 1972 13. Stemmermann, G.A., Yatani, R.: Diverticulosis and polyps of the large intestine. A necropsy study of Hawaii Japanese. Cancer 31:1260, 1973 14. Sato, E., Ouchi, A., Sasano, N., Ishidate, T.: Polyps and diverticulosis of large bowel in autopsy population of Akita prefecture, compared with Miyagi. Cancer 37:1316, 1976 15. Eide, T.J., Stalsberg, H.: Polyps of the large intestine in northern Norway. Cancer 42:2839, 1978 16. Marigo, C., Correa, P., Haenszel, W.: Cancer and "cancer related" colorectal lesions in Sao Paulo, Brazil. Int. J. Cancer 22:645, 1978 17. Vatn, M.H., Stalsberg, H.: The prevalence of polyps of the large intestine in Oslo: An Autopsy Study. Cancer 49:819, 1982 18. Bargava, D.K., Chopra, P.: Colorectal adenomas in a tropical country. Dis, Colon Rectum 31:692, 1988 19. Clark, J.C., Collan, Y., Eide, T.J., Est6ve, J., Ewen, S., Gibbs, N.M., Jensen, O.H., Koskela, E., MacLennan, R., Simpson, J.G., Stalsberg, H., Zaridze, D.G.: Prevalence of polyps in an autopsy series from areas with varying incidence of large bowel cancer. Int. J. Cancer 36:179, 1985 20. Eide, T.J.: The age-, sex-, and site-specific occurrence of adenomas and carcinomas of the large intestine within a defined population. Scand. J. Gastroenterol. 21:1083, 1986 21. Knoernschild, H.E.: Growth rate and malignant potential of coIonic polyps: Early results. Surg. Forum 14:137, 1963 22. Rickert, R.R., Auerbach, O., Garfinkel, L., Hammond, E.C., Frasca, J.M.: Adenomatous lesions of the large bowel. An autopsy survey. Cancer 43:1847, 1979 23. Hoff, G., Foerster, A., Vatn, M.H., Sauar, J., Borsen, S.: Epidemiology of polyps in the rectum and colon, Recovery and evaluation of unresected polyps 2 years after detection. Scand. J. Gastroenterol. 21:853, 1986 24. Williams, A.R., Balasooriya, B.A.W., Day, D.W.: Polyps and cancer of the large bowel: A necropsy study !n Liverpool. Gut 23:835, 1982 25. de Jong, V.W., Day, N.E., Muir, C.S., Barclay, T.H.C., Bras, G., Foster, F.H., Jussawalla, D.J., Kurihara, M., Linden, G., Martinez, J., PaYne, P.M., Pedersen, E., Ringertz, N., Shanmugaratnam, T.: The distribution of cancer within the large bowel. Int. J. Cancer 10:463, 1972
World J. Surg. Voi. 15, No. 1, Jan./Feb. 1991 26. Eide, T.J., Schweder, T.: Clustering of adenomas in the large intestine. Gut 25:1262, 1984 27. Lasser, A.: Synchronous primary adenocarcinomas of the colon and rectum. Dis. Colon Rectum 21:20, 1978 28. Berge, T., Ekelund, G., Mellner, G., Pihl, B., Wenckert, A.: Carcinoma of the colon and rectum in a defined population. An epidemiological, clinical and post mortem investigation of colorectal carcinoma and coexisting polyps in Malrnr Sweden. Acta Chir. Scand. [Suppl.] 438:1, 1973 29. Muto, T., Bussey, H.J.R, Morson, B.C.: The evolution of cancer of the colon and rectum. Cancer 36:2251, 1975 30. Shinya, H., Wolff, W.J.: Morphology/anatomic distribution and cancer potential of colonic polyps. An analysis of 7000 polyps endoscopically removed. Am. Surg. 190:679, 1979 31. Eide, T.J.: Prevalence and morphological features of adenomas of the large intestine in individuals with and without colorectal carcinoma. Histopathol. 10:111, 1985 32. Muto, T., Kamiya, J., Sawada, T., Konishi, F., Sugihara, K., Kubota, Y., Adaij, M., Agawa, S., Saito, Y., Morioka, Y., Tanprayoon, T.: Small "fiat adenomas" of the large bowel with special reference to its clinicopathologic features. Dis. Colon Rectum 28:847, 1985 33. Kronborg, O., Hage, E., Adamsen, S., Deichgraeber, E.: Follow-up after colorectal polypectomy. II. Repeated examinations of the colon every 6 months after removal of sessile adenomas and adenomas with the highest degrees of dysplasia. Scand. J. Gastroenterol. 18:1095, 1983 34. Jensen, P.: Et klinisk-patologisk studie over sammenhaengen mellom colorectale adenomer og carcinom. Thesis, KCbenhavn Universitet, KCbenhavn, 1989 35. Kussin, S.Z., Lipkin, M., Winawer, S.J.: Inherited colon cancer: Clinical implications. Am. J. Gastroenterol. 72:448, 1979 36. Burt, R.W., Bishop, D.T., Cannon, C.A., Dowdle, M.A., Lee, R.G., Sckolnick, M.H.: Dominant inheritance of adenomatous colonic polyps and colorectal cancer. N. Engl. J. Med. 312:1540, !985 37. Cannon,Albright, L.A., Skolnick, M.H., Bishop, D.T., Lee, R.G., Burr, R.W.: Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers. N. Engl. J. Med. 319:533, 1988 38. Vogelstein, B., Fearon, E.R., Hamilton, S.R., Kern, S.E., Preisinger, A.C., Leppert, M., Nakamura, Y., White, R., Smits, A,M.M., Bos, J.: Genetic alterations during colorectal-tumor development. N. Engl, J. Med. 319:525, 1988 39. Wildrick, D.M.: Molecular genetic studies of colon cancer. Hematol, Oncol. Clin. North Am. 3:1, 1989
World Journal of Surgery 9 1991 by the Soci6t6 lnternationale de Chirurgie
Natural History of Adenomas Tor J. Eide, M.D. Department of Morphology II, Institute of Medical Biology, University of Tromsr Tromsr Norway One-third of individuals over the age of 55 years have single or multiple colorectal adenomas. During a subsequent period of 10 years, 3-5% of adenoma-bearing individuals will probably develop a carcinoma. The rather low conversion rate from benign to malignant disease indicates that most individuals with adenomas will never develop colorectal carcinoma. More knowledge is required to predict the outcome of the individual adenoma in a given patient. This will probably be obtained by increasing progress within gene technology and through large prospective follow-up studies of adenoma-bearing patients.
adenoma for becoming malignant? and 2) Can one variable or a set of Variables accurateiy predict the risk of subsequent malignancy for the individual adenoma/patient? Thus, the study of adenomas not only plays a role in clarification of carcinogenesis, but also has an important practical implication in the prevention of colorectal malignancy [10]. Epidemiology
The incidence of col0rectal cancer has been steadily increasing, particularly among those populations that have adopted a Western way of life. In many of these countries, colorectal cancer is among the 2 or 3 most frequent types of cancers. The surgical cure rate has improved to some extent during recent decades, but additional new therapy has been shown to have limited value (unpublished data, Cancer Registry of Norway). These facts make the study of precursors of cancer of the large intestine very important because the clarification of precancerous states provides the best hope for cancer prevention [1]. The diseases which are known to predispose to colorectal cancer are hereditary adenomatous polyposis, chronic colitis, and adenomas. Since the 2 former diseases are fairly rare or can adequately be cured before malignancy develops, they contribute very little to the total colorectal cancer burden. Since the study of Schmieden and Westhues, published in 1927 [2], there is accumulating scientific evidence that adenomas play an important role in the pathogenesis of colorectal cancer; however, there are still details concerning the relationship between the 2 types of lesions which are not clarified. Although the "adenoma-carcinoma sequence" theory has been favored by most [1, 3-5] as the main pathogenesis of colorectal cancer, the "de novo" origin of cancer has received more attention in recent years as an alternative pathway in some of the cases [6--8]. Due to the high prevalence of adenomas and the relatively far less frequent incidence of carcinomas, only a small proportion of adenomas give rise to carcinomas [9]. Therefore, important questions to be asked are: 1) What is the essential marker of an Reprint requests: Tor J. Eide, M.D., Department of Morphology II, Institute of Medical BiOlogy, University of Tromsr P.O. Box 977, 9001 Tromsr Norway.
Important evidence of a precursor role of adenomas has been derived from studies demonstrating an association between the frequencies by which adenomas and carcinomas (Fig. 1) occur in different populations [11-18]. Since data based on clinical recording of adenomas may be biased due to selection of patients and diagnostic methods, most accurate epidemiological data on adenomas are obtained through autopsy studies. In a multicenter autopsy study emphasizing the relationship between the prevalence of adenomas and the total incidence of large bowel cancer, the highest proportion of autopsies with adenomas was observed in the population of Aberdeen, Scotland, which has a high incidence of carcinomas [19]. Correspondingly, the autopsy population of Kuopio, Finland had both the lowest prevalence of adenomas and the lowest incidence of colorectal carcinomas, whereas Tromsr Norway showed intermediate figures for both types of lesions. In the same study, the segmental distribution of adenomas within the colon was found to be similar to the subsite distribution of carcinomas, with some modifications [19]. A more detailed analysis of the distribution of the 2 types of lesions in the Tromsr population showed a change in the predilection site of adenomas from the distal part of the colon in younger patients to the proximal part in older patients of both sexes [20]. A similar change in the subsite distribution was also found for carcinomas, but only in males and this occurred 10 years later than for adenomas. Although the segmental distribution of adenomas in autopsy studies is in accordance with the cancer incidence in the different colonic segments, this is not the case for the rectum. The lowest proportion of adenomas is found in the rectum, the segment in which cancer is most frequent [19]. The latter finding suggests that the adenoma-carcinoma sequence is either less important in this part of the bowel or that more rectal than colonic adenomas become malignant. More important, perhaps,
4 Q O
o
World J. Surg. Voi. 15, No. 1, Jan./Feb. 1991 100Y.-..~
Males
5040-
C L13 0
ca C o_ U _r
Incidence, Males
....
Aberdeen, Scotland
Q
o
Accumulating
9
3020-
eTromsr
9
Japanese
Norway
Kuopio, Sao Paulo, Brazil 9 Finland 9 9 Miyagi, Japan
109 Call, Columbia I 10
I 20
I 30
I 40
I 50
I 60
|
70
I
40
/
80
Prevalence of adenomas in per cent
Fig. 1. Prevalence of adenomas and incidence of carcinomas in different populations.
is that these discrepancies can be ascribed to regression and disappearance of adenomas [21]. It is likely that this happens more frequently in pedunculated than in sessile lesions. Pedunculated adenomas occur in the sigmoid colon and rectum more often than in other segments of the large intestine [15, 22]. It is, therefore, reasonable to suggest that more rectal than colonic adenomas regress because of the shape of the lesion and the more pronounced mechanical forces of the fecal bulk in this part of the bowel. More direct evidence of the high proportion of regression of rectal adenomas was observed by Hoff and associates [23] who found regression of adenomas in the distal 10 cm of the large intestine more often among unresected polyps than for the average colonic segment. The frequencies of both adenomas and carcinomas increase with increasing age in both sexes [19]. The accumulated incidence curve of adenomas based on data from the Norwegian Cancer Registry precede the corresponding incidence curve of carcinomas by about 5 years (Fig. 2), which is additional evidence of a precursor role of adenomas. It should be kept in mind, however, that many adenomas are first diagnosed and reported to the Cancer Registry simultaneously with the diagnosis of colorectal carcinoma, indicating a longer timespan between the 2 types of lesions than these curves indicate. Most autopsy and clinical studies have shown a predominance of adenomas in males [13, 14, 19, 22, 24] whereas the incidence of colorectal cancer is more evenly distributed between the 2 sexes [25]; however, if these data are related to age, it seems that adenomas are more prevalent among younger females than in younger males, which corresponds to a higher cancer incidence in younger females [20]. On the other hand, older males have higher frequencies of both adenomas and carcinomas than females. As previously commented, there are some segments relative to others within the large intestine which more often give rise to adenomas and carcinomas. In addition, there is a weak but significant effect of clustering of adenomas [26] within the individual patient. This implies that when multiple adenomas occur, they tend to group within areas of the large intestine. Similarly, synchronous carcinomas occur more often within the same segment than can be expected by chance [27]. Also, adenomas and carcinomas, when they occur in the same bowel,
20
14
25-34
45-54
65-74
85+ age
Fig. 2. Accumulating incidence of colorectal adenomas and carcinomas recorded in the Norwegian Cancer Registry in the period 1983-1985.
tend to cluster [28]. Thus, there seem to be areas specific to each individual patient which are more prone for both benign and malignant neoplastic development than others. This effect comes in addition to the site-specific occurrence in the large intestine of adenomas and carcinomas within each age and sex group. Morphology
Because most adenomas never become malignant, it is important to be aware of particular morphological features of adenomas that may be associated with an increased risk of malignancy. The presence of villi and severe grade of dysplasia, in addition to large size, are all associated with increased frequency of focal malignancy in adenomas [29, 30]. Since these morphological features frequently occur in the same adenomas, they are highly correlated and one of these features may merely be the result of 1 or 2 of the others. Since it is reasonable to suggest that morphological features associated with malignancy occur more frequently in cancer patients, adenomas occurring in the general autopsy population have been compared with adenomas occurring in colorectal cancer patients [31]. From these data, it can be derived that factors which initiate the growth of adenomas and factors which promote the growth of the individual adenoma to large sizes seem to be more prevalent in patients with colorectal cancer than in those without cancer. Factors initiating villous structures and advanced grade of dysplasia in adenomas seem not to be significantly more prevalent in individuals with cancer than in those without cancer. The frequently repeated demonstration of loci of invasive cancer in adenomas provides the strongest evidence of their premalignant nature [29, 30]. Another way of determining the precursor role of colorectal adenomas is to histologically exam-
T.J. Eide: Colorectal Polyps: Natural History
ine carcinomas for remnants of adenomas. This has been found to occur in 14-23% of all colorectal carcinomas. When related to the stage of carcinoma, remnants of adenomas have been found in close to 60% of carcinomas limited to the submucosal layer [4, 29]. The high proportion of adenomatous remnants in carcinomas in a very early stage of the disease has been taken to indicate that most colorectal cancer develops through a stage of benign disease; h o w e v e r , dysplastic epithelium has been observed in flat mucosa [32] and this can probably lead to immediate infiltration [8]. Thus. this could be regarded as a " d e n o v o " pathway of malignancy, which is a term applied to small carcinomas, 5-15 mm in diameter, in which no residual adenomatous tissue can be identified [5]. The fact that patients with carcinomas containing remnants of adenomas have been observed to have coexisting adenomas in the same resected specimen more frequently than patients with carcinomas m which no adenomatous remnants can be detected [4], may indicate 2 alternative pathways in the development of colorectal cancer: one in which the patient develops malignancy through a stage of benign polypoid growth (the "adenoma-carcinoma sequence") and one in which the patient develops dysplastic epithelium which has the property to grow invasively directly from fiat mucosa C'de novo"). Does morphology of the resected adenoma provide any information regarding the risk of subsequent adenomas or carcinomas? Kronborg and colleagues [33] found a higher recurrence rate among patients with adenomas larger than 2 cm and with villous adenomas. The risk was not related to severity of dysplasia. Jensen [34] found (among 479 adenoma patients) 14 subsequent colorectal carcinomas, which was significantly different from the expected number of 6.5. Grade of dysplasia and size of adenomas were variables which significantly contributed to the risk of carcinoma. Genetics and Inheritance
Beside the inheritance of familial adenomatous polyposis and other rare polyposis syndromes, the contribution of heritable factors to the genesis of colorectal cancer and adenomas is in its embryonic stage of knowledge. First-degree relatives of patients with colorectal cancer generally have a 2 or 3-fold increased risk of colorectal cancer [35, 36]. Systematic proctosigmoidoscopy screening for adenomas in pedigree members of colorectal cancer patients and spouse controls revealed in one study [36] a detection rate of adenomas of 21%, compared to only 9% in controls. The results were taken to indicate an autosomal dominant pattern of inheritance. A broader screening for polyps was performed in an additional study of 670 persons in 34 Utah kindereds [37]. Likelihood analysis strongly supported the dominant inheritance of a susceptibility to colorectal adenomas and cancers with a gene frequency of 19%. According to the most likely genetic model, the authors conclude that polyps and colorectal cancers occur only in genetically susceptible persons. In a study looking for genetic alteration, ras-gene mutation occurred in 58% of adenomas larger than 1 cm, but in only 9% of adenomas under 1 cm in size [38]. Sequences on chromosome 5 were lost in 29% and 35% of adenomas and carcinomas, respectively. A specific region of chromosome 18 was deleted frequently in carcinomas (73%) and in advanced adenomas
5
(47%), but only occasionally in earlier-stage adenomas. The results have been taken to indicate a model of colorectal carcinogenesis in which the steps required for the development of cancer often involve the mutational activation of an oncogene coupled with the loss of several genes that normally suppress tumorigenesis. During progression from adenoma to carcinoma, ras-gene mutations and 5 q allelic deletions are likely to be earlier events whereas allelic losses from chromosomes 17 p and 18 q seem to occur more often in advanced tumors [39]. R6sum6
A partir de 55 ans, on voit se d6velopper chez un tiers de la population un ou plusieurs ad6nomes colorectaux. Dans les 10 arts ~t venir, 3 ~ 5% de ces patients ad6nomateux deviendront cancereux. Le taux plut6t bas de passage de l'ad6nome au cancer signifie que la plupart des individus ayant des ad6nomes n'auront jamais de cancer col0rectal. I1 faut 6]argir nos connaissances pour pr6voir le devenir de chaque patient ad6nomateux. On y parviendra probablement grfice au progr~s constant dans la technologie des g~nes et grglce aux grandes 6tudes prospectives de suivi des patients h ad6nome. Resumen
Una tercera parte de los individuos mayores de 55 afios poseen adenomas fmicos o mt~ltiples de la regi6n colorrectal. En el curso d e l siguiente decenio, 3-5% de las personas con adenomas tienen la probabilidad de desarrollar un carcinoma. L a relativamente baja tasa de conversi6n del adenoma benigno a neoplasia maligna indica que la mayorfa de aquel!as que tienen un adenoma jam~is habr~in de desarrollar carcinoma colorrectal. Se requiere mayores conocimientos para lograr predecir la evoluci6n final del paciente con adenoma. Tales conocimientos probablemente ser~in obtenidos mediante e! progreso en la tecnologia gen6tica y a trav6s de amplios estudios prospectivos de Seguimiento de los pacientes con adenomas. References
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