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Genetics of gastrointestinal polyposis
00165085/78/7406-1325$02.00/O G~~~~E~IKIWGY 74~1325-1330,1978 Copyright0 1978by the AmericanGastroankologicalAesociation
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Vol. 74, No. 6 Printed in USA.
IN
GASTROENTEROLOGY
GENETICS OF GASTROINTESTINAL H. J. R.
BUSSEY,
A.
M.
0.
POLYPOSIS
VEALE,
AND B.
C.
MORSON
Pathology Department, St. Mart’s Hospital, London, England
This review deals with the types of gastrointestinal polyposis in which genetic factors play an essential part, namely, the hamartomatous lesions of Peutz-Jeghers syndrome and multiple juvenile polyposis and the neoplastic tumors of familial polyposis coli and multiple adenomas. The mode of inheritance, associated lesions, malignancy potential, and possible interrelationships between the various types of polyposis are discussed. The knowledge that the lesions are inherited should enable other family members to be investigated and treated at an early stage, a matter of considerable importance in the prevention of cancer when there is an associated risk of gastrointestinal carcinoma. Polyposis of the gastrointestinal tract is a complex subject about which there is considerable confusion. A variety of conditions produce multiple tumors in the gastrointestinal tract, none of which is common and most so rare that few persons or even institutions ever see enough examples to accumulate accurate data. The differential diagnosis is further complicated by the number of parameters which should be considered before deciding to which category a particular case should be assigned. The parameters include the number of polyps present, their distribution in the gastrointestinal tract, whether or not there are also other associated extragastrointestinal lesions and their nature, the presence of benign or malignant neoplasms of the gastrointestinal tract, the observation of a familial incidence and if this is environmental or genetic in origin, and the histological nature of the polyps. Precise information about each of these factors may not be available. An accurate assessment of the histology of the polyps is probably the most important step in determining the type of polyposis, and any opportunity of removing material for microscopic examination should never be missed. It is, however, with the familial incidence of ~gastrointestinal polyposis that this paper is primarily concerned and particularly when this is attributable to a genetic factor. The more important gastrointestinal polyposis syndromes can be divided into three histological groups: (1) inflammatory, (2) hamartomatous, and (3) neoplastic. There is no evidence of a simple genetic factor in inflammatory disease of the large intestine, although a familial incidence has been occasionally reported in Received June 2, 1977. Accepted November 28,1977. Address requests for reprints to: Dr. B. C. Morson, Pathology Department, St. Mark’s Hospital, City Road, London EClV 2PS, England.
ulcerative colitis,’ Crohn’s disease,2 and benign lymphoid polyposis.3 Stronger evidence of familial disease is found in the hamartomatous group of syndromes. The Peutz-Jeghers syndrome is generally recognized as an autosomal inherited dominant character. Less is known about juvenile polyposis, but here also there are indications that some cases at least result from inheritance. The classic example of inherited gastrointestinal polyposis belongs to the neoplastic group and is, of course, familial polyposis coli. The possibility that adenomas of the large intestine, even when they occur singly or in small numbers, may also result from genetic action has been suggested.4 The polyposis conditions in which there is a possible or proved genetic etiology are, therefore, relatively few in number and can be listed as follows: (1) hamartomatous: (a) Peutz-Jeghers syndrome, and (b) juvenile polyposis; and (2) neoplastic: (a) familial polyposis coli, and (b) multiple adenomas. These conditions are discussed below in more detail. Peutz- Jeghers syndrome. The Peutz-Jeghers syndrome is a combination of gastrointestinal polyps and pigmentation of the skin. The characteristic cutaneous pigmentation is a spotting of the perioral skin, lips, and buccal mucosa with black or dark brown specks about l-2 mm in diameter. These may be found at other sites, mainly on the fingers and toes. The polyps are hamartomas formed of mucus-secreting epithelium supported on a delicate branching stroma containing smooth muscle. The tumors can occur throughout the whole gastrointestinal tract or be limited to various segments. They are most commonly found in the small intestine where their presence accounts for the usual symptom of intermittent abdominal colic caused by recurring intussusception. In the earlier reports of the disease, histological
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interpretation of the polyps was confused and many were said to be malignant because of the presence of epithelium apparently invading muscle. Later, when the hamartomatous nature of the polyps was recognized,5J6 their malignant potential was considered to be negligible. However, there are probably at least 20 authentic cases of gastrointestinal cancer arising in patients with the Peutz-Jeghers syndrome. In the majority of these patients, the malignant tumors were present in the stomach or duodenum.‘+ Other sites recorded are jejunum or ileum’+‘* and colon.‘*’I3In the reports of the association of Peutz-Jeghers syndrome and colonic carcinoma, reference is also made to the presence of adenomas in the colon.‘*,13 The colonic carcinomas are more likely to have been derived from the adenomas present rather than from the Peutz-Jeghers polyps. It is noticeable that, with one exception, the patients with gastric and duodenal carcinomas were under the age of 40 years. The association of the PeutzJeghers syndrome with gastric and duodenal cancer in patients of this low age group would seem to be more than coincidental. It must be concluded that the PeutzJeghers syndrome does have a malignant potential, although this would appear to be small; Scully has also recorded that about 5% of females suffering from the syndrome develop sex cord cell tumors of the ovary. l4 Juvenile polyposis. The tumors in this type of polyposis are also hamartomas composed of an excess of lamina propria in which epithelium-lined tubules are embedded. These may undergo cystic dilatation. Secondary inflammation is common and this is partly attributable to necrosis consequent upon interruption of the blood supply by twisting of the pedicle of the polyp. These polyps can occur anywhere in the gastrointestinal tract but are most common in the large intestine, being in many instances confined to this region.15 Bleeding, resulting in severe anemia, malnutrition, and physical retardment are the main symptoms. About 20% of patients with juvenile polyposis have other congenital defects, such as heart lesions, malrotation of the bowel, Meckel’s diverticulum, and enlarged heads of abnormal shape. It is probable that juvenile polyposis, in at least some cases, is the result of an inheritable genetic defect, but a definite decision on this point will have to await more prolonged observation of affected families. The St. Mark’s Hospital Polyposis Register contains records of just over 50 cases of juvenile polyposis encountered in 36 families. In three-quarters of these families there appears to be only 1 affected member. The fact that about one-quarter of the investigated families contains 2 to 5 members with polyposis is suggestive of a genetic origin in this group. The more numerous solitary cases may result from environmental factors or arise from new genetic mutation. It could be that both explanations are in part correct. What is sure is that observation for at least a further generation will be necessary before an answer can be given. The associated congenital lesions mentioned previously are mainly concentrated in the solitary cases. At first, this suggested a further differentiation from the cases which occur in
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families where several members are affected. Although this disparity in incidence of congenital lesions between single and multiple cases remains, the division between the groups has become less sharp. Another factor which still has to be resolved is the malignant potential of juvenile polyps. Hamartomatous lesions are often stated to have no malignant potential, but there is no reason why they should not have a potential as least as great as that of the tissues from which they arise; possibly there is even more potential because the tissues are increased in amount and are in an abnormal situation. The mucosa of the large intestine is prone to produce neoplastic growth. It would, therefore, not be surprising if adenomas or carcinomas occurred in association with juvenile polyposis. Most of the tumors present in juvenile polyposis have the characteristic structure of the isolated juvenile polyps found in children, but a proportion show atypical epithelial changes indistinguishable from the mild or moderate dysplasia (atypia) seen in adenomas, although it is seldom that severe dysplasia is seen. The proportion of patients with adenomatous tumors is approximately the same for both solitary and multiple types of juvenile polyposis. Associated intestinal cancer has been observed in some patients with juvenile polyposis and also in other family members. This is particularly noticeable in those persons belonging to families containing multiple cases and has also been reported elsewhere.16The problem is to ascertain the actual incidence of malignancy among juvenile polyposis patients and to decide if it differs from that expected in the general population. If, as appears to be the case, the incidence is somewhat higher than expected, this may be explained by the increased amount of intestinal epithelium present and its abnormal arrangement or as a further example of the heterogeneity found in the polyposis disorders. It is hoped that observations on the clinical, histopathological, and genetic aspects of the larger series of cases of juvenile polyposis which have been collected will be published shortly by E. Lovett, H. J. R. Bussey, and B. C. Morson. It is certain, however, that the final answer on the genetics of this disease will depend on following up a large series of families over a longer period of time. One misconception should, however, be corrected. Veale et al. in 1966 originally reported the apparent association of adenomatous polyposis coli and juvenile polyposis in different members of the same family.15An example of this was cited where the father was thought to have adenomatous polyps and his daughter juvenile polyps. A review of the histology in the light of later observations now indicates that both individuals probably had juvenile polyposis but that, in the case of the father, some of the polyps available for study showed the atypical epithelial changes mentioned above, the adenomatous element being rather dominant. Familial polyposis coli. Familial polyposis is probably the most common of the polyposis conditions attributal* Its familial occurrence was ble to a genetic defect. 4,17* recorded nearly a century ago, and the high incidence of associated cancer of the colon and rectum has been
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fully substantiated over a period of time nearly as long. The main characteristic of polyposis coli is the presence of numerous adenomatous tumors in the large intestine. The number usually varies in individual cases from about 300 to 3000 with an average of approximately 1000. Only rarely are there less than 300 polyps present, the lowest figure recorded in the St. Marks Hospital series being about 150. At the other end of the range, 5000 or more adenomas may occasionally be met with. On the basis of these observations it has been suggested that the figure of 100 tumors forms a convenient division between polyposis coli and the multiple adenomas found in nonpolyposis persons. l8 The average age at which the disease was diagnosed in 338 patients on the St. Mark’s Hospital Register, who presented with symptoms, was 36.3 years, the range being from 4 to 73 years, although these extremes are rarely encountered. That the adenomas actually appeared much earlier is seen by comparing these ages with those at which polyposis was diagnosed in those family members called up for examination because they were known to be at risk. In this group, the average age was 23.8 years and the range from 8 to 57 years. Polyposis was confirmed in about three-quarters of the call-up group before tha age of 30 years, whereas in the group presenting with symptoms the proportion diagnosed by the same age was only one-third. The importance of early diagnosis in polyposis coli is shown by comparing the incidence rate of associated large bowel cancer in the two groups. Nearly two-thirds (65.2%) of the patients who presented because of symptoms already had carcinoma, whereas the proportion in the call-up group was only 7.5%. A noticeable feature of polyposis patients with intestinal cancer is the much earlier onset of malignant disease compared with the general population. The average age of diagnosis of colorectal cancer in these patients is about 39 years which is at least 25 years less than for the average in the general population. The genetic nature of familial polyposis is no longer in dispute. It is inherited as a Mendelian dominant character and, as it is not sex-linked, polyposis coli can be inherited by either sex from either sex in equal ratio. Each child of a polyposis parent has a 50:50 chance of developing the disease. Doubts are sometimes expressed about whether the patient with polyposis, but without evidence of the condition in any other family member, is really suffering from the same disease. Occasionally such patients appear to be solitary cases because the medical details of the family history are unavailable or inaccurate. Sometimes illegitimacy may be the explanation, but probably the majority of the solitary cases are new mutants provided by nature to replace affected families that die out. The children of such individuals are certainly exposed to the same risk of inheriting polyposis as are those of affected members of families with a strong history. Gardner’s syndrome. A major problem in the genetics of polyposis coli still awaiting an answer is its relationship to Gardner’s syndrome. Twenty-five years ago Gardner and his co-workers described a familial combi-
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nation of lesions which later became associated with his name.‘9*2° The earlier reports referred to a triad of multiple large intestinal polyps, multiple osteomas of the head, and multiple cysts and soft fibromas of the skin. The scope of the syndrome was subsequently modified, mainly by enlargement, by Gardner himself Controversy as to what should and by other workers .21-24 or should not be included in the syndrome has been followed by disagreement on the type of genetic activity invo1ved.25’ 26Can the various clinical manifestations be explained by a single gene mutation or is a more complex mechanism involved? Is Gardner’s syndrome a completely different entity from familial polyposis coli, sharing only the numerous adenomas of the large intestine? Is even this feature common to both or does it differ quantitatively? Among the 230 families with polyposis coli recorded in the St. Marks Hospital Polyposis Register, it is possible to find well documented families in which the affected members have a high incidence rate of the extracolonic lesions of Gardner’s syndrome and other families in which there is no such association. It is tempting to regard these differences as attributable to variable genetic activity, but this could be too easy a dismissal of the problem. An attempt will be made to review the available evidence. In the first place it would appear that the adenomatous polyposis is similar whether or not extracolonic lesions are present. Variations occur in the number, size, distribution, and age of appearance of the adenomas, but the range of variation is similar for both types of polyposis. l8 The incidence of associated large intestinal malignancy is similar for both as is also the mode of inheritance of the lesions. The two most likely explanations are either that Gardner’s syndrome is a separate genetic entity in which the genetic defect for polyposis coli is accompanied by a second genetic defect at a different locus, which has pleiotropic effects resulting in the extracolonic lesions of the syndrome, or that all polyposis coli is Gardner’s syndrome, but there is a much wider variation in expressivity of the extracolonic lesions. An exact inventory of the extracolonic lesions cannot be given, but almost certainly the following should be included 1. Osteomas, usually multiple. These are more commonly observed on the skull and mandible, but capable of occurring in any bone. lg**O 2. Various dental abnormalities. Examples are impacted teeth, supernumerary teeth, dental cysts, early and complete 10~s.~~ 3. Epidermoid cysts. These may appear anywhere on the body surface but are most common on the legs, face, scalp, and arms in that order.*’ Originally fibromas of the skin were also included,20but these are encountered only rarely and no example has been seen in the St. Marks Hospital series. 4. Lesions attributable to fibroblastic activity. The most notable of these is the desmoid tumor which arises in abdominal wall scars or in the abdominal cavity itself.22,28These tumors occur in almost 1 in 12 patients
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undergoing surgery for polyposis and are seldom found in patients who have not been operated on. Other forms of trauma, such as childbirth, may account for the lesions although rarely there may be no obvious explanation. Desmoid tumors of the abdominal cavity are potentially lethal in their ability to produce obstruction of the intestine or ureters and this tendency is probably increased, rather than diminished, by attempts to remove the desmoid tumors by surgery. Similar therapeutic problems may sometimes result from excessive fibroblastic activity which causes infiltration and distortion of the mesentery of the small intestine. A further example of the propensity of fibroblasts to overreact in polyposis patients is seen in the increase of postoperative small bowel obstruction attributable to fibrous bands after surgery for polyposiszg 5. Extracolonic malignant disease. Cancers of many sites have been reported in familial polyposis patients, not all of which can perhaps be justified. Three sites, however, appear to have a strong claim for inclusion and, in order of known frequency, are the periampullary region of the duodenum,23*30,31 thyroid,24,32 and the central nervous system. 33The last is the so-called Turcot’s syndrome. Of these, the duodenal carcinomas, of which about 30 examples are known, are not only the most common but also the most interesting because, in some of these patients, other tumors of the upper gastrointestinal tract are also present. 34,35Rare examples of adenomas of the small intestine, usually few in number, have been reported in the past,36,37but the increased use of endoscopy in recent years has led to further observations on the presence of polyps in the stomach and duodenum of polyposis patients. The gastric polyps appear mainly to be hyperplastic or hamartomatous31in nature and rarely adenomatous, and their incidence rate is unknown. Some duodenal polyps have proved to be hamartomatous and others adenomatous. There are two unpublished examples of undoubted duodenal adenomatosis coexisting with colonic adenomatosis in patients with Gardner’s syndrome in the St. Mark’s Hospital Polyposis Register. The fact that hamartomas and adenomas of the small intestine may exist in Gardner’s syndrome patients suggests that this feature of the syndrome may well be a pleiotropic manifestation of the same gene. In the two inherited diseases of Peutz-Jeghers syndrome and juvenile polyposis the genetic defect is expressed through the whole gastrointestinal tract. It would not, therefore, be surprising if a genetic mutation affecting the large intestine, as is the case in familial polyposis coli, also had some effect on the remainder of the gastrointestinal tract. It is probable that the above list of extracolonic lesions associated with polyposis coli will be added to in the future. Doubts still exist as to how many of the items, or how many of any individual item, qualify a patient for admission to the Gardner syndrome group. There is no doubt that the more intensive the investigation of the polyposis patient, the greater the incidence of extracolonic lesions. The most outstanding example
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of this has been the work of Utsunomiya and Nakamura38 on the presence of radioopaque lesions in the mandibles of over 90% of polyposis patients and their absence from nonaffected members of polyposis families, Peutz-Jeghers patients, and nonpolyposis members of the general population who have a few large intestinal adenomas. Ushio et al., investigating 24 polyposis patients from families, with respect to polyps of the stomach, duodenum, and colon, bone disease, dental abnormalities, and epidermoid cysts, came to the conclusion that “familial polyposis coli and Gardner’s syndrome are substantially the same entity.“39 Danes, however, found an increased incidence of tetraploidy in the skin flbroblasts of patients with Gardner’s syndrome which could be useful in the differentiation of these patients from those with familial polyposis coli.40 As evidence accumulates, it seems increasingly probable that a genetic disease exists in which the main characteristic is a factor for excessive tissue growth which expresses itself in the formation of both hamartomatous and neoplastic tumors in various organs of the body and whose constant and most conspicuous feature is the presence of multiple adenomas of the colon and rectum. The difference between familial polyposis coli and Gardner’s syndrome may well be only one of differing penetrance of the extracolonic lesions. Multiple adenomas. An analysis of patients with adenomas of the large intestine, other than polyposis cases, suggests that only 1 or 2% develop more than 5 adenomas and that, even in this group, the figure of 50 adenomas is seldom exceeded. It has been mentioned previously that the lowest number of polyps found in a case of polyposis was about 150. It has, therefore, been suggested that the figure of 100 adenomas is a useful dividing line between the polyposis and nonpolyposis adenoma-producing patients. The term “multiple adenomas” has been adopted for the condition in the latter group of patients, even though in some cases only a solitary adenoma has been recorded. From a study of polyposis coli and of adenomas and carcinomas of the large intestine in the nonpolyposis population, Veale4 came to the conclusion that all adenomas of the large intestine had a genetic origin. He postulated that there could be two possible mutated allelic genes P and p, responsible for the appearance of adenomas. Polyposis coli was an autosomal dominant character resulting from the inheritance of P, whereas p produced only a few adenomas as a recessive inheritance. This was a satisfactory explanation of certain irregularities in the data observed in polyposis patients which suggested that there might be two types of polyposis. These could now be genotypes Px and Pp, x being the normal gene on the locus. The patient of Px genotype is likely to have polyposis later in life and in a less severe form, whereas the Pp type is characterized by a more aggressive course at an earlier age. The hypothesis, however, has a further use in explaining the existence of the cancer families reported by Lynch et al. and other authors.4143 In these families there is a high incidence rate of intestinal cancer which is not attributable to the presence of polyposis. If an
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individual of the homozygous genotype pp is liable to develop a few adenomas, there could be a variable incidence of adenomas in families determined by possible combinations of spouses of differing genotypes. If both parents were normal genotype XX or only one was px or pp and the other XX, none of the children would develop adenomas. When both parents were px, onequarter of the children would be liable to have intestinal adenomas later in life. However, if one marriage partner is homozygous (pp) and the other heterozygous (px>, half of the children would be homozygous. Finally, when both parents are homozygous with respect to p, all of the children would be homozygous, too. In such a situation there would be a 100% liability for family members to develop adenomas of the large intestine and, because evidence has accumulated indicting the adenoma as the main, and possibly only, source of intestinal carcinoma,44*45there would be a corresponding increase in intestinal malignancy. The increase in malignancy need not be of the same order of magnitude because not all adenomas necessarily undergo malignant degeneration. If a large sibship results from a union of homozygous parents as suggested, the basis is laid for the appearance of a family in which the incidence of colorectal cancer is sufficiently high to be mistaken for a dominant characteristic when taken in isolation from other possible combinations of genotypes. It might be thought that marriages in which both parents are of the homozygous pp type would be exceedingly rare. Veale, however, taking the figure of about 10% as the best possible estimate of the incidence of intestinal adenomas in the general population, calculates that approximately half of the population are heterozygous with respect to the p gene. This implies that every other marriage involves a heterozygote, making a heterozygous-homozygous union not uncommon and a double homozygous one far from rare. Further support for Veale’s hypothesis arises out of the investigations of Lovett into the medical histories of relatives of about 250 patients admitted to St. Mark’s Hospital with cancer of the colon or rectum.46In approximately 25% of the families, there was at least 1 other member who had had intestinal cancer. An analysis of the available death certificates of family members showed that the number of deaths from intestinal cancer was more than 4 times the expected number. A patient with a relatively large number of adenomas was likely to have a strong family history of intestinal cancer. It is hoped that this work will be helpful in indicating those families at greatest risk of bowel cancer and that more effective cancer control will be achieved by colonoscopic removal of adenomas in the premalignant phase of the adenoma-carcinoma sequence. Finally, it should be noted that certain logical consequences can be expected if Veale’s hypotesis is correct. For instance, individuals suffering from ulcerative colitis would not develop intestinal cancer unless they were of pp genotype. In support of this, it has to be remembered that the histological changes observed in the condition of precancer found in colitis are similar to the epithelial dysplasia seen in adenomas. Moreover, a
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suggestive family history may sometimes be obtained. One patient admitted to St. Mark’s Hospital suffering from colitis and a carcinoma of the colon is known to have had a father with cancer of the rectum and a son who developed an adenoma of the colon at the age of 15 years. It has already been mentioned that juvenile polyposis has a higher incidence of associated intestinal carcinoma than might have been expected in a condition which is hamartomatous in nature. Veale’s hypothesis might well provide an explanation. If 10% of the general population are at risk of producing adenomas, a similar proportion of individuals of pp genotype could be expected among patients with juvenile polyposis. This factor would go a long way in explaining the mixed histological features of juvenile polyp and adenoma sometimes seen in these cases. Problems in the classification of gastrointestinal polyposis. The polyposis syndromes already discussed
have been dealt with as though they were distinct and separate entities, as indeed they mostly are. However, cases have been reported in which there appears to be an overlapping of syndromes and the patient presents with polyps of more than one histological type. Such cases are rare but are being increasingly recorded. For instance, Donnelly et al. report a case where the polyps in a colectomy specimen proved to be a mixture of ganglioneurofibromas and juvenile p01yps.~’The multiple skin lesions of von Recklinghausen’s disease are accompanied in some patients by similar lesions in the More recently a case of juvegastrointestinal tract. 48*49 nile polyposis in association with von Recklinghausen’s disease has been reported.50Adenomas and adenocarcinomas have been found in 2 members of a family with the Peutz-Jeghers syndrome (Dodds et a1.13). It is not altogether surprising that different histological types of polyps, such as neurofibromas, juvenile polyps, and Peutz-Jeghers polyps, all of which are essentially hamartomatous in origin, should be found in 1 patient. Such conditions are likely to be rare and it is not easy to accumulate a series large enough to assess accurately such factors as genetic origin, malignancy potential, and interrelationship. Moreover, it must be accepted that histological classification is not without error and imprecision. This should be remembered when polyposis syndromes are separated from one another on the basis of histological differences. The fact that the basic lesions in the reported examples of multiple pathology are generally considered to have a genetic origin may be significant. The little that is known already about them suggests that further investigation might be valuable in the study of the origin of gastrointestinal polyposis and possibly throw light on the mechanics of genetic mutation. Although this review of the genetics of gastrointestinal polyposis indicates that much remains to be investigated, one fact emerges clearly. In each of the four conditions discussed in detail, Peutz-Jeghers syndrome, juvenile polyposis, familial polyposis coli, and multiple adenomas, there is some degree of associated malignancy. This is slight in the first two conditions but
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definite and strong in the last two. It is this association 22. McAdam WAF, Goligher JC: The occurrence of desmoids in patients with familial polyposis coli. Br J Surg 57:618-631, 1970 of malignancy potential with genetic origin which provides the clinician with a means of exercising some 23. MacDonald JM, Davis WC, Crago HR, et al: Gardner’s syndrome and periampullary malignancy. Am J Surg 113:425-430, 1967 degree of cancer prevention. The fact that the predispos24. Crail HW: Multiple primary malignancies arising in rectum, ing disease can be inherited not only indicates where brain and thyroid. U.S. Nav Med Res Lab Rep 49123-128, 1949 other cases can be expected, but also affords the oppor- 25. McKusick VA: Genetic factors in intestinal polyposis. JAMA tunity of intercepting the normal course of the disease 182:271-277, 1962 before cancer supervenes. The extent to which cancer 26. Smith WG: Familial multiple polyposis: research tool for invesprevention can be effective has been shown in the case tigating the etiology of carcinoma of the colon? Dis Colon of familial polyposis. It is to be hoped that similar Rectum 11:17-31, 1968 success will be achieved with the more difficult problem 27. Leppard B, Bussey HJR: Epidermoid cysts, polyposis coli and Gardner’s syndrome. Br J Surg 62:387-393, 1975 of cancer prevention in patients with multiple adeno28. Smith WG: Desmoid tumors in familial multiple polyposis. Mayo mas. REFERENCES 1. Morris PJ: Familial ulcerative colitis. Gut 6:176-178, 1965 2. Hislop IG, Grant AK: Genetic tendency in Crohn’s disease. Gut l&994-995, 1969 3. Louw JH: Polypoid lesions of the large bowel in children with particular reference to benign lymphoid polyposis. J Pediatr Surg 3: 195-209, 1968 4. Veale AMO: Intestinal polyposis. Eugenics Laboratory Memoirs, series 49. London, Cambridge University Press, 1965 6. Dormandy TL: Gastrointestinal polyposis with mucocutaneous pigmentation (Peutz-Jeghers syndrome). N Engl J Med 265:1093-1103,1141-1146, 1186-1190, 1957 6. Morson BC: Some peculiarities in the histology of intestinal polyps. Dis Colon Rectum 5337-344, 1962 7. Achord JL, Proctor HD: Malignant degeneration and metastasis in Peutz-Jeghers syndrome. Arch Intern Med 111:498-502, 1963 8. Williams JP, Knudsen A: Peutz-Jeghers syndrome with metastasizing duodenal carcinoma. Gut 6:179-184,1965 9. Reid JD: Duodenal carcinoma in the Peutz-Jeghers syndrome. Cancer 18:970-977, 1965 10. Mackman S, Perna G, Gossett F: Peutz-Jeghers syndrome with metastases to an abdominal incision. Arch Surg 9899-102, 1969 II. Beinfield MS, Changus GW: Peutz-Jeghers syndrome: report of a case of small intestinal polyposis and carcinoma associated with melanin pigmentation of the lips and buccal mucosa. Gastroenterology 35534-539, 1958 12. Shibata HR, Phillips MJ: Peutz-Jeghers syndrome with jejunal and colonic adenocarcinomas. Can Med Assoc J 103:285-287, 1910 13. Dodds WJ, Schulte WJ, Hensley GT, et al: Peutz-Jeghers syndrome and gastrointestinal malignancy. Amer J Roentgen01 Radium Ther Nucl Med 115:374-377,1972 14. Scully RE: Sex cord tumor with annular tubules: a distinctive ovarian tumor of the Peutz-Jeghers syndrome. Cancer 25:11071121, 1970 15. Veale AMO, McCall I, Bussey HJR, et al: Juvenile polyposis coli. J Med Genet 3:5-16, 1966 16. Stemper TJ, Kent TH, Summers RW: Juvenile polyposis and gastrointestinal carcinoma: a study of a kindred. Ann Intern Med 83:839-846, 1975 17. Dukes CE: Familial intestinal polyposis. Ann Eugen 17:1-29, 1952 18. Bussey HJR: Familial polyposis coli. Baltimore, Johns Hopkins Press, 1975 19. Gardner EJ, Plenk HP: Hereditary pattern for multiple osteomas in the family group. Am J Hum Genet 4:31-36, 1952 20. Gardner EF, Richards RC: Multiple cutaneous and subcutaneous lesions occurring simultaneously with hereditary polyposis and osteomatosis. Am J Hum Genet 5:139-147,1953 21. Gardner EJ: Follow-up study of a family group exhibiting dominant inheritance for a syndrome including intestinal polyps, osteomas, fibromas and epidermal cysts. Am J Hum Genet 14:376-390. 1962
Clin Proc 34:31-38,1959 29. Lockhart-Mummery HE: Intestinal polyposis: the present position. Proc R Sot Med 60:381-388, 1967 30. McFarlane PH Jr, Scheetz WL, Knisley RE: Gardner’s syndrome: report of two families. J Oral Surg 26:632-638, 1968 31. Parks TG, Bussey HJR, Lockhart-Mummery HE: Familial polyposis coli associated with extracolonic abnormalities. Gut 11:323-329, 1970 32. Camiel MR, Mule JE, Alexander LL, et al: Association of thyroid carcinoma with Gardner’s syndrome in siblings. N Engl J Med 278:1058-1059, 1968 33. Turcot J, Despres JP, Pierre FS: Malignant tumours of the central nervous system associated with familial polyposis of the colon. Dis Colon Rectum 2:465-468,1959 34. Cabot RC: Case records of the Massachusetts General Hospital, case no. 21061. N Engl J Med 212:263-267,1935 35. Melmed RN, Bouchier IAD: Duodenal involvement in Gardner’s syndrome. Gut 13:524-527, 1972 36. Hoffman DC, Goligher JC: Polyposis of the stomach and small intestine in association with familial polyposis coli Br J Surg 58:126-128, 1971 37. Heald RJ: Gardner’s syndrome in association with two tumours of the ileum. Proc R Sot Med 60:914-915, 1967 38. Utsunomiya J, Nakamura T: The occult osteomatous changes in the mandible in patients with familial polyposis coli. Br J Surg 62:45-51, 1975 39. Ushio K, Saragawa M, Doi H, et al: Lesions associated with Familial polyposis coli. Studies of lesions of the stomach, duodenum, bones and teeth. Gastrointest Radio 1:67-80, 1976 40. Danes BS: The Gardner syndrome: a study in cell culture. Cancer 36:2327-2333, 1975 41. Lynch HT, Harris RE, Organ CH, et al: The surgeon, genetics and cancer control: the cancer family syndrome. Ann Surg 185:435-440, 1977 42. Mathis M: Familial carcinoma of the colon. A family tree from the Canton of Argau. Schweiz Med Wochenschr 92:1673-1678, 1962 43. Lovett E: Familial cancer of the gastrointestinal tract. Br J Surg 63:19-22, 1976 44. Morson BC: The polyp-cancer sequence in the large bowel. Proc R Sot Med 67:451-457,1974 45. Muto T, Bussey HJR, Morson BC: The evolution of cancer of the colon and rectum. Cancer 36:2251-2270, 1975 46. Lovett E: Family studies in cancer of the colon and rectum. Br J Surg 63:13-18,1976 47. Donnelly WH, Sieber WK, Yunis EJ: Polypoid ganglioneurofibromatosis of the large bowel. Arch Path01 87:537-541, 1969 48. Levy D, Khatir R: Intestinal neurofibromatosis with malignant degeneration: a report of a case. Dis Colon Rectum 3:140-144, 1960 49. Ghrist TD: Gastrointestinal involvement in neurofibromatosis. Arch Intern Med 112:357-362, 1963 50. Raskin JB, Dodd H: Juvenile polyposis coli concurrent with neurofibromatosis. South Med J 69:1374-1376,1976
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IN
GASTROENTEROLOGY
GENETICS OF GASTROINTESTINAL H. J. R.
BUSSEY,
A.
M.
0.
POLYPOSIS
VEALE,
AND B.
C.
MORSON
Pathology Department, St. Mart’s Hospital, London, England
This review deals with the types of gastrointestinal polyposis in which genetic factors play an essential part, namely, the hamartomatous lesions of Peutz-Jeghers syndrome and multiple juvenile polyposis and the neoplastic tumors of familial polyposis coli and multiple adenomas. The mode of inheritance, associated lesions, malignancy potential, and possible interrelationships between the various types of polyposis are discussed. The knowledge that the lesions are inherited should enable other family members to be investigated and treated at an early stage, a matter of considerable importance in the prevention of cancer when there is an associated risk of gastrointestinal carcinoma. Polyposis of the gastrointestinal tract is a complex subject about which there is considerable confusion. A variety of conditions produce multiple tumors in the gastrointestinal tract, none of which is common and most so rare that few persons or even institutions ever see enough examples to accumulate accurate data. The differential diagnosis is further complicated by the number of parameters which should be considered before deciding to which category a particular case should be assigned. The parameters include the number of polyps present, their distribution in the gastrointestinal tract, whether or not there are also other associated extragastrointestinal lesions and their nature, the presence of benign or malignant neoplasms of the gastrointestinal tract, the observation of a familial incidence and if this is environmental or genetic in origin, and the histological nature of the polyps. Precise information about each of these factors may not be available. An accurate assessment of the histology of the polyps is probably the most important step in determining the type of polyposis, and any opportunity of removing material for microscopic examination should never be missed. It is, however, with the familial incidence of ~gastrointestinal polyposis that this paper is primarily concerned and particularly when this is attributable to a genetic factor. The more important gastrointestinal polyposis syndromes can be divided into three histological groups: (1) inflammatory, (2) hamartomatous, and (3) neoplastic. There is no evidence of a simple genetic factor in inflammatory disease of the large intestine, although a familial incidence has been occasionally reported in Received June 2, 1977. Accepted November 28,1977. Address requests for reprints to: Dr. B. C. Morson, Pathology Department, St. Mark’s Hospital, City Road, London EClV 2PS, England.
ulcerative colitis,’ Crohn’s disease,2 and benign lymphoid polyposis.3 Stronger evidence of familial disease is found in the hamartomatous group of syndromes. The Peutz-Jeghers syndrome is generally recognized as an autosomal inherited dominant character. Less is known about juvenile polyposis, but here also there are indications that some cases at least result from inheritance. The classic example of inherited gastrointestinal polyposis belongs to the neoplastic group and is, of course, familial polyposis coli. The possibility that adenomas of the large intestine, even when they occur singly or in small numbers, may also result from genetic action has been suggested.4 The polyposis conditions in which there is a possible or proved genetic etiology are, therefore, relatively few in number and can be listed as follows: (1) hamartomatous: (a) Peutz-Jeghers syndrome, and (b) juvenile polyposis; and (2) neoplastic: (a) familial polyposis coli, and (b) multiple adenomas. These conditions are discussed below in more detail. Peutz- Jeghers syndrome. The Peutz-Jeghers syndrome is a combination of gastrointestinal polyps and pigmentation of the skin. The characteristic cutaneous pigmentation is a spotting of the perioral skin, lips, and buccal mucosa with black or dark brown specks about l-2 mm in diameter. These may be found at other sites, mainly on the fingers and toes. The polyps are hamartomas formed of mucus-secreting epithelium supported on a delicate branching stroma containing smooth muscle. The tumors can occur throughout the whole gastrointestinal tract or be limited to various segments. They are most commonly found in the small intestine where their presence accounts for the usual symptom of intermittent abdominal colic caused by recurring intussusception. In the earlier reports of the disease, histological
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interpretation of the polyps was confused and many were said to be malignant because of the presence of epithelium apparently invading muscle. Later, when the hamartomatous nature of the polyps was recognized,5J6 their malignant potential was considered to be negligible. However, there are probably at least 20 authentic cases of gastrointestinal cancer arising in patients with the Peutz-Jeghers syndrome. In the majority of these patients, the malignant tumors were present in the stomach or duodenum.‘+ Other sites recorded are jejunum or ileum’+‘* and colon.‘*’I3In the reports of the association of Peutz-Jeghers syndrome and colonic carcinoma, reference is also made to the presence of adenomas in the colon.‘*,13 The colonic carcinomas are more likely to have been derived from the adenomas present rather than from the Peutz-Jeghers polyps. It is noticeable that, with one exception, the patients with gastric and duodenal carcinomas were under the age of 40 years. The association of the PeutzJeghers syndrome with gastric and duodenal cancer in patients of this low age group would seem to be more than coincidental. It must be concluded that the PeutzJeghers syndrome does have a malignant potential, although this would appear to be small; Scully has also recorded that about 5% of females suffering from the syndrome develop sex cord cell tumors of the ovary. l4 Juvenile polyposis. The tumors in this type of polyposis are also hamartomas composed of an excess of lamina propria in which epithelium-lined tubules are embedded. These may undergo cystic dilatation. Secondary inflammation is common and this is partly attributable to necrosis consequent upon interruption of the blood supply by twisting of the pedicle of the polyp. These polyps can occur anywhere in the gastrointestinal tract but are most common in the large intestine, being in many instances confined to this region.15 Bleeding, resulting in severe anemia, malnutrition, and physical retardment are the main symptoms. About 20% of patients with juvenile polyposis have other congenital defects, such as heart lesions, malrotation of the bowel, Meckel’s diverticulum, and enlarged heads of abnormal shape. It is probable that juvenile polyposis, in at least some cases, is the result of an inheritable genetic defect, but a definite decision on this point will have to await more prolonged observation of affected families. The St. Mark’s Hospital Polyposis Register contains records of just over 50 cases of juvenile polyposis encountered in 36 families. In three-quarters of these families there appears to be only 1 affected member. The fact that about one-quarter of the investigated families contains 2 to 5 members with polyposis is suggestive of a genetic origin in this group. The more numerous solitary cases may result from environmental factors or arise from new genetic mutation. It could be that both explanations are in part correct. What is sure is that observation for at least a further generation will be necessary before an answer can be given. The associated congenital lesions mentioned previously are mainly concentrated in the solitary cases. At first, this suggested a further differentiation from the cases which occur in
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families where several members are affected. Although this disparity in incidence of congenital lesions between single and multiple cases remains, the division between the groups has become less sharp. Another factor which still has to be resolved is the malignant potential of juvenile polyps. Hamartomatous lesions are often stated to have no malignant potential, but there is no reason why they should not have a potential as least as great as that of the tissues from which they arise; possibly there is even more potential because the tissues are increased in amount and are in an abnormal situation. The mucosa of the large intestine is prone to produce neoplastic growth. It would, therefore, not be surprising if adenomas or carcinomas occurred in association with juvenile polyposis. Most of the tumors present in juvenile polyposis have the characteristic structure of the isolated juvenile polyps found in children, but a proportion show atypical epithelial changes indistinguishable from the mild or moderate dysplasia (atypia) seen in adenomas, although it is seldom that severe dysplasia is seen. The proportion of patients with adenomatous tumors is approximately the same for both solitary and multiple types of juvenile polyposis. Associated intestinal cancer has been observed in some patients with juvenile polyposis and also in other family members. This is particularly noticeable in those persons belonging to families containing multiple cases and has also been reported elsewhere.16The problem is to ascertain the actual incidence of malignancy among juvenile polyposis patients and to decide if it differs from that expected in the general population. If, as appears to be the case, the incidence is somewhat higher than expected, this may be explained by the increased amount of intestinal epithelium present and its abnormal arrangement or as a further example of the heterogeneity found in the polyposis disorders. It is hoped that observations on the clinical, histopathological, and genetic aspects of the larger series of cases of juvenile polyposis which have been collected will be published shortly by E. Lovett, H. J. R. Bussey, and B. C. Morson. It is certain, however, that the final answer on the genetics of this disease will depend on following up a large series of families over a longer period of time. One misconception should, however, be corrected. Veale et al. in 1966 originally reported the apparent association of adenomatous polyposis coli and juvenile polyposis in different members of the same family.15An example of this was cited where the father was thought to have adenomatous polyps and his daughter juvenile polyps. A review of the histology in the light of later observations now indicates that both individuals probably had juvenile polyposis but that, in the case of the father, some of the polyps available for study showed the atypical epithelial changes mentioned above, the adenomatous element being rather dominant. Familial polyposis coli. Familial polyposis is probably the most common of the polyposis conditions attributal* Its familial occurrence was ble to a genetic defect. 4,17* recorded nearly a century ago, and the high incidence of associated cancer of the colon and rectum has been
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fully substantiated over a period of time nearly as long. The main characteristic of polyposis coli is the presence of numerous adenomatous tumors in the large intestine. The number usually varies in individual cases from about 300 to 3000 with an average of approximately 1000. Only rarely are there less than 300 polyps present, the lowest figure recorded in the St. Marks Hospital series being about 150. At the other end of the range, 5000 or more adenomas may occasionally be met with. On the basis of these observations it has been suggested that the figure of 100 tumors forms a convenient division between polyposis coli and the multiple adenomas found in nonpolyposis persons. l8 The average age at which the disease was diagnosed in 338 patients on the St. Mark’s Hospital Register, who presented with symptoms, was 36.3 years, the range being from 4 to 73 years, although these extremes are rarely encountered. That the adenomas actually appeared much earlier is seen by comparing these ages with those at which polyposis was diagnosed in those family members called up for examination because they were known to be at risk. In this group, the average age was 23.8 years and the range from 8 to 57 years. Polyposis was confirmed in about three-quarters of the call-up group before tha age of 30 years, whereas in the group presenting with symptoms the proportion diagnosed by the same age was only one-third. The importance of early diagnosis in polyposis coli is shown by comparing the incidence rate of associated large bowel cancer in the two groups. Nearly two-thirds (65.2%) of the patients who presented because of symptoms already had carcinoma, whereas the proportion in the call-up group was only 7.5%. A noticeable feature of polyposis patients with intestinal cancer is the much earlier onset of malignant disease compared with the general population. The average age of diagnosis of colorectal cancer in these patients is about 39 years which is at least 25 years less than for the average in the general population. The genetic nature of familial polyposis is no longer in dispute. It is inherited as a Mendelian dominant character and, as it is not sex-linked, polyposis coli can be inherited by either sex from either sex in equal ratio. Each child of a polyposis parent has a 50:50 chance of developing the disease. Doubts are sometimes expressed about whether the patient with polyposis, but without evidence of the condition in any other family member, is really suffering from the same disease. Occasionally such patients appear to be solitary cases because the medical details of the family history are unavailable or inaccurate. Sometimes illegitimacy may be the explanation, but probably the majority of the solitary cases are new mutants provided by nature to replace affected families that die out. The children of such individuals are certainly exposed to the same risk of inheriting polyposis as are those of affected members of families with a strong history. Gardner’s syndrome. A major problem in the genetics of polyposis coli still awaiting an answer is its relationship to Gardner’s syndrome. Twenty-five years ago Gardner and his co-workers described a familial combi-
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nation of lesions which later became associated with his name.‘9*2° The earlier reports referred to a triad of multiple large intestinal polyps, multiple osteomas of the head, and multiple cysts and soft fibromas of the skin. The scope of the syndrome was subsequently modified, mainly by enlargement, by Gardner himself Controversy as to what should and by other workers .21-24 or should not be included in the syndrome has been followed by disagreement on the type of genetic activity invo1ved.25’ 26Can the various clinical manifestations be explained by a single gene mutation or is a more complex mechanism involved? Is Gardner’s syndrome a completely different entity from familial polyposis coli, sharing only the numerous adenomas of the large intestine? Is even this feature common to both or does it differ quantitatively? Among the 230 families with polyposis coli recorded in the St. Marks Hospital Polyposis Register, it is possible to find well documented families in which the affected members have a high incidence rate of the extracolonic lesions of Gardner’s syndrome and other families in which there is no such association. It is tempting to regard these differences as attributable to variable genetic activity, but this could be too easy a dismissal of the problem. An attempt will be made to review the available evidence. In the first place it would appear that the adenomatous polyposis is similar whether or not extracolonic lesions are present. Variations occur in the number, size, distribution, and age of appearance of the adenomas, but the range of variation is similar for both types of polyposis. l8 The incidence of associated large intestinal malignancy is similar for both as is also the mode of inheritance of the lesions. The two most likely explanations are either that Gardner’s syndrome is a separate genetic entity in which the genetic defect for polyposis coli is accompanied by a second genetic defect at a different locus, which has pleiotropic effects resulting in the extracolonic lesions of the syndrome, or that all polyposis coli is Gardner’s syndrome, but there is a much wider variation in expressivity of the extracolonic lesions. An exact inventory of the extracolonic lesions cannot be given, but almost certainly the following should be included 1. Osteomas, usually multiple. These are more commonly observed on the skull and mandible, but capable of occurring in any bone. lg**O 2. Various dental abnormalities. Examples are impacted teeth, supernumerary teeth, dental cysts, early and complete 10~s.~~ 3. Epidermoid cysts. These may appear anywhere on the body surface but are most common on the legs, face, scalp, and arms in that order.*’ Originally fibromas of the skin were also included,20but these are encountered only rarely and no example has been seen in the St. Marks Hospital series. 4. Lesions attributable to fibroblastic activity. The most notable of these is the desmoid tumor which arises in abdominal wall scars or in the abdominal cavity itself.22,28These tumors occur in almost 1 in 12 patients
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undergoing surgery for polyposis and are seldom found in patients who have not been operated on. Other forms of trauma, such as childbirth, may account for the lesions although rarely there may be no obvious explanation. Desmoid tumors of the abdominal cavity are potentially lethal in their ability to produce obstruction of the intestine or ureters and this tendency is probably increased, rather than diminished, by attempts to remove the desmoid tumors by surgery. Similar therapeutic problems may sometimes result from excessive fibroblastic activity which causes infiltration and distortion of the mesentery of the small intestine. A further example of the propensity of fibroblasts to overreact in polyposis patients is seen in the increase of postoperative small bowel obstruction attributable to fibrous bands after surgery for polyposiszg 5. Extracolonic malignant disease. Cancers of many sites have been reported in familial polyposis patients, not all of which can perhaps be justified. Three sites, however, appear to have a strong claim for inclusion and, in order of known frequency, are the periampullary region of the duodenum,23*30,31 thyroid,24,32 and the central nervous system. 33The last is the so-called Turcot’s syndrome. Of these, the duodenal carcinomas, of which about 30 examples are known, are not only the most common but also the most interesting because, in some of these patients, other tumors of the upper gastrointestinal tract are also present. 34,35Rare examples of adenomas of the small intestine, usually few in number, have been reported in the past,36,37but the increased use of endoscopy in recent years has led to further observations on the presence of polyps in the stomach and duodenum of polyposis patients. The gastric polyps appear mainly to be hyperplastic or hamartomatous31in nature and rarely adenomatous, and their incidence rate is unknown. Some duodenal polyps have proved to be hamartomatous and others adenomatous. There are two unpublished examples of undoubted duodenal adenomatosis coexisting with colonic adenomatosis in patients with Gardner’s syndrome in the St. Mark’s Hospital Polyposis Register. The fact that hamartomas and adenomas of the small intestine may exist in Gardner’s syndrome patients suggests that this feature of the syndrome may well be a pleiotropic manifestation of the same gene. In the two inherited diseases of Peutz-Jeghers syndrome and juvenile polyposis the genetic defect is expressed through the whole gastrointestinal tract. It would not, therefore, be surprising if a genetic mutation affecting the large intestine, as is the case in familial polyposis coli, also had some effect on the remainder of the gastrointestinal tract. It is probable that the above list of extracolonic lesions associated with polyposis coli will be added to in the future. Doubts still exist as to how many of the items, or how many of any individual item, qualify a patient for admission to the Gardner syndrome group. There is no doubt that the more intensive the investigation of the polyposis patient, the greater the incidence of extracolonic lesions. The most outstanding example
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of this has been the work of Utsunomiya and Nakamura38 on the presence of radioopaque lesions in the mandibles of over 90% of polyposis patients and their absence from nonaffected members of polyposis families, Peutz-Jeghers patients, and nonpolyposis members of the general population who have a few large intestinal adenomas. Ushio et al., investigating 24 polyposis patients from families, with respect to polyps of the stomach, duodenum, and colon, bone disease, dental abnormalities, and epidermoid cysts, came to the conclusion that “familial polyposis coli and Gardner’s syndrome are substantially the same entity.“39 Danes, however, found an increased incidence of tetraploidy in the skin flbroblasts of patients with Gardner’s syndrome which could be useful in the differentiation of these patients from those with familial polyposis coli.40 As evidence accumulates, it seems increasingly probable that a genetic disease exists in which the main characteristic is a factor for excessive tissue growth which expresses itself in the formation of both hamartomatous and neoplastic tumors in various organs of the body and whose constant and most conspicuous feature is the presence of multiple adenomas of the colon and rectum. The difference between familial polyposis coli and Gardner’s syndrome may well be only one of differing penetrance of the extracolonic lesions. Multiple adenomas. An analysis of patients with adenomas of the large intestine, other than polyposis cases, suggests that only 1 or 2% develop more than 5 adenomas and that, even in this group, the figure of 50 adenomas is seldom exceeded. It has been mentioned previously that the lowest number of polyps found in a case of polyposis was about 150. It has, therefore, been suggested that the figure of 100 adenomas is a useful dividing line between the polyposis and nonpolyposis adenoma-producing patients. The term “multiple adenomas” has been adopted for the condition in the latter group of patients, even though in some cases only a solitary adenoma has been recorded. From a study of polyposis coli and of adenomas and carcinomas of the large intestine in the nonpolyposis population, Veale4 came to the conclusion that all adenomas of the large intestine had a genetic origin. He postulated that there could be two possible mutated allelic genes P and p, responsible for the appearance of adenomas. Polyposis coli was an autosomal dominant character resulting from the inheritance of P, whereas p produced only a few adenomas as a recessive inheritance. This was a satisfactory explanation of certain irregularities in the data observed in polyposis patients which suggested that there might be two types of polyposis. These could now be genotypes Px and Pp, x being the normal gene on the locus. The patient of Px genotype is likely to have polyposis later in life and in a less severe form, whereas the Pp type is characterized by a more aggressive course at an earlier age. The hypothesis, however, has a further use in explaining the existence of the cancer families reported by Lynch et al. and other authors.4143 In these families there is a high incidence rate of intestinal cancer which is not attributable to the presence of polyposis. If an
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individual of the homozygous genotype pp is liable to develop a few adenomas, there could be a variable incidence of adenomas in families determined by possible combinations of spouses of differing genotypes. If both parents were normal genotype XX or only one was px or pp and the other XX, none of the children would develop adenomas. When both parents were px, onequarter of the children would be liable to have intestinal adenomas later in life. However, if one marriage partner is homozygous (pp) and the other heterozygous (px>, half of the children would be homozygous. Finally, when both parents are homozygous with respect to p, all of the children would be homozygous, too. In such a situation there would be a 100% liability for family members to develop adenomas of the large intestine and, because evidence has accumulated indicting the adenoma as the main, and possibly only, source of intestinal carcinoma,44*45there would be a corresponding increase in intestinal malignancy. The increase in malignancy need not be of the same order of magnitude because not all adenomas necessarily undergo malignant degeneration. If a large sibship results from a union of homozygous parents as suggested, the basis is laid for the appearance of a family in which the incidence of colorectal cancer is sufficiently high to be mistaken for a dominant characteristic when taken in isolation from other possible combinations of genotypes. It might be thought that marriages in which both parents are of the homozygous pp type would be exceedingly rare. Veale, however, taking the figure of about 10% as the best possible estimate of the incidence of intestinal adenomas in the general population, calculates that approximately half of the population are heterozygous with respect to the p gene. This implies that every other marriage involves a heterozygote, making a heterozygous-homozygous union not uncommon and a double homozygous one far from rare. Further support for Veale’s hypothesis arises out of the investigations of Lovett into the medical histories of relatives of about 250 patients admitted to St. Mark’s Hospital with cancer of the colon or rectum.46In approximately 25% of the families, there was at least 1 other member who had had intestinal cancer. An analysis of the available death certificates of family members showed that the number of deaths from intestinal cancer was more than 4 times the expected number. A patient with a relatively large number of adenomas was likely to have a strong family history of intestinal cancer. It is hoped that this work will be helpful in indicating those families at greatest risk of bowel cancer and that more effective cancer control will be achieved by colonoscopic removal of adenomas in the premalignant phase of the adenoma-carcinoma sequence. Finally, it should be noted that certain logical consequences can be expected if Veale’s hypotesis is correct. For instance, individuals suffering from ulcerative colitis would not develop intestinal cancer unless they were of pp genotype. In support of this, it has to be remembered that the histological changes observed in the condition of precancer found in colitis are similar to the epithelial dysplasia seen in adenomas. Moreover, a
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suggestive family history may sometimes be obtained. One patient admitted to St. Mark’s Hospital suffering from colitis and a carcinoma of the colon is known to have had a father with cancer of the rectum and a son who developed an adenoma of the colon at the age of 15 years. It has already been mentioned that juvenile polyposis has a higher incidence of associated intestinal carcinoma than might have been expected in a condition which is hamartomatous in nature. Veale’s hypothesis might well provide an explanation. If 10% of the general population are at risk of producing adenomas, a similar proportion of individuals of pp genotype could be expected among patients with juvenile polyposis. This factor would go a long way in explaining the mixed histological features of juvenile polyp and adenoma sometimes seen in these cases. Problems in the classification of gastrointestinal polyposis. The polyposis syndromes already discussed
have been dealt with as though they were distinct and separate entities, as indeed they mostly are. However, cases have been reported in which there appears to be an overlapping of syndromes and the patient presents with polyps of more than one histological type. Such cases are rare but are being increasingly recorded. For instance, Donnelly et al. report a case where the polyps in a colectomy specimen proved to be a mixture of ganglioneurofibromas and juvenile p01yps.~’The multiple skin lesions of von Recklinghausen’s disease are accompanied in some patients by similar lesions in the More recently a case of juvegastrointestinal tract. 48*49 nile polyposis in association with von Recklinghausen’s disease has been reported.50Adenomas and adenocarcinomas have been found in 2 members of a family with the Peutz-Jeghers syndrome (Dodds et a1.13). It is not altogether surprising that different histological types of polyps, such as neurofibromas, juvenile polyps, and Peutz-Jeghers polyps, all of which are essentially hamartomatous in origin, should be found in 1 patient. Such conditions are likely to be rare and it is not easy to accumulate a series large enough to assess accurately such factors as genetic origin, malignancy potential, and interrelationship. Moreover, it must be accepted that histological classification is not without error and imprecision. This should be remembered when polyposis syndromes are separated from one another on the basis of histological differences. The fact that the basic lesions in the reported examples of multiple pathology are generally considered to have a genetic origin may be significant. The little that is known already about them suggests that further investigation might be valuable in the study of the origin of gastrointestinal polyposis and possibly throw light on the mechanics of genetic mutation. Although this review of the genetics of gastrointestinal polyposis indicates that much remains to be investigated, one fact emerges clearly. In each of the four conditions discussed in detail, Peutz-Jeghers syndrome, juvenile polyposis, familial polyposis coli, and multiple adenomas, there is some degree of associated malignancy. This is slight in the first two conditions but
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definite and strong in the last two. It is this association 22. McAdam WAF, Goligher JC: The occurrence of desmoids in patients with familial polyposis coli. Br J Surg 57:618-631, 1970 of malignancy potential with genetic origin which provides the clinician with a means of exercising some 23. MacDonald JM, Davis WC, Crago HR, et al: Gardner’s syndrome and periampullary malignancy. Am J Surg 113:425-430, 1967 degree of cancer prevention. The fact that the predispos24. Crail HW: Multiple primary malignancies arising in rectum, ing disease can be inherited not only indicates where brain and thyroid. U.S. Nav Med Res Lab Rep 49123-128, 1949 other cases can be expected, but also affords the oppor- 25. McKusick VA: Genetic factors in intestinal polyposis. JAMA tunity of intercepting the normal course of the disease 182:271-277, 1962 before cancer supervenes. The extent to which cancer 26. Smith WG: Familial multiple polyposis: research tool for invesprevention can be effective has been shown in the case tigating the etiology of carcinoma of the colon? Dis Colon of familial polyposis. It is to be hoped that similar Rectum 11:17-31, 1968 success will be achieved with the more difficult problem 27. Leppard B, Bussey HJR: Epidermoid cysts, polyposis coli and Gardner’s syndrome. Br J Surg 62:387-393, 1975 of cancer prevention in patients with multiple adeno28. Smith WG: Desmoid tumors in familial multiple polyposis. Mayo mas. REFERENCES 1. Morris PJ: Familial ulcerative colitis. Gut 6:176-178, 1965 2. Hislop IG, Grant AK: Genetic tendency in Crohn’s disease. Gut l&994-995, 1969 3. Louw JH: Polypoid lesions of the large bowel in children with particular reference to benign lymphoid polyposis. J Pediatr Surg 3: 195-209, 1968 4. Veale AMO: Intestinal polyposis. Eugenics Laboratory Memoirs, series 49. London, Cambridge University Press, 1965 6. Dormandy TL: Gastrointestinal polyposis with mucocutaneous pigmentation (Peutz-Jeghers syndrome). N Engl J Med 265:1093-1103,1141-1146, 1186-1190, 1957 6. Morson BC: Some peculiarities in the histology of intestinal polyps. Dis Colon Rectum 5337-344, 1962 7. Achord JL, Proctor HD: Malignant degeneration and metastasis in Peutz-Jeghers syndrome. Arch Intern Med 111:498-502, 1963 8. Williams JP, Knudsen A: Peutz-Jeghers syndrome with metastasizing duodenal carcinoma. Gut 6:179-184,1965 9. Reid JD: Duodenal carcinoma in the Peutz-Jeghers syndrome. Cancer 18:970-977, 1965 10. Mackman S, Perna G, Gossett F: Peutz-Jeghers syndrome with metastases to an abdominal incision. Arch Surg 9899-102, 1969 II. Beinfield MS, Changus GW: Peutz-Jeghers syndrome: report of a case of small intestinal polyposis and carcinoma associated with melanin pigmentation of the lips and buccal mucosa. Gastroenterology 35534-539, 1958 12. Shibata HR, Phillips MJ: Peutz-Jeghers syndrome with jejunal and colonic adenocarcinomas. Can Med Assoc J 103:285-287, 1910 13. Dodds WJ, Schulte WJ, Hensley GT, et al: Peutz-Jeghers syndrome and gastrointestinal malignancy. Amer J Roentgen01 Radium Ther Nucl Med 115:374-377,1972 14. Scully RE: Sex cord tumor with annular tubules: a distinctive ovarian tumor of the Peutz-Jeghers syndrome. Cancer 25:11071121, 1970 15. Veale AMO, McCall I, Bussey HJR, et al: Juvenile polyposis coli. J Med Genet 3:5-16, 1966 16. Stemper TJ, Kent TH, Summers RW: Juvenile polyposis and gastrointestinal carcinoma: a study of a kindred. Ann Intern Med 83:839-846, 1975 17. Dukes CE: Familial intestinal polyposis. Ann Eugen 17:1-29, 1952 18. Bussey HJR: Familial polyposis coli. Baltimore, Johns Hopkins Press, 1975 19. Gardner EJ, Plenk HP: Hereditary pattern for multiple osteomas in the family group. Am J Hum Genet 4:31-36, 1952 20. Gardner EF, Richards RC: Multiple cutaneous and subcutaneous lesions occurring simultaneously with hereditary polyposis and osteomatosis. Am J Hum Genet 5:139-147,1953 21. Gardner EJ: Follow-up study of a family group exhibiting dominant inheritance for a syndrome including intestinal polyps, osteomas, fibromas and epidermal cysts. Am J Hum Genet 14:376-390. 1962
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