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Natural history of colorectal cancer
Natural History of Colorectal Cancer Sidney J. Winawer, MD
Colorectal cancer arises from a precursor lesion, the adenomatous polyp, which forms in a field of epithelial cell hyperproliferation and crypt dysplasia. Progression from this precursor lesion to colorectal cancer is a multistep process, accompanied by alterations in several suppressor genes that result in abnormalities of cell regulation, and has a natural history of 10 –15 years. Environmental factors and inherited susceptibility play major roles in this sequence of events. As a result of familial and genetic studies, we now have a better understanding of various high-risk groups and the application of screening methods to these individuals and to people at average risk. In the future, further identification of genetically predisposed individuals and colonoscopic screening of the general population may provide new opportunities for control of colorectal cancer through secondary prevention, and a better understanding of lifestyle factors and their modification will lead to improved strategies for primary prevention. Am J Med. 1999;106(1A):3S– 6S. © 1999 by Excerpta Medica, Inc.
From the Gastroenterology and Nutrition Service, Memorial SloanKettering Cancer Center, New York, New York. Requests for reprints should be addressed to Sidney J. Winawer, MD, Gastroenterology and Nutrition Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021. © 1999 by Excerpta Medica, Inc. All rights reserved.
C
olorectal cancer is the second leading cause of cancer death in the United States, yet when diagnosed before symptoms occur, it has a high probability of cure. The mortality associated with colorectal cancer has been falling gradually for a number of years, perhaps as a result of improved surgery, the implementation of adjuvant therapy, and earlier diagnosis. A more recent slight downward trend in the incidence of colorectal cancer remains to be explained but may be related to .20 years of widely practiced colonoscopic polypectomy.
NATIONAL POLYP STUDY The National Polyp Study (NPS) demonstrated the natural history of colorectal cancer as it arises from premalignant adenomatous polyps.1 Eligibility criteria included the presence of one or more colorectal adenomas but no invasive cancer. Patients enrolled in the study had all polyps removed at baseline and then were followed .6 years by colonoscopy, barium enema, fecal occult blood testing, and questionnaires. Of all the polyps removed at baseline, two thirds were adenomatous (neoplastic), with the potential to grow and transform into cancer, and one third were nonadenomatous. Nonadenomatous polyps can be divided into primarily hyperplastic and normal mucosal tags, neither of which develops into cancer. At follow-up, a high cumulative percentage of patients examined colonoscopically for the first time 3 years after entering the study had adenomatous polyps, about half of which were probably missed initially and about half of which were newly developed. By correlating patient age with adenoma histology, it was shown that an average of 5.5 years was required for the transformation of a large (.1 cm) adenomatous polyp into cancer, the so-called adenoma-adenocarcinoma sequence. Correlation of adenoma size with histology showed that transformation of the smallest polyps into cancer took about 10 years. These cancers were detected by colonoscopy, not by the appearance of symptoms, which would have taken even more time. Thus, the NPS supports a long natural evolution of colorectal cancer from an adenoma. The study showed that people grow polyps quite commonly. Adenomatous polyps are found commonly after colonoscopic clearing, but only a small percentage— 3.3% in the NPS—are pathologically advanced at follow-up examinations, defined by a diameter .1 cm, or high-grade dysplasia, or invasive cancer. Because almost everyone grows adenomas, reducing the frequency of pathologically advanced polyps is increasingly being used 0002-9343/99/$19.00 3S PII S0002-9343(99)00338-6
A Symposium: Natural History of Colorectal Cancer/Winawer
Figure 1. Observed and expected colorectal cancer incidence in the National Polyp Study (NPS) cohort following colonoscopic polypectomy. The colorectal cancers observed over approximately 6 years in a cohort of patients who had had their polyps cleared colonoscopically (NPS observed) were compared with the colorectal cancers observed in two polyp-bearing cohorts of patients who had not had their polyps cleared by colonoscopy (Mayo Clinic and St. Mark’s) and in a general population of subjects (NPS expected). Colonoscopic polypectomy resulted in a sharp reduction in the incidence of colorectal cancer compared with the incidence in the untreated cohorts. Mayo Clinic data are from Gastroenterology2; St. Mark’s data are from N Engl J Med.3 The NPS expected data are from SEER (Surveillance, Epidemiology, and End Results), the National Cancer Institute’s general population registry, as reported in DHHS publication NIH 90-2789.4 (Reprinted with permission from N Engl J Med.1)
as the important endpoint for primary and secondary intervention studies. The NPS also showed that removing adenomatous polyps at baseline sharply reduced the expected incidence of colorectal cancer over approximately 6 years, compared with the findings from studies of adenoma-bearing cohorts whose members did not have their colons cleared by colonoscopy and from a general population cohort (Figure 1).2– 4 The goal of screening is not only to detect early colorectal cancers but also to find premalignant polyps and remove them. Removal of premalignant polyps interrupts the natural history of the adenoma-adenocarcinoma sequence. This is one of the most powerful cancer prevention strategies currently available. Superimposing other secondary prevention strategies on colonoscopy and polypectomy could provide an additional benefit.
HIGH-RISK GROUPS About 75% of people with colorectal cancer would have been classified as being at average risk before diagnosis. This group includes men and women at least 50 years old who have no other risk factors, the so-called sporadic group. The other 25% belong to groups at increased risk. 4S
January 25, 1999
THE AMERICAN JOURNAL OF MEDICINEt
The increased risk is related to inflammatory bowel disease in 1%, to familial adenomatous polyposis in 1%, and to hereditary nonpolyposis colorectal cancer (HNPCC) in 5%. The remaining 15%–20% of high-risk individuals have a family history of colorectal cancer in close relatives without an identified genetic predisposition. Hereditary Nonpolyposis Colorectal Cancer Among families with HNPCC, as well as familial polyposis, not only is the incidence of colorectal cancer quite high but also colorectal cancer appears at a younger age than in the general population, in which 90% of colorectal cancers occur after age 50 (Figure 2). The Amsterdam criteria for HNPCC include $3 relatives with colorectal cancer, at least one of whom is under the age of 50 and two of whom are first-degree relatives (siblings or parents),5 although others have broadened the criteria to capture additional patients. The natural history of the adenoma-adenocarcinoma sequence in HNPCC is strikingly different from that in the general population, because the mechanism of carcinogenesis is different. Patients with HNPCC have defects in mismatch repair genes, resulting in a destabilization of the genome that permits many other mutations to occur; this can lead to
Volume 106 (1A)
A Symposium: Natural History of Colorectal Cancer/Winawer
Figure 2. Cumulative incidence of colorectal cancer by age of onset in patients with genetic syndromes compared with that in the general population. In these genetic syndromes, the incidence is much higher and the onset is at a younger age. Ninety percent of colorectal cancers in the general population occur after age 50. (Reprinted with permission from Gastroenterology.5)
rapid transformation from normal mucosa to large adenomas and to colorectal cancer. Indeed, recurrent small and large adenomas and colorectal cancers can appear within 6 months to 1 year of colonoscopic clearing of polyps. Accordingly, in these patients, screening must begin at a younger age and be performed much more frequently than in the general population. Family History Without an Identified Genetic Predisposition Individuals who have one or two first-degree relatives with colorectal cancer appear to have a two-fold increase in risk, compared with spouse controls. Studies have shown an additional correlation between cancer risk in relatives of probands (index cases) with colorectal cancer and the age at which the diagnosis was made in the proband.6 The same phenomenon was seen in the NPS.7
To date, genetic mutations have not been discovered in persons with one or two close relatives with colorectal cancers, except in the case of Ashkenazi Jews. The Ashkenazi Jews migrated from Germany to Eastern Europe, where they congregated in small villages and married within their communities, allowing founder-effect mutations to occur in a manner like those discovered in Finland in persons with HNPCC.8 This founder-effect mutation has been demonstrated to be on the APC gene. It has been calculated that about 6% of all Ashkenazi Jews in the United States have this genetic mutation and that about 28% of Ashkenazim with a family history of colorectal cancer have it.9 If an individual Ashkenazi has a family history of colorectal cancer together with the mutation, his or her lifetime risk for colorectal cancer may approach that of a person with the HNPCC mutation. These preliminary observations require additional study.
GENETIC MUTATIONS In familial adenomatous polyposis, numerous genetic mutations on chromosome 5 have been observed and reported extensively. Genetic mutations have been described on at least four chromosomes in patients with HNPCC, but these mutations account for only a small proportion of those who express this syndrome, implying that many more mutations remain to be discovered. In familial polyposis, the entire colon is usually studded with small adenomas (except in an attenuated form), while in HNPCC, there are fewer adenomas and most are found in the proximal colon.
CURRENT CONCEPTS OF COLORECTAL CARCINOGENESIS It is now believed that the normal colonic mucosa undergoes transformation as a result of cellular mutations in the APC gene. These are somatic mutations that are not inherited and may be related to nutritional effects as well as to other environmental factors. Hyperproliferation and aberrant crypt foci develop and may progress to form small and then larger adenomas, which may eventually transform into cancer. Fewer than one in 20 small adenomas will grow into large adenomas and then transform
January 25, 1999
THE AMERICAN JOURNAL OF MEDICINEt
Volume 106 (1A)
5S
A Symposium: Natural History of Colorectal Cancer/Winawer
into cancer. Invasion and metastasis of the cancer depends on additional factors in the tissues. Time, however, is on the side of the patient. The 10 –15-year time frame of this process provides an opportunity for both primary and secondary prevention. Public awareness of these opportunities remains poor, however. Increasing awareness and utilization of known preventive approaches needs greater emphasis.
1. Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med. 1993;329:1977– 1981. 2. Stryker SJ, Wolff BG, Culp CE, et al. Natural history of untreated colonic polyps. Gastroenterology. 1987;93:1009 – 1013. 3. Atkin WS, Morson BC, Cuzick J. Long-term risk of colorectal
January 25, 1999
5.
6.
7.
REFERENCES
6S
4.
THE AMERICAN JOURNAL OF MEDICINEt
8.
9.
cancer after excision of rectosigmoid adenomas. N Engl J Med. 1992;326:658 – 662. Gloeckler-Reis LA, Hankey BF, Edwards BK, eds. Cancer Statistics Review, 1973–1987. Bethesda, MD: Department of Health and Human Services, 1990. DHHS publication NIH 90-2789. Winawer SJ, Fletcher RH, Miller L, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology. 1997;112:594 – 642. St. John DJB, McDermott FT, Hopper JL, et al. Cancer risk in relatives of patients with common colorectal cancer. Ann Intern Med. 1993;118:785–790. Winawer SJ, Zauber AG, Gerdes H, et al. Risk of colorectal cancer in the families of patients with adenomatous polyps. National Polyp Study Workgroup. N Engl J Med. 1996;334: 82– 87. Mecklin JP, Jarvinen HJ, Peltokallio P. Cancer family syndrome. Genetic analysis of 22 Finnish kindreds. Gastroenterology. 1986;90:328 –333. Laken SJ, Petersen GM, Gruber SB, et al. Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nat Genet. 1997;17:79 – 83.
Volume 106 (1A)
Colorectal cancer arises from a precursor lesion, the adenomatous polyp, which forms in a field of epithelial cell hyperproliferation and crypt dysplasia. Progression from this precursor lesion to colorectal cancer is a multistep process, accompanied by alterations in several suppressor genes that result in abnormalities of cell regulation, and has a natural history of 10 –15 years. Environmental factors and inherited susceptibility play major roles in this sequence of events. As a result of familial and genetic studies, we now have a better understanding of various high-risk groups and the application of screening methods to these individuals and to people at average risk. In the future, further identification of genetically predisposed individuals and colonoscopic screening of the general population may provide new opportunities for control of colorectal cancer through secondary prevention, and a better understanding of lifestyle factors and their modification will lead to improved strategies for primary prevention. Am J Med. 1999;106(1A):3S– 6S. © 1999 by Excerpta Medica, Inc.
From the Gastroenterology and Nutrition Service, Memorial SloanKettering Cancer Center, New York, New York. Requests for reprints should be addressed to Sidney J. Winawer, MD, Gastroenterology and Nutrition Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021. © 1999 by Excerpta Medica, Inc. All rights reserved.
C
olorectal cancer is the second leading cause of cancer death in the United States, yet when diagnosed before symptoms occur, it has a high probability of cure. The mortality associated with colorectal cancer has been falling gradually for a number of years, perhaps as a result of improved surgery, the implementation of adjuvant therapy, and earlier diagnosis. A more recent slight downward trend in the incidence of colorectal cancer remains to be explained but may be related to .20 years of widely practiced colonoscopic polypectomy.
NATIONAL POLYP STUDY The National Polyp Study (NPS) demonstrated the natural history of colorectal cancer as it arises from premalignant adenomatous polyps.1 Eligibility criteria included the presence of one or more colorectal adenomas but no invasive cancer. Patients enrolled in the study had all polyps removed at baseline and then were followed .6 years by colonoscopy, barium enema, fecal occult blood testing, and questionnaires. Of all the polyps removed at baseline, two thirds were adenomatous (neoplastic), with the potential to grow and transform into cancer, and one third were nonadenomatous. Nonadenomatous polyps can be divided into primarily hyperplastic and normal mucosal tags, neither of which develops into cancer. At follow-up, a high cumulative percentage of patients examined colonoscopically for the first time 3 years after entering the study had adenomatous polyps, about half of which were probably missed initially and about half of which were newly developed. By correlating patient age with adenoma histology, it was shown that an average of 5.5 years was required for the transformation of a large (.1 cm) adenomatous polyp into cancer, the so-called adenoma-adenocarcinoma sequence. Correlation of adenoma size with histology showed that transformation of the smallest polyps into cancer took about 10 years. These cancers were detected by colonoscopy, not by the appearance of symptoms, which would have taken even more time. Thus, the NPS supports a long natural evolution of colorectal cancer from an adenoma. The study showed that people grow polyps quite commonly. Adenomatous polyps are found commonly after colonoscopic clearing, but only a small percentage— 3.3% in the NPS—are pathologically advanced at follow-up examinations, defined by a diameter .1 cm, or high-grade dysplasia, or invasive cancer. Because almost everyone grows adenomas, reducing the frequency of pathologically advanced polyps is increasingly being used 0002-9343/99/$19.00 3S PII S0002-9343(99)00338-6
A Symposium: Natural History of Colorectal Cancer/Winawer
Figure 1. Observed and expected colorectal cancer incidence in the National Polyp Study (NPS) cohort following colonoscopic polypectomy. The colorectal cancers observed over approximately 6 years in a cohort of patients who had had their polyps cleared colonoscopically (NPS observed) were compared with the colorectal cancers observed in two polyp-bearing cohorts of patients who had not had their polyps cleared by colonoscopy (Mayo Clinic and St. Mark’s) and in a general population of subjects (NPS expected). Colonoscopic polypectomy resulted in a sharp reduction in the incidence of colorectal cancer compared with the incidence in the untreated cohorts. Mayo Clinic data are from Gastroenterology2; St. Mark’s data are from N Engl J Med.3 The NPS expected data are from SEER (Surveillance, Epidemiology, and End Results), the National Cancer Institute’s general population registry, as reported in DHHS publication NIH 90-2789.4 (Reprinted with permission from N Engl J Med.1)
as the important endpoint for primary and secondary intervention studies. The NPS also showed that removing adenomatous polyps at baseline sharply reduced the expected incidence of colorectal cancer over approximately 6 years, compared with the findings from studies of adenoma-bearing cohorts whose members did not have their colons cleared by colonoscopy and from a general population cohort (Figure 1).2– 4 The goal of screening is not only to detect early colorectal cancers but also to find premalignant polyps and remove them. Removal of premalignant polyps interrupts the natural history of the adenoma-adenocarcinoma sequence. This is one of the most powerful cancer prevention strategies currently available. Superimposing other secondary prevention strategies on colonoscopy and polypectomy could provide an additional benefit.
HIGH-RISK GROUPS About 75% of people with colorectal cancer would have been classified as being at average risk before diagnosis. This group includes men and women at least 50 years old who have no other risk factors, the so-called sporadic group. The other 25% belong to groups at increased risk. 4S
January 25, 1999
THE AMERICAN JOURNAL OF MEDICINEt
The increased risk is related to inflammatory bowel disease in 1%, to familial adenomatous polyposis in 1%, and to hereditary nonpolyposis colorectal cancer (HNPCC) in 5%. The remaining 15%–20% of high-risk individuals have a family history of colorectal cancer in close relatives without an identified genetic predisposition. Hereditary Nonpolyposis Colorectal Cancer Among families with HNPCC, as well as familial polyposis, not only is the incidence of colorectal cancer quite high but also colorectal cancer appears at a younger age than in the general population, in which 90% of colorectal cancers occur after age 50 (Figure 2). The Amsterdam criteria for HNPCC include $3 relatives with colorectal cancer, at least one of whom is under the age of 50 and two of whom are first-degree relatives (siblings or parents),5 although others have broadened the criteria to capture additional patients. The natural history of the adenoma-adenocarcinoma sequence in HNPCC is strikingly different from that in the general population, because the mechanism of carcinogenesis is different. Patients with HNPCC have defects in mismatch repair genes, resulting in a destabilization of the genome that permits many other mutations to occur; this can lead to
Volume 106 (1A)
A Symposium: Natural History of Colorectal Cancer/Winawer
Figure 2. Cumulative incidence of colorectal cancer by age of onset in patients with genetic syndromes compared with that in the general population. In these genetic syndromes, the incidence is much higher and the onset is at a younger age. Ninety percent of colorectal cancers in the general population occur after age 50. (Reprinted with permission from Gastroenterology.5)
rapid transformation from normal mucosa to large adenomas and to colorectal cancer. Indeed, recurrent small and large adenomas and colorectal cancers can appear within 6 months to 1 year of colonoscopic clearing of polyps. Accordingly, in these patients, screening must begin at a younger age and be performed much more frequently than in the general population. Family History Without an Identified Genetic Predisposition Individuals who have one or two first-degree relatives with colorectal cancer appear to have a two-fold increase in risk, compared with spouse controls. Studies have shown an additional correlation between cancer risk in relatives of probands (index cases) with colorectal cancer and the age at which the diagnosis was made in the proband.6 The same phenomenon was seen in the NPS.7
To date, genetic mutations have not been discovered in persons with one or two close relatives with colorectal cancers, except in the case of Ashkenazi Jews. The Ashkenazi Jews migrated from Germany to Eastern Europe, where they congregated in small villages and married within their communities, allowing founder-effect mutations to occur in a manner like those discovered in Finland in persons with HNPCC.8 This founder-effect mutation has been demonstrated to be on the APC gene. It has been calculated that about 6% of all Ashkenazi Jews in the United States have this genetic mutation and that about 28% of Ashkenazim with a family history of colorectal cancer have it.9 If an individual Ashkenazi has a family history of colorectal cancer together with the mutation, his or her lifetime risk for colorectal cancer may approach that of a person with the HNPCC mutation. These preliminary observations require additional study.
GENETIC MUTATIONS In familial adenomatous polyposis, numerous genetic mutations on chromosome 5 have been observed and reported extensively. Genetic mutations have been described on at least four chromosomes in patients with HNPCC, but these mutations account for only a small proportion of those who express this syndrome, implying that many more mutations remain to be discovered. In familial polyposis, the entire colon is usually studded with small adenomas (except in an attenuated form), while in HNPCC, there are fewer adenomas and most are found in the proximal colon.
CURRENT CONCEPTS OF COLORECTAL CARCINOGENESIS It is now believed that the normal colonic mucosa undergoes transformation as a result of cellular mutations in the APC gene. These are somatic mutations that are not inherited and may be related to nutritional effects as well as to other environmental factors. Hyperproliferation and aberrant crypt foci develop and may progress to form small and then larger adenomas, which may eventually transform into cancer. Fewer than one in 20 small adenomas will grow into large adenomas and then transform
January 25, 1999
THE AMERICAN JOURNAL OF MEDICINEt
Volume 106 (1A)
5S
A Symposium: Natural History of Colorectal Cancer/Winawer
into cancer. Invasion and metastasis of the cancer depends on additional factors in the tissues. Time, however, is on the side of the patient. The 10 –15-year time frame of this process provides an opportunity for both primary and secondary prevention. Public awareness of these opportunities remains poor, however. Increasing awareness and utilization of known preventive approaches needs greater emphasis.
1. Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med. 1993;329:1977– 1981. 2. Stryker SJ, Wolff BG, Culp CE, et al. Natural history of untreated colonic polyps. Gastroenterology. 1987;93:1009 – 1013. 3. Atkin WS, Morson BC, Cuzick J. Long-term risk of colorectal
January 25, 1999
5.
6.
7.
REFERENCES
6S
4.
THE AMERICAN JOURNAL OF MEDICINEt
8.
9.
cancer after excision of rectosigmoid adenomas. N Engl J Med. 1992;326:658 – 662. Gloeckler-Reis LA, Hankey BF, Edwards BK, eds. Cancer Statistics Review, 1973–1987. Bethesda, MD: Department of Health and Human Services, 1990. DHHS publication NIH 90-2789. Winawer SJ, Fletcher RH, Miller L, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology. 1997;112:594 – 642. St. John DJB, McDermott FT, Hopper JL, et al. Cancer risk in relatives of patients with common colorectal cancer. Ann Intern Med. 1993;118:785–790. Winawer SJ, Zauber AG, Gerdes H, et al. Risk of colorectal cancer in the families of patients with adenomatous polyps. National Polyp Study Workgroup. N Engl J Med. 1996;334: 82– 87. Mecklin JP, Jarvinen HJ, Peltokallio P. Cancer family syndrome. Genetic analysis of 22 Finnish kindreds. Gastroenterology. 1986;90:328 –333. Laken SJ, Petersen GM, Gruber SB, et al. Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nat Genet. 1997;17:79 – 83.
Volume 106 (1A)