CASE REPORT

Identical Twins Discordant for Ulcerative Colitis with Colon Cancer W I L L I A M B I S O R D I , MD, and C H A R L E S J. L I G H T D A L E , MD

A basic and as yet unanswered question is whether the d o c u m e n t e d increased incidence of colon cancer in ulcerative colitis relates to the effect of the chronic inflammatory disease or to a predisposition to develop both diseases independently. There has been m u c h evidence to show that inheritance plays a role in the o c c u r r e n c e of both these diseases (1). Ulcerative colitis has been shown to o c c u r m o r e frequently in certain families (2-4), and a high incidence of colon c a n c e r has also been found in certain family groups who do not have inflammatory bowel disease (5-8). The study of identical twins affected with ulcerative colitis has shown instances where both siblings were affected (9-11), and other instances where the disease has been discordant, affecting only one twin (12, 13). This suggests a complex hereditary predisposition, and not full genetic penetrance. The following report details the occurr e n c e of severe chronic ulcerative colitis in a patient who subsequently developed colon cancer, and whose identical twin is apparently free of disease.

CASE REPORT Richard H. suffered recurrent bouts of bloody diarrhea since age 6, and was diagnosed as having ulcerative colitis on the basis of sigmoidoscopy and barium enema. During exacerbations he received treatments including parenteral ACTH, corticosteroid enemas, and salicylazosulfapyridine. At the age of 22 he developed symptoms of intestinal obstruction, and at operation he was found to have his entire colon involved by inflammatory disease. From the Department of Medicine, Gastroenterology Service, Memorial Sloan-Kettering Cancer Center, New York, New York, and the Cornell University Medical College, New York, New York. Dr. Lightdale is the recipient of an American Cancer Society Junior Faculty Fellowship Award. Address for reprint requests: Dr. Charles J. Lightdale, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York.

Digestive Diseases, Vol. 2l, No. l (January 1976)

There was a large obstructing and perforating carcinoma of the splenic flexure, and a second separate smaller carcinoma in the descending colon. There were widespread metastases to lymph nodes, peritoneum, and liver. A subtotal colectomy was performed with ileoproctostomy. The tumors and metastases were interpreted as anaplastic adenocarcinoma of colonic origin. Colon pathology was compatible with long-standing universal ulcerative colitis. The patient has been placed on a chemotherapy program at Memorial Hospital.

Family History The patient's twin brother, Robert H. has been in excellent general health and free of gastrointestinal disease. He has had no history of arthritis, jaundice, skin, or eye disease. He is felt to be an identical twin on the basis of appearance in childhood, before the brother's disease caused growth impairment. Furthermore, the brothers are felt to be monozygotic on the basis of major and minor blood typing, HL-A typing, and fingerprint analyses. Both twins were blood types A+, with identical preliminary antigens of A2/Cl +/D+ ,E+,e+/M+ ,N neg/Le(a) neg, and identical supplementary antigens Pneg/C(w) neg/ Kneg,k+/Fz(a)+,Fz(b)neg/S+,s+/Jk(a)+. Both were HL-A types 2,9,W-5, and W-17. There is no other family history of chronic gastrointestinal disease or cancer.

DISCUSSION In a literature review, we have been unable to find a previous report of ulcerative colitis occuring in a twin that was later complicated by colon cancer. Ulcerative colitis and a d e n o c a r c i n o m a of the colon are of unknown etiology, but family grouping strongly suggests a genetic influence in both diseases (1). A l m y and Sherlock postulated that ulcerative colitis might involve either an autosomal dominant gene with reduced penetrance, the combined actions of multiple genes, or a genetic predisposition plus environmental influences (9). The report of m o n o z y g o t i c twins discordant for ulcer7 1

BISORDI AND LIGHTDALE

ative colitis supports the hypothesis that the disease is not inherited as a dominant gene with full penetrance (12). Aside from twin studies, it has become evident that first-degree relatives of patients with ulcerative colitis are affected much more commonly with this disease than the general population, with estimates ranging from 5% to !5% (1). A polygenic liability has been suggested as the most likely explanation. Colon cancer occurs with increased frequency in ulcerative colitis, Crohn's disease (14, 15), familial polyposis syndromes, and also in certain family groups without obvious predisposing colonic disease (16). "Cancer families" have been described by Lynch and Krush with increased incidences of colon cancer, and also other primary malignant neoplasms (6). Twin studies have not yet been of help in deciding the influence of heredity in colon cancer, although several pairs of affected twins have beeh reported (1). One report involved monozygotic twins who developed nearly identical symptoms within 6 days of each other (8). There is much to suggest that the colon cancer that occurs in ulcerative colitis is different from the usual adenocarcinoma of the colon and is due at least in part to the inflammatory disease. For example, Edwards and Truelove found the risk of colon cancer is greater if ulcerative colitis occurs at an early age, and the risk increases with time (17). More severe universal disease also increases the risk, In the Mayo Clinic series, with ulcerative colitis in children, the risk of cancer was 3% in 10 years, 23% in 20 years, and 43% after 35 years (18). The cancers that occur in patients with ulcerative colitis tend to be a more anaplastic undifferentiated variety than that seen in de n o v o cases of colon cancer and are often multifocal (19). Whether all colon cancers arise in epithelium that has undergone common premalignant changes associated in time with adenomatous features is a hypothesis being actively investigated (19-22). Still, as McConnel! has suggested, there is the possibility that a hereditary predisposition to~levelop cancer exists independently of hereditary susceptibility to ulcerative colitis (1). He cites a report of two brothers with ulcerative colitis, both of whom developed colon cancer, but the cancer in one case occurred 14 years after symptoms and the other 4 years after symptoms (23). The twins reported here are identical on the basis of appearance, blood types, HL-A analyses, and fingerprints. One twin developed ulcerative colitis at

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age 6, and had universal disease. When 16 years later he developed multifocal anaplastic colon cancer, he was in the extremely high-risk group. In the coincident sets of monozygotic twins with ulcerative colitis recorded, the disease appeared in both members of a set within a 3-year period. Therefore, on the basis of the evidence so far, it would seem unlikely that the asymptomatic twin here will develop ulcerative colitis now, more than 16 years after his brother's onset of disease. The unaffected twin has declined examination unless he becomes symptomatic. The twins reported support the postulate that ulcerative colitis results from a combined action of multiple genes without full penetrance, or genetic predisposition plus environmental influences. In patients with ulcerative colitis, it is possible that a separate genetic susceptibility for cancer is present. However, the case here suggests that the development of cancer is related primarily to the inflammatory disease, and its age of onset, dt~ration, activity, and extent, rather than an independent genetic determinant. SUMMARY

A 22-year-old patient with a 16-year history of ulcerative colitis who developed multifocal anaplastic colon cancer is presented. His identical twin, proven by blood type, HL-A, and fingerprint analyses, has been completely asymptomatic. This report suggests that ulcerative colitis results from a polygenic predisposition without full penetrance. Subsequent development of colon cancer seems more likely related to the inflammatory disease than an independent genetic determinant. REFERENCES 1. McConne!l RB: The Genetics of Gastrointestinal Disorders. London, Oxford, 1966, pp 128--155 2. Sherlock P, Bell BM, Steinberg H, Almy TP: Familial occurrence of regional enteritis and ulcerative colitis. Gastroenterology 45:413--420, 1963 3. Morris PJ: Familial ulcerative colitis. Gut 6:176-178, 1965 4. Kirsner JB, Spencer JA: Familial occurrence of ulcerative colitis, regional enteritis, and ileocolitis. Ann Intern Med 59:133-144, !963 5. Lynch HT, Krush AJ: Heredity and adenocarcinoma of the colon. Gastroenterology 53:517-527, 1967 6. Lynch HT, Krush AJ: Differential diagnosis of the cancer family syndrome. Surg Gynecol Obstet 136:221-224, 1973 7. Fielding NF: Familial non-polypotic carcinoma of colon. Br Med J !:512-513, 1969 Digestive Diseases, Vol. 21, No. 1 (January 1976)

IDENTICAL TWINS DISCORDANT FOR COLITIS WITH CANCER

8. Kluge T: Familial cancer of the colon. Acta Chir Scand 127:382-398, 1964 9. Almy TP, Sherlock P: Genetic aspects of ulcerative colitis and regiorlttl erlteritis. Gastroenterology 51:757-761, 1966 I0. Lyons CR, Postlewait RW: Chronic ulcerative colitis in twins. Gastroenterology 10:545-550, 1948 11. Webb LR Jr: The occurrence of lalcerative colitis in twin males. Gastroenterology 15:523-524, 1950 12. Qazi GH, Piken IE, Fierst S: Discordant occurrence of ulcerative colitis in identical twins. Gastroenterology 65:134--136, 1973 13. Gregg JA, Baggenstoss AH: Discordance for ulcerative colitis in identical twins concordant for cholestatic liver disease. Am J Dig Dis 15:667-671, 1970 14. Weedon DD, Shorter RG, Ilstrup DM, Huizenga KA, Taylor WF: Crohn's disease and cancer. N Engl J Med 289:10991103, 1973 15. Lightdale CJ, Sternberg SS, Posner G, Sherlock P: Carcinoma complicating Crohn's disease. A report of seven cases and review of the literature. Am J Med 59:262-268, 1975

Digestive Diseases, Vol. 21, No. l (January 1976)

16. Wennstrom J, Pierce ER, McCusick VA: Hereditary benign and malignant lesions of the large bowel. Cancer 34(Suppl):850-857, 1974 17. Edwards FC, Truelove SC: The course and prognosis of ulcerative colitis. Part IV. Carcinoma of the colon. Gut 5:1522, 1964 18. Devroede GJ, Taylor WF, Sauer WG, Jackman RJ, Stickler GB: Cancer risk and life expectancy of children with ulcerative colitis. N. Engl J Med 285:17-21, 1971 19. Fenoglio CM, Lane N: The anatomical precursor of colorectal carcinoma. Cancer 34(Suppl):819--823, 1974 20. Morson BC: Evaluation of cancer of the colon and rectum. Cancer 34(Suppl):845-849, 1974 21. Lipkin M: Phase 1 and phase 2 proliferative lesions of colonic epithelial cells in diseases leading to colonic cancer. Cancer 34(Suppl):878-888, 1974 22. Gassaniga AB, Gassaniga DA! Carcinoma of the colon following chronic ulcerative colitis; report of two unusual cases in brothers. Dis Colon Rectum 5:437--443, 1962

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Identical twins discordant for ulcerative colitis with colon cancer.

A 22-year-old patient with a 16-year history of ulcerative colitis who developed multifocal anaplastic colon cancer is presented. His identical twin, ...
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