Journal of the Royal Society of Medicine Volume 85 June 1992
M J Underwood MB chB V W Johnson MB FRCP New Cross Hospital, Wolverhampton WV10 OQP
Department of Medicine,
Keywords: colorectal cancer; cancer family syndrome
Introduction Although it has been known for over a century that some cases of colorectal cancer are familial it is only in recent years that attention has focused on detecting those individuals with a genetic predisposition, many of whom are in the younger age groups, so that they and their families can be offered regular screening. Colorectal cancer is the commonest gut malignancy and the second commonest cancer in developed countries with an increasing incidence in England and Wales (Figures 1 and 2). Patients with a Dukes stage A carcinoma have a 90% 5-year survival but unfortunately 80% of patients are stage B or C at diagnosis and stage C patients show only a 25% 5-year survival rate', with the histological type of tumour having no effect upon prognosis2. There has been little overall change in the mortality of this disease3, although a recent study from Helsinki has reported a significant improvement in survival with tumours confined to the bowel wall4. In recent years there has been increasing interest in determiningthe importance of inherited colon cancers and attention has been focused on detecting those individuals with a genetic predisposition so that they and their families can be offered regular screening resulting hopefully in a substantial reduction in mortality. Historical perspectives The familial nature of polyposis coli was recognized by Cripps in 18825 and Smith described the association of this condition with colorectal carcinoma in 18876. The wider concept of familial cancer involving other
Figure 2. Age-specific incidence rates of colorectal cancer in men in England and Wales
organs including the colon and uterus, in what has become known as the cancer family syndrome, was firstly clearly deseribed by Warthin in 1913 in Michigan, when he did a retrospective histological analysis of 600 cases of carcinoma7. In 1977 Lynch et aL found that 7% of the general population had three or more first degree relatives with cancer contributing to the cancer family syndrome8 and in three studies quoted by Kussin et aL in 1979, of a total of 2484 first degree relatives of 596 probands with sporadic colorectal cancer, three times as many cases of colorectal cancer were detected than expected9. Lynch et aL estimated that up to 20% of colorectal cancers have a familial basisl' and in 1986 Mecklin et aL reported that it had -been estimated that up to 5% of all colonic carcinomata may be inherited as an autosomal dominant trait".
Based on case presented to Clinical Section, 13 May 1988
Figure 1. Age-specific incidence rates of colorectal cancer in women in England and Wales
Inherited colorectal cancer can be classified into polyposis and non-polyposis syndromes. The polyposis group consists of familial polyposis, heritable solitary colonic polyps, juvenile polyposis and Gardener's, Turcot's and Peutz-Jegher's syndromes. The nonpolyposis type comprises site-specific colon cancer (Lynch Syndrome I), the cancer family syndrome(Lynch Syndrome II), gastrocolonic cancer, Torres syndrome and what Kussin et aL described as sporadic colon cancer with a 'suggestive' family history9. Site-specific colon cancer (Lynch Syndrome I) is typified by the appearance of colonic malignancies at an early age. A high frequency of solitary adenomatous
0141-0768/92 060339-03/$02.00/0 © 1992 The Royal Society of Medicine
Journal of the Royal Society of Medicine Volume 85 June 1992
polyps is seen among family members and the syndrome appears to be inherited in an autosomal dominant fashion. Multiple primary colonic neoplasia is common (both synchronous and metachronous) and up to 80% of these cancers may occur in the proximal colon with about 68% of these occurring in the caecum'0. Lynch's Syndrome II (the cancer family syndrome) is characterized by all of the features of Lynch Syndrome I with additional risks for the early development of cancer in the female genital tract (endometrium and ovary) and at other sites. He also noted an increased frequency of prolonged survival in these patients12. An increased risk of developing colorectal cancer is reported in people who have a first-degree relative with the disease and this lifetime risk has been shown to be in the range of 10-15%13. The risks in nonpolyposis cancer family syndromes were reviewed from the literature by Kussin who quoted a life time risk of cancer of 50% to progeny of an affected parent with a mean age of onset of 48 years and second primaries occurring at a rate of about 3% per year. Over the age of 18 years the risk of a second primary was over 40% and nearly 90% of the second primaries were in the colon or endometrium. Triple primaries were also noted involving the colon or endometrium at an incidence of 70% over 12 years9. In 1986 Mecklin et al. published a careful genetic analysis of 22 Finnish kindreds with the cancer family syndrome, identified by investigating the families of young patients with colorectal cancer over a 20-year period. Of 196 malignancies 61% were colorectal, 15% undefined, 10% endometrial, 4% gastric and 3% biliary in origin. Their cancer family patients represented 0.4% of all colorectal cancers in Finland from 1961 to 1980 with a minimum frequency of 1/25 100 to 21400. However, due to the strict entry criteria for the trial, they felt that this figure was probably an underestimation. They also found autosomal dominant transmission with the highest incidence occurring between 40 and 49 years, supporting Lynch's figures and the cumulative risk in descendants was 50% at 69 years'4.
Screening Screening for colorectal cancer over the years has relied upon faecal occult blood testing and although false negatives and false positives limit the reliability of this method, the use of a new radial immunodiffusion technique may improve detection with an acceptable level of false positive results'5 and annual screening for occult faecal blood is recommended for these high risk patients'2. A randomized controlled trial of faecal occult blood screening has recently shown that symptomless colorectal cancers can be diagnosed after detection of occult blood in the faeces and that cancers diagnosed in this way are generally at a less advanced stage than those appearing in a control population'6. Various genetic markers have been found to be associated with inherited colon cancer such as mandibular osteomas in 76% of familial polyposis and 24% of colorectal cancer without known familial predisposition'7. Tumour markers or 'biomarkers' have been reported as potential indicators of phenotypic expression of a genetic trait in patients at high risk of developing colon cancer. These include abnormal growth of cultured skin fibroblasts, chromosome
tetraploidy in cultured skin cells, defects in recognitive immunity in mixed leucocyte cultures, a deficiency of DNA repair in circulating lymphocytes and synthesis of abnormal DNA by surface epithelial cells in the biopsy specimens and colonic washings18. Screening in the future may rely upon the detection of a heritable colorectal cancer gene and recent molecular genetic evidence has shown that the gene for familial adenomatous polyposis (the apc gene), occurs in a high proportion of colorectal cancers but perhaps carrying a different class of mutation within it19. Due to the predominance of proximal colonic lesions routine proctosigmoidoscopy does not result in adequate screening and depending upon availability, colonoscopy or proctosigmoidoscopy with air contrast barium enema are recommended every 2-3 years'2. Alternatively, recent work has suggested that colonic ultrasonography following the retrograde instillation of fluid into the colon is an effective diagnostic procedure and may find application as a screening procedure for neoplastic disease of the colon20. Because of the high frequency of endometrial carcinoma it has also been suggested that female patients should have annual pelvic examinations with endometrial biopsy every 3 years'2. Patient management Initial diagnosis and subsequent management may be difficult as exemplified by a 49-year-old woman seen in our department, who presented in 1971 with a 6-month history of alternating diarrhoea, constipation and blood staining of her faeces. She stated that her 43-year-old sister had undergone a craniotomy for a cerebral metastasis from a colonic cancer and simultaneously her 74-year-old mother had had a colonic carcinoma diagnosed. A maternal aunt had also died as a result of a colonic cancer and her maternal grandmother had died from a gastric carcinoma (Figure 3). Physical examination and sigmoidoscopy were normal but a barium enema showed a polyp in the sigmoid colon. Colonoscopy revealed a large, fixed, broad based polyp at 30 cm but no other lesion. Histology of the lesion showed a papillary tumour with severe epithelial atypia. Following this she underwent sigmoid colectomy and histological sections of the operative specimen showed a moderately differentiated mucinous adenocarcinoma arising in a villous adenoma with moderate spread into the pericolic fat but no lymph node involvement. The diagnosis was thus a Dukes' Grade B adenocarcinoma. This patient has been reviewed annually since then and she remains well at the age of 70 years with no evidence of tumour recurrence. The surgical management of patients such as ours is both complex and controversial. Due to the high incidence of metachronous colonic lesions initial hji
Figure 3. An example of familial colorectal cancer
Journal of the Royal Society of Medicine Volume 85 June 1992
surgery may be extended to include a total colectomy with ileo-anal anastomosis. Prophylactic surgical intervention in women of these families has to be carefully considered. Having had a colectomy for colorectal cancer should a prophylactic hysterectomy be done and when a hysterectomy for endometrial cancer has been performed should a prophylactic colectomy be considered or simply annual colorectal screening performed? There are various difficulties in making the diagnosis of cancer family syndrome in that a history from several generations is required, death certification is often unreliable because the cause of death may not be due to cancer and previous malignancy may not be listed on the certificate. Also histological proof of the carcinoma is often not available. The fact that a person belongs to a cancer family syndrome may therefore be appreciated-some time after a local resection has been performed. In this particular group of patients the choice is between further prophylactic surgery or intensive surveillance and no direct evidence is available at present to indicate the most effective form of management.
Conclusion In order to obtain detailed family histories from these patients and to facilitate the tracing of relatives and the collection of information on screening for epidemiological study, we agree with Lynch et aL8 that a National Registry of cancer family syndromes, including familial colorectal cancer should be set up. This is particularly important at a time when increasing international efforts are being made to map the structure of the human genome21'. Using this cumulative information it should then be possible to define more accurately the various types of syndromes, with a view to developing a clearer perspective of the interplay of genetic and environmental factors. This would improve detection, assess treatment and possibly develop methods of prophylaxis, with ultimately an improvement in patient management and prognosis. References 1 Taylor I. Colon polyps and colon cancer. Med Int 1986; 26:1063-6 2 Sasaki 0, Atkin WS, Jass JR. Mucinous carcinoma ofthe rectum. Histopathology 1987;11:259-72 3 Moore JRL, LaMont JT. Colorectal cancer: risk factors and screening strategies. Arch Intern Med 1984;144: 1819-23 4 Jarvinen HJ, Ovaska J, Mecklin J-P. Improvements in the treatment and prognosis of colorectal cancer. Br J Surg 1988;75:25-7
5 Cripps WH. Two cases of disseminated polypus of the rectum. Trans Path Soc Lond 1882;33:165-8 6 Smith T. Three cases of multiple polypi of the lower bowel occurring in one family. St Bartholomew's Hosp Rep 1887;23:225-9 7 Warthin AS. Heredity with reference to carcinoma: as shown by the study of the cases examined in the pathological laboratory of the University of Michigan, 1895-1913. Arch Intern Med 1913;12:546-55 8 Lynch HT, Lynch J, Lynch P. Management and control of familial cancer. In: Mulvihill JJ, Miller RW, Fraumeni JF eds. Genetics ofhuman cancer. New York: Raven Press, 1977:235-55 9 Kussin SZ, Lipkin M, Winawer SJ. State of the art. Inherited colon cancer: clinical implications. Am J Gastroenterol 1979;72:448-57 10 Lynch PM, Lynch HT, Harris RE. Hereditary proximal colonic cancer. Dis Colon Rectum 1977;20:661-8 11 Mecklin J-P, Jarvinen HJ. Clinical features of colorectal carcinoma in cancer family syndrome. Dis Colon Rectum 1986;29:160-4 12 Lynch HT, Lynch PM, Albano WA, Lynch JF. The cancer syndrome: a status report. Dis Colon Rectum 1981;24:311-22 13 Eddy DM, Nugent FW, Eddy JF, Coller J, Gilbertson V, Gottlieb LS. Screening for colorectal cancer in a high risk population. Gastroenterology 1987;92:682-92 14 Mecklin J-P, Jarvinen HJ, Peltokallio P. Cancer family syndrome: genetic analysis of 22 Finnish kindreds.
Gastroenterology 1986;90:328-33 15 Frommer DJ, Kapparis A, Brown MK. Improved screening for colorectal cancer by immunological detection of occult blood. BMJ 1988;296:1092-4 16 Hardcastle JD, Thomas WM, Chamberlain J, et al Randomised controlled trial of faecal occult blood screening for colorectal cancer. Lancet 1989;ii:1160-4 17 Sondergaard JO, Svendsen LB, Witt IN, Bulow S, Lauritsen KB, Tetens G. Mandibular osteomas in the cancer family syndrome. Br J Cancer 1985;52:941-3 18 Sherlock P, Winawer SJ. Are there markers for the risk of colorectal cancer? N Engl J Med 1984;311:118-19 19 Ashton-Rickhart PG, Dunlop MG, Nakamura Y, et aL High frequency of apc loss in sporadic colorectal carcinoma due to breaks clustered in 5q21-22. Oncogene 1989;4:1169-74 20 Limberg B. Diagnosis of large bowel tumours by colonic ultrasonography. Lancet 1990;i:144-6 21 Dorozynaki A. French go after the human genome. BMJ 1991;302:132-3 22 McKusick VA. The morbid anatomy of the human genome: a review of gene mapping in clinical medicine (part IV). Medicine 1988;67:1-19
(Accepted 1 October 1991)