Colorectal Adenomas in the Lynch Syndromes. Results of a Colonoscopy Screening Program

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1 GASTROENTEROLOGY 1990;98: ALIMENTARY TRACT Colorectal Adenomas in the Lynch Syndromes Results of a Colonoscopy Screening Program STEPHEN J. LANSPA, HENRY T. LYNCH, THOMAS C. SMYRK, PATRICIA STRAYHORN, PATRICE WATSON, JANE F. LYNCH, JOSEPH X. JENKINS, and HENRY D. APPELMAN Department of Medicine-Gastroenterology, Department of Preventive Medicine, and Department of Pathology, Creighton University School of Medicine, and the Hereditary Cancer Consultation Center, Omaha, Nebraska; and Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan. Forty-four asymptomatic putative Lynch syndrome patients participated in a colonoscopy screening program. There were 18 men and 26 women; mean age was 44 yr. Thirty percent of Lynch syndrome patients had at least one adenoma; 200/0 had multiple adenomas. In 180/0 of the patients, adenomas were discovered proximal to the splenic flexure. In a reference group of 88 age- and sex-matched patients, 11 % had adenomas, 40/0 had multiple adenomas, and 1 % had right-sided adenomas. Twenty-one Lynch syndrome patients had follow-up colonoscopies. Of 7 patients with adenomas on initial examinations, 6 had adenomas at follow-up. Of 14 patients with negative initial examination results, 3 had adenomas at follow-up. The prevalence of adenomas in the Lynch syndromes is greater than in an unselected reference group. The adenomas are more proximally located, corresponding to the site of cancer distribution in the Lynch syndromes. A high rate of synchronous and metachronous lesions is found. Our findings support the hypothesis that adenomatous changes are the premalignant lesion in the Lynch syndromes. We also found evidence of heterogeneity among Lynch syndrome families in adenoma incidence. Increasing interest has been given to the role of genetics in the etiology of colorectal cancer. The best-known hereditary syndromes predisposing to colorectal cancer are those associated with multiple polyps of the colorectum, referred to as familial adenomatous polyposis. These disorders account for <10/0 of the total colorectal cancer burden. Hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II) is at least 7-8 times more common than familial adenomatous polyposis (1-6). The designation nonpolyposis was chosen to indicate that the colon is not carpeted with adenomas, as is typical of familial adenomatous polyposis; it is not meant to imply that adenomas do not occur. In fact, adenomas may be the premalignant lesion in the Lynch syndromes. Our purpose is to describe the number, distribution, and pathology of colorectal polyps in a cohort of at-risk but asymptomatic Lynch syndrome patients compared with an age- and sex-matched reference group. Methods Patients at risk for the Lynch syndromes who underwent colonoscopy in tliis study were asymptomatic and had no history of colon cancer or colonic polyps. These patients were from well-documented Lynch syndrome families and had at least one first degree relative with colon cancer, thus putting them at 500/0 risk of carrying the putative Lynch syndrome cancer-prone genets). To be considered a welldocumented Lynch syndrome family, a family was required to have at least three generations affected by colorectal and other syndrome cancers, frequently diagnosed at early ages and occurring in a pattern consistent with autosomal dominant transmission of cancer proneness, in the absence of florid polyposis. Colonoscopy was performed in routine fashion using intravenous light sedation. All adenomas were resected at the time of initial colonoscopy in all patients but one who had multiple polyps, including a 3-cm sessile polyp in the cecum. This patient underwent subtotal colectomy. Abbreviation used in this paper: OR, odds ratio by the American Gastroenterological Association /90/$3.00

2 1118 LANSPA ET AL. GASTROENTEROLOGY Vol. 98, No.5 The reference subject pool consisted of 242 patients undergoing colonoscopy during one calendar year performed at the Creighton University Gastrointestinal Unit. Because of the risk involved with colonoscopy, the use of normal volunteers as controls was deemed ethically unfeasible. Patients with inflammatory bowel disease or a history of colonic cancer or polyps were excluded. Family history was not a cause for exclusion. Endoscopic findings did not affect inclusion in the reference group. In the reference group, colonoscopies were generally performed on patients with guaiac-positive stools, changes in bowel habits, chronic diarrhea, constipation, or abdominal pain, wherein the attending physician felt colonoscopy was warranted. This comparison group had a higher mean age (58 yr) but similar sex ratio compared with the Lynch group. From this reference pool, two patients were age- and sex-matched to each of the Lynch syndrome kindred patients. When exact age matches were unavailable, the closest available references were used. Matches were made without consideration of endoscopic findings of either the case or reference patients. Comparisons between case and reference patients were made according to the method of Mantel and Haenszel. This procedure tests the difference between the case and reference proportions using a x 2 statistic while allowing for the matching of more than one reference patient to each study case. The method also provides an estimate of the odds ratio (OR) to indicate the magnitude of the intergroup difference by a ratio of the proportion of affected cases to the proportion of affected reference patients, with adjustment for matching. Informed consent was obtained for all participants. The protocol was approved by the Institutional Review Board of Creighton University. Results Forty-four patients from 5 Lynch syndrome families participated: 18 men and 26 women. The mean age was 42.2 yr (range, yr). The mean age of the 88 reference patients (36 men, 52 women) was 44.4 yr (range yr). The cecum was reached in all Lynch syndrome patients and in 980/0 of the age- and sex-matched reference group. In two of 88 reference patients, the colonoscope could be advanced only to the ascending colon. No further attempt was made to visualize the cecum by barium studies or repeat endoscopy. Both patients were under age 40 yr and had negative endoscopies. Twenty-one of the Lynch syndrome patients had follow-up colonoscopies. There were two endoscopic complications of prolonged bleeding requiring transfusion. Both patients had undergone multiple polypectomies, and bleeding stopped in both patients without surgery or endoscopic cautery. Prevalence of Adenomas Thirty percent (13 of 44) of Lynch syndrome patients had adenomas compared with 11 % (10 of 88) in the reference group (p < 0.02, OR = 3). The Lynch syndrome patients had more frequent right colon adenomas; lesions were present in 18% of patients (8 of 44) compared with 1 % of those in the reference group (1 of 88); p < 0.001, OR = 16). They had more frequent synchronous adenomas, with lesions present in 20% of patients (9 of 44) compared with 4% of those in the reference group (4 of 88; p < 0.01, OR = 4.5) (Figure 1). The increased prevalence of adenomas was most apparent in the younger «40 yr old) casel reference group, in which adenomas were found in 22% (5 of 23) of Lynch patients and 4% of those in the reference group (2 of 46; p < 0.04, OR = 5). In the older group (;do yr), polyps were found in 38% of Lynch syndrome patients (8 of 21) and 19% of the reference group (8 of 42; p < 0.12, OR = 2.3). Tests comparing the proportion of cases in the two groups with any adenomas and with right colon adenomas were redone, treating the two reference patients in whom the cecum had not been examined as if they had been found to have right colon adenomas. The differences between the two groups were still significant in these analyses. Morphology of Adenomas Seven of the Lynch syndrome patients (16%), all of whom were from the same family, had adenomas that have been previously described as "flat adenomas" (7). Six of the seven patients had multiple flat adenomas (small, slightly raised lesions in which adenomatous tubules clustered at the luminal surface) (Figure 2). Five patients with flat adenomas had only flat adenomas. The remaining two had additional ~ Z W 25 ~ 0.: u I- Z w () 15 0:: W a Any LEGEND IIIllIII Lynch syndrome patients (n=44) Control patients (n=88) Rt colon Multiple ADENOMAS FOUND IN PATIENTS Figure 1. Lynch syndrome patients had a higher prevalence of adenomas, with a more proximal distribution and a higher incidence of synchronous adenomas.

3 May 1990 ADENOMAS IN THE LYNCH SYNDROMES 1119 Figure 2. A. Diminutive sessile polyp (arrow) in the cecum of a patient from a Lynch syndrome family. Histologic study after polypectomy showed features of "flat adenoma." B. Four small adenomas (arrows) in the cecum of a patient from a Lynch syndrome family. Each patient has a firstdegree relative with colon cancer, thus putting them at 50% risk of carrying the putative Lynch syndrome gene. pedunculated tubular adenomas. None of the reference patients had flat adenomas. When we excluded the 12 members of this family from the analysis, we found that there was no excess of adenomas in the 32 remaining Lynch syndrome patients (6 of 32 Lynch syndrome patients affected vs. 10 of 64 controls, p < 0.70). There was also no significant excess of right colon adenomas (3 of 32 Lynch syndrome patients vs. 1 of 64 controls, p < 0.08; OR = 6), although this difference was nearly significant. Nearly all cases of multiple adenomas previously reported were found in patients from the excluded kindred. Incidence of Adenomas Twenty-one Lynch syndrome patients underwent follow-up colonoscopy after an average of 24 mo (range, 4-40 mol. Seven patients had adenomas at the time of the initial examinations which were removed and examined histologically; six of these had adenomas at the time of follow-up colonoscopy. Fourteen patients had negative initial examinations; three had adenomas at the time of follow-up colonoscopy. Discussion The term cancer family syndrome was originally ascribed to two families showing an autosomal dominant inheritance pattern of adenocarcinoma of the colon in the absence of florid polyposis and the presence of an excess of carcinoma of the endometrium (8). This disorder was subsequently called hereditary nonpolyposis colorectal cancer (9). Because colonic polyps have been observed in these syndromes (10-12), the term hereditary nonpolyposis colorectal cancer may be misleading and inappropriate. In comparing prevalence and incidence of adenomas in the Lynch syndrome patients with those of the general population, the variable of age must be considered because in the hereditary syndrome, colon cancer has a much earlier age of onset (13) and precursor biomarkers (such as adenomas) might therefore affect younger patients. Endoscopic prevalence studies for adenomas in the general asymptomatic population have not been performed, and autopsy studies are likely to exceed colonoscopic studies in adenoma findings. The prevalence of adenomas in our age- and sex-matched reference group corresponds to other endoscopic surveys of patients referred for colonoscopy in US centers (14) when age is taken into consideration. Our reference group may have a lower incidence of neoplasms than some reported studies because of young age and because patients with prior neoplasms were excluded. The mean age of patients undergoing colonoscopy in our general practice is 58 yr, and the prevalence of neoplasia was 230/0 when patients with prior colon tumors or history of inflammatory bowel disease were excluded. Six percent of patients had high-grade dysplasia or adenocarcinoma. Our finding of ademmas in 30% of high-risk patients differs from previous reports of adenomas in the Lynch syndromes. Love and Morrissey (15) studied 42 asymptomatic Lynch syndrome patients and found adenomas in 17%. This group included 8 patients with previously diagnosed cancer. Mecklin and Jarvinen (10) suggested that Lynch syndrome families had fewer adenomas than patients in the general popula-

4 1120 LANSPA ET AL. GASTROENTEROLOGY Vol. 98, No.5 tion. His patients had a 140/0 prevalence of adenomas. In a separate report, Mecklin et al. found adenomas in 19% of colons resected for malignancy in Lynch syndrome patients compared with 16% in the general population (3). A note of caution in the interpretation of adenomas in these patients is warranted. Specifically, if the single family with flat adenomas is excluded, then the polyp phenotype does not change significantly from the reports of Love and Morrissey (15) and those of Mecklin (10). This raises the possibility that families classified as Lynch syndrome on the basis of the family history of colorectal cancer and the absence of classic F AP may be heterogeneous in colonic phenotype, including a subset of families with multiple flat adenomas that are clinically distinct from other Lynch syndrome families. This caution applies not only to the number of patients affected with adenocarcinoma, but also to the number of patients with right colon adenomas and multiple adenomas. Most autopsy and endoscopic surveys show a propensity for distal distribution of adenomas, similar to the distribution of sporadic colorectal cancer (14). No previous data exist on the distribution of adenomas in the Lynch syndromes. We found a pronounced proximal distribution of adenomas compared with reference patients (Figure 3). In all, 112 adenomas were detected in the 44 Lynch syndrome patients, and 78 of these were in the right colon. Among the 88 reference patients, 14 adenomas were found, two of which were in the right colon. In 242 colonoscopies on unselected patients in our general practice, 55 patients had 88 polyps distributed as follows: 21 (24%) in the cecum or Figure 3. Distribution of adenomas in Lynch syndrome patients during the present study compared with references and the distribution of initial colorectal cancers in Lynch syndrome families [reprinted and adapted with permission (13)] and in an unselected series of colorectal cancer cases [reprinted and adapted with permission (18)].

5 May 1990 ADENOMAS IN THE LYNCH SYNDROMES 1121 ascending colon, 6 (7 % ) in the transverse colon, 42 (48% ) in the descending and sigmoid colon, and 19 (220/0) in the rectum. In our Lynch syndrome series, 9 of 13 patients with adenomas had synchronous lesions; 6 patients had 3-5 adenomas, 1 had 13 adenomas, and 1 had 70 adenomas. In our reference group, 4 of 10 patients with adenomas had synchronous lesions, and none of these had more than 2 adenomas. In Love's series of 42 Lynch syndrome patients, 3 of 7 patients with adenomas had multiple adenomas (11) at the time of colonoscopy. In the study of Mecklin et ai. (3), the percentage of synchronous adenomas in Lynch syndrome patients with cancer was similar to the rate seen in sporadic colon cancer cases (19% and 16%). We found that Lynch syndrome patients who have adenomas removed at the time of initial colonoscopy will continue tq have adenomas on subsequent examinations (86% ). The distribution and high number of synchronous and metachronous adenomas in the Lynch syndromes mirror the distribution and multiplicity of colonic cancers seen in the syndrome (13) (Figure 3). Colonoscopic follow-up of adenomas in patients not selected for Lynch syndrome will yield metachronous lesions in 3%-18% (16). Implications for Management The flat adenoma was originally described by Muto et ai. (7). We have reported this lesion in a putative Lynch syndrome family (12). Although not proven, the presence of flat adenomas may be a phenotypic biomarker for a colon cancer-associated genotype (17). We believe it is prudent to consider the flat adenoma a risk marker when found in surveillance of members of putative Lynch syndrome families. Alternatively, the presence of flat adenomas may mean that the family is not a typical Lynch syndrome kindred, but may represent a variant which. in addition to being characterized by flat adenomas. also shows a larger number of adenomas and a later age of colorectal cancer onset. Endoscopists should be aware that small sessile lesions may be adenomatous and should be studied by biopsy. We have seen flat adenomas in our general practice. Five of 242 (2 % ) unselected patients undergoing colonoscopy had single flat adenomas. We have shown that patients from families with Lynch syndrome who are at 50% risk of carrying the putative cancer-prone gene have a greater prevalence of adenomas than age- and sex-matched reference patients. They have a markedly increased incidence of synchronous and metachronous adenomatous polyps. The distribution within the colon corresponds to reported distribution of colonic malignancies in the syndromes. Caution should be used in the interpretation of these data. The underlying genetic defect in the Lynch syndrome is unknown. Thus we cannot say that all of these families share the same genetic defect. There may be genetic and phenotypic heterogeneity in this set of families; therefore. the findings of flat adenomas and increased prevalence of adenomas may not be characteristic of all of the families. This collection of patients does not include enough members of given families to allow evaluation of this question. Although we have not discovered any colonic cancersin our screening program to date. Love has shown cancers arising in adenomas in Lynch syndrome patients (11). Our findings support the hypothesis that adenomas are the premalignant lesion in the Lynch syndromes. In patients from known Lynch syndrome families. we recommend yearly colonoscopy beginning at age 25 yr and aggressive follow-up of even diminutive polyps. In patients younger than 40 yr with right-sided colonic adenomas. especially with flat adenoma or multiple adenomas. attention should be paid to family history. References 1. Lynch PM, Lynch HT. Colon cancer genetics. New York: Van Nostrand Reinhold, Mecklin IP, larvinen HI, Peltokallio P. Cancer Family Syndrome: genetic analysis of 22 Finnish kindreds. Gastroenterology 1986;90: Mecklin IP, Sipponen P, larvinen HI. Histopathology of colorectal carcinomas and adenomas in the Cancer Family Syndrome. Dis Colon Rectum 1986;29: Mecklin IP. Frequency of hereditary colorectal carcinoma. Scand I GastroenteroI1987;22: Lynch HT, Kimberling WI. Albano WA, Lynch IF, Biscone K, Schuelke GS, Sandberg AA, Lipkin M, Deschner EE, Mikol YB, Elston RC, Bailey-Wilson IE, Danes BS. Hereditary nonpolyposis calorectal cancer; parts I and II. Cancer 1985;56: Lynch HT. Lanspa SI, Boman BM, Smyrk T. Watson P, Lynch IF, Lynch PM, Cristofaro G, Bufo P, Tauro AV, Mingazzini p, DiGiulio E. Hereditary nonpolyposis colorectal cancer-lynch syndromes I and II. Gastrointest Clin North Am 1988;17: Muto T. Kamiya I. Sawada T, Konishi F. Sugihara K, Kubota y, Adachi M, Agawa S. Saito y, Morioka Y, Tanprayoon T. Small flat adenoma of the large bowel with special reference to his clinicopathologic features. Dis Colon Rectum 1985;28: Lynch HT, Shaw MW, Magnuson CW, Larsen AL. Krush AJ. Hereditary factors in two large midwestern kindreds. Arch Intern Med 1966;117: Boland CR, Troncale Fl. Familial cancer without antecedent polyposis. Ann Intern Med 1984;100: Mecklin I, larvinen HI. Clinical features of colorectal carcinoma in the Cancer Family Syndrome. Dis Colon Rect 1986;29: Love RR. Adenomas are precursor lesions for malignant growth in non polyposis hereditary carcinoma of the colon and rectum. Surg Gynecol Obstet 1986;162: Lynch HT, Smyrk T, Lanspa SI, Marcus IN. Kriegler M, Lynch IF. Appelman HD. Flat adenomas in a colon cancer-prone kindred. JNCI 1988;71:

6 1122 LANSPA ET AL. GASTROENTEROLOGY Vol. 98, No Lynch HT, Watson P, Lanspa SJ, Marcus J, Smyrk T, Fitzgibbons RJ Jr, Kriegler M, Lynch JF. Natural history of colorectal cancer in hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II). Dis Colon Rectum 1988;31: Burt RW, Samowitz WS. The adenomatous polyp and the hereditary polyposis syndromes. Gastrointest Clin North Am 1988;17: Love RR, Morrissey JF. Colonoscopy in asymptomatic individuals with a family history of colorectal cancer. Arch Intern Med 1984;144: Grossman S, Milos ML, Tekawa IS, Jewell NP. Colonoscopic screening of persons with suspected risk factors for colon cancer. II. Past history of colorectal neoplasms. Gastroenterology 1989;96: Lanspa SJ, Lynch H, Smyrk T, Marcus J, Fitzgibbons R Jr, Kriegler M, Lynch J, Watson p, Appelman H. Multiple proxi- mal adenomas with atypical features in hereditary colon cancer: a new syndrome? (abstr). Gastroenterology 1988;94: A eart RW, Melton LJ. Maruta M, Dockerty MB, Frydenberg HB, O'Fallon WM. Trends in right and left-sided colon cancer. Dis Colon Rectum 1983;26: Received March 29,1989. Accepted October 14, Address requests for reprints to: Stephen J. Lanspa, M.D., F.A.C.P., Assistant Professor of Medicine-Gastroenterology, Creighton University Medical Center, 601 North 30th Street, Omaha, Nebraska Supported by NCI Grants 5 ROl CA Al and 5 ROl CA