5 Management of familial adenomatous polyposis ALLAN D. SPIGELMAN SHIRLEY V. HODGSON JAMES P. S. THOMSON

THE FAMILY Familial adenomatous polyposis (FAP), a disorder in which intestinal polyps have an extremely high malignant potential, is inherited in an autosomal dominant fashion. Management of this condition therefore involves counselling and screening of at-risk relatives of affected individuals as well as the patients themselves. These activities are best performed in collaboration with dedicated registries, which record full family histories for each patient. Forty-two registries worldwide belong to the Leeds Castle Polyposis Group (LCPG) which was established in 1985, and which takes its name from the site of its first meeting. Each registry has a major interest in patients with FAP. The most recent meeting of the LCPG occurred in Florida in May 1991. Reports from registries in Denmark, Northern Ireland, the West Midlands region of the United Kingdom, Italy, Singapore, Korea and Australia confirmed that registry activity has led to the discovery of more patients with FAP than had been the case before the establishment of registries in these countries. Of particular importance was the observation that registration of families, with systematic call-up of relatives, was accompanied by a lower prevalence of colorectal cancer and by improved survival in those who were found to have FAP when screened in this way. For example, the Danish Polyposis Registry found colorectal cancers in 68% of non-screened patients and in only 3% of screened patients, while the Singapore Polyposis Registry found colorectal cancers in 89% and 13%, respectively, in these groups. Furthermore, all 16 deaths from colorectal cancer recorded by the Singapore Registry occurred in the unscreened population (LCPG, 1991). In its first 36 months of activity, the Northern Region Polyposis Registry in the UK increased the number of identified gene carriers of patients with FAP from 56 to 65 individuals in a population of 3.1 million people, and achieved a 15-fold increase in the number of at-risk relatives screened (Rhodes et al, 1991). The mean age of diagnosis of patients detected by screening was 24.7 years, compared with a mean age of 36.6 years for patients detected by symptoms; while only one of the 25 people in the screen-detected group had colorectal cancer at the time of Baillit?re’s Clinical GastroenterologyVol. 6, No. 1, March 1992 ISBN O-7020-1622-5

75 Copyright 0 1992, by BailWe All rights of reproduction in any form

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surgery, 10 of the 31 patients in the ‘symptom-detected group’ had colorectal cancer. These findings confirm those of the National Registry of FAP families established in the Netherlands in 1984 (Vasen et al, 1990). Eightytwo families were registered by 1988, and 230 patients had been confirmed to have FAP. Of these 230 patients, 104 were symptomatic (at an average age of 24 years) and 126 were detected by screening (at an average age of 35 years). Colorectal cancer was present in 49 of the former group but in only five of the latter. Management of the polyposis patient in isolation from his family, as so often happens in the absence of a registry, can thus be seen to represent a lost opportunity in the prevention of cancer. New approaches to screening Screening of asymptomatic at-risk relatives has traditionally been by sigmoidoscopic examination of the rectum and sigmoid colon. The first examination is performed at or around puberty. Random biopsies are often taken to detect adenomas which are invisible to the naked eye (microadenomas; Figure 1).

Figure 1. Colonic microadenomas. Reproduced with permission of the Medicine Group UK Ltd.

As a consequence of the advances in our understanding of the molecular biology of FAP (the FAP gene is now thought to reside in segment 21 of the long arm of chromosome 5-Groden et al, 1991; Joslyn et al, 1991; Kinzler et al, 1991a,b; Nishisho et al, 1991), and with increasing appreciation of the fact that FAP has significant extracolonic manifestations (Bulow, 1990; Parks, 1990), differing approaches to screening are emerging.

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Congenital hypertrophy

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of the retinal pigment epithelium

One apparently benign extracolonic marker for FAP is the presence of multiple areas of congenital hypertrophy of the retinal pigment epithelium (CHRPE) in the eye (Figure 2). The presence of these lesions in most (but not in all) patients with FAP was first reported by Blair and Trempe (1980). CHRPE has been found in more than 80% of patients with FAP in most series (Llopis and Menezo, 1987; Traboulsi et al, 1987; Berk et al, 1988; Chapman et al, 1989; Polkinghorne et al, 1990). Eye examination is through

Figure 2. Congenital hypertrophy Murday (1989) with permission.

of the retinal pigment epithelium.

From Northover

and

a maximally dilated pupil using indirect ophthalmoscopy. The lesions are typically discrete, darkly pigmented lesions, and measure between 50 and 200 pm in diameter. The retina may be depigmented around them. It is rare for normal individuals to have more than five of these lesions (Polkinghorne et al, 1990). The presence of lesions totalling four or more in both eyes may be taken as a positive test for the presence of FAP in an at-risk individual (specificity 95%, sensitivity 78%-Traboulsi et al, 1987). However, there is interfamily variation in the expression of this extracolonic manifestation. Thus in some families CHRPE is a consistent finding in affected individuals, while in other families CHRPE is consistently absent in gene carriers (Traboulsi et al, 1987; Romania et al, 1989).

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CHRPE can be integrated with other measures of risk to allow more precise risk analysis to be performed (Houlston et al, 1990). This is important because regular sigmoidoscopies are recommended until the risk for each individual falls below 1% . Despite a normal sigmoidoscopy at age 35 years, the risk for FAP for a member of an FAP family is still 5% (Murday and Slack, 1989). DNA markers

Linkage analysis depends on the availability of blood samples from other members of the family, for which correct paternity assessment is essential. Linkage involves tracking the FAP gene through the family using linked marker genes very close to the FAP gene itself. Thus if an individual at risk for FAP inherits from an affected parent different marker genes to those inherited by their affected siblings, their risk of having inherited the FAP gene is very small. However, a residual risk remains, because the marker gene may not have been coinherited with the FAP gene in that particular instance. The chance of this occurring decreases the closer the marker gene is to the FAP gene. Table 1. Risk of FAP to offspring of an affected person. % risk Age (years) 15 20 25 30

Without prior investigation

With normal sigmoidoscopy

With low linkage risk

Without CHRPE

50 50 50 50

30 20

2.2 1.3 0.6 0.3

0.6 0.3 0.2

10 5

0.1

Table 1 shows how risk estimates can be altered by the use of CHRPE and linkage analysis. These risk estimates are obtained using markers identifying loci linked to FAP with a recombination fraction of 0.05, and by making the assumption that CHRPE is positive in 80% of patients with FAP and in 0% of normals. In practice the linkage information is often more accurate than this. This technique is exemplified by the study of Dunlop et al (1991), who applied linked DNA markers to 41 asymptomatic at-risk relatives of patients with FAP. Of the 15 individuals shown to have FAP in this study, four had already been discharged from follow-up on the basis of negative colonic screening in the third and fourth decades of life; one of these four individuals was found to have carcinoma in the resected colon. This form of gene tracking cannot be done in families where there is only one affected individual. In these families DNA analysis to detect a specific mutation in the FAP gene will soon become feasible; other members of that family can then be tested for the specific mutation detected. It will be necessary to identify the mutation in each family before the at-risk relatives

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can be screened because there are likely to be many different alterations in the FAP gene which can cause the same condition. Prenatal screening

Prenatal tests are available in informative familial cases using similar linkage analysis. The acceptability of such testing in FAP is a very personal question, and the decision as to whether to opt for such testing should be one made by the family. Counselling Those who counsel patients and their families must be aware of the different paths FAP can take. They must be able to provide information as to the likely investigations required and the courses of treatment available. Counsellors include all those who deal with patients with FAP. Registry staff are, however, usually more accessible during office hours, and thus may be the first to encounter patient enquiries. A sympathetic approach to the patient and his or her family is paramount. Many patients are keen to learn what advances have been made in the understanding and treatment of FAP, so it is mandatory that counsellors keep up to date with developments. The LCPG plays a valuable role in this by bringing together workers from many disciplines. THE PATIENT Having made the diagnosis of FAP, other management issues include how to eliminate the risk of large bowel cancer (while achieving minimal morbidity) and what to do about the extracolonic manifestations of FAP. The latter include tumours of the stomach, duodenum, small bowel, liver, pancreas, bile ducts, thyroid, brain and bone, as well as desmoid tumours. The large bowel Prophylactic removal of this target organ is generally recommended by or during the third decade of life because of the inevitable development of cancer in one or more of the hundreds of polyps which are characteristically present. The arbitrary number of 100 polyps on which the diagnosis was once based has largely been abandoned-if a patient has 99 adenomatous polyps he or she still has FAP! How much large bowel to remove, and how to restore intestinal continuity are subjects of much debate. The options are proctocolectomy and Brooke ileostomy, colectomy and ileorectal anastomosis, or restorative proctocolectomy with an ileoanal anastomosis, usually with a temporary covering ileostomy (Jagelman, 1991). There is little dispute as to treatment in those patients who have a low rectal cancer; total proctocolectomy and ileostomy is the operation of choice.

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Reports of cancer of the ileostomy developing many years after this operation has been performed indicate that these patients must also undergo lifelong follow-up (Gadacz et al, 1990). Total proctocolectomy and ileostomy is otherwise rarely recommended today. The remaining patients are eligible for the two other procedures outlined above. At St Mark’s Hospital, London, colectomy and i!eorectal anastomosis is the first option for most patients with FAP, with restorative proctocolectomy being reserved mainly for those with plentiful rectal polyps. The factors to consider when deciding between a pouch operation and an ileorectal anastomosis are (a) patient compliance with postoperative surveillance of the rectal stump, (b) the risk of cancer developing in the retained rectal stump or in the pouch, (c) the comparative morbidity and function of the two procedures, and (d) the risk for other, perhaps life-threatening, manifestations of FAP. Surveillance and management of the rectal stump A major factor when deciding which operation to perform is the potential compliance of the patient with respect to the need for frequent postoperative examinations of the rectal stump. If the patient is not likely to attend for follow-up, then the pouch procedure is usually recommended. If, as is more commonly the case, the patient is willing and able to comply with an on-going postoperative surveillance programme, then the choice once again is either colectomy with an ileorectal anastomosis or with construction of a pouch. At St Mark’s Hospital, postoperative examinations of the rectal stump are performed at least every 6 months (Thomson, 1990). Ideally the rectal stump should be inspected with a flexible video-endoscope after administration of a mini-enema. The flexible instrument provides a view nonpareilfar better than that obtained with the rigid sigmoidoscope. This method of examination allows the appearance of the rectal stump to be recorded for objective comparison with its appearance at subsequent examinations. Those with dense rectal polyps preoperatively, but without cancer, may be left with a rectal stump, in the hope that the rectal polyps will undergo regression, as has been described (Feinberg et al, 1988; Nicholls et al, 1988). This phenomenon may be explained by the reduction in mucosal cell proliferation that has been observed in patients who have undergone colectomy for FAP (Farmer et al, 1991) and also in patients undergoing the same operation for ulcerative colitis (Tonelli et al, 1991). If, on the other hand, rectal polyps do not regress, but increase in size, or show (on biopsy) severe dysplasia or villous architecture, then intervention is indicated. Options for management in these circumstances include electrocoagulation by diathermy, cryotherapy and neodymium-yttriumaluminium-garnet (Nd-YAG) laser fulguration (Herrera et al, 1990). Drugs have also been used successfully to treat rectal polyps; recent reports describe the use of sulindac, 5fluorouracil and calcium. Waddell et al (1989) observed that almost all rectal polyps disappeared over the course of 6 to 12

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months in seven patients given oral sulindac. All but two of these patients had undergone colectomy and ileorectal anastomosis at least 7 years earlier, so that the phenomenon of regression of rectal polyps after colectomy was an unlikely explanation for these findings. Itoh et al (1991) reported that intraluminal chemotherapy using 5-fluorouracil was effective in controlling rectal polyps in four patients with FAP, all of whom had undergone colectomy long before treatment. Calcium has been used because it reduces colonic cell hyperproliferation (Lipkin and Newmark, 1985). However, this effect is lost as cells move down the adenoma-carcinoma sequence, so that growth inhibition observed in tubular adenomas is not seen in villous adenomas (Friedman et al, 1989). A dissenting study (Stern et al, 1990a) found that long-term calcium supplementation failed to suppress cell proliferation in the rectal stump. Several randomized human clinical trials now in progress will provide more information about the effect of calcium on intestinal polyp growth (Lipkin et al, 1991). The risk of cancer in the remaining mucosa

In patients managed at St Mark’s Hospital, the cumulative risk of the development of a rectal stump cancer is about 10% at 2.5 years, with a cumulative mortality of about 5% (Thomson, 1990). The Mayo Clinic have reported a higher risk for rectal cancer in the stump in a much older group of patients (Bess et al, 1980); 32% of 143 patients developed cancer in this site over a mean follow-up period of 19.5 years. Whatever the true risk, it is all but eliminated in those undergoing the pouch procedure, so long as this is accompanied by an anal mucosectomy. The importance of removing this at-risk mucosais emphasized by the results of histopathological analysis of the anorectal strippings taken from 14 patients with familial adenomatous polyposis; precancerous dysplasia was present in specimens from 12 of these patients (Tsunoda et al, 1990). However, residual islets of rectal mucosa may be left at the anorectal muscular cuff despite apparently complete mucosectomy (O’Connell et al, 1987). Regeneration of rectal mucosa has been observed in patients who have had an anorectal mucosectomy but in whom a 1 cm strip of mucosa was left intact above the dentate line (Wolfstein et al, 1982). Moreover, adenomas have been found in pelvic reservoirs (Shepherd, 1990)) and cancer has been observed in an ileoanal reservoir constructed for ulcerative colitis (Stern et al, 1990b). The long-term malignant potential of an ileal pouch for FAP remains unknown, so that surveillance of the pouch by pouchoscopy and biopsy is mandatory (Shepherd, 1990). Comparative

morbidity

and function

The pouch procedure is more technically demanding than colectomy and ileorectal anastomosis. Nevertheless, Everett and Forty (1989) reported excellent results with minimal morbidity in 10 patients with FAP who underwent pelvic ileal reservoir construction. Similarly, Beart and Welling (1990) reviewed 55 patients who had the same procedure at the Mayo Clinic between 1981 and 1986. There were no episodes of postoperative sepsis, but

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small bowel obstruction developed in eight patients (15%) and three of these patients required reoperation. One patient became impotent, and one patient developed pouchitis. A much more significant complication rate after ileal pouch surgery (45% of 75 patients, including one death) was reported by a Canadian group (Skarsgard et al, 1989). Madden et al (1991) compared the complications sustained by 37 patients who had had the pouch procedure with 62 patients who had had an ileorectal anastomosis at St Mark’s Hospital between 1977 and 1989. While there was little difference in bowel function between the two operations, the complication rate was significantly higher in the pouch patients, as was the reoperation rate. This higher morbidity may also have an impact on the patient’s relatives, who might be reluctant to attend for screening should they perceive these complications as a likely consequence of their own treatment. In this context it is interesting to note the report from the Northern Region Registry, based in Newcastle, England, which stated that the main reasons for the refusal of at-risk patients to undergo screening were fear of a stoma and fear of impotence (Chapman et al, 1991). One way to prevent many of the complications recorded is to avoid constructing a defunctioning ileostomy, thereby making it a one-stage procedure. Although this was done safely in 13 of the patients (Everett and Forty, 1989; Beart and Welling, 1990), the absence of a stoma may prejudice recovery should the anastomosis leak. Criteria that permit the surgeon to avoid construction of a covering stoma are adequate experience of pouch formation and the absence of technical problems, such as tension at the anastomosis (Jarvinen and Luukkonen, 1991). Taking these studies into consideration, it is possible to see why consensus

Figure

3. Fundic

gland

polyps

in the stomach.

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is lacking as to which operation to employ. Colectomy and ileorectal anastomosis remains the operation of choice at St Mark’s Hospital (Madden et al, 1991) and at the Cleveland Clinic (Jagelman, 1991), but the pouch procedure is now the most frequently performed operation for FAP at the Mayo Clinic (Beart and Welling, 1990). We would like to emphasize that these issues should be discussed with the patient before a final decision is reached. How best to deal with the colon must also take into account the fact that FAP is not a disease wholly confined to the large bowel: all germ layers are involved (Parks, 1990). The stomach

Gastric polyps are found in just over 50% of FAP patients at St Mark’s Hospital, and are of two distinct types (Spigelman et al, 1989; Domizio et al, 1990). Polyps of the first, and more numerous, variety are found predominantly in the body and fundus of the stomach, and were present in 52 of 102 patients studied. They are usually soft, not pedunculated, small (< 5 mm) and are of the same hue as the surrounding mucosa (Figure 3). They typically exhibit mucosal glandular dilatation (Figure 4). These polyps are not premalignant, and are in any case too numerous to remove endoscopically. We take representative biopsies of these polyps at screening endoscopy. Gastric polyps of the second variety were found in only seven of the 102 patients. They were adenomas, and were located mainly in the distal stomach. Significant duodenogastric reflux of bile was demonstrated in these patients (Spigelman et al, 1991a), suggesting that administration of agents

Figure

4. Typical

cystic

gland

dilatation

in a fundic

gland polyp

(haematoxylin

and eosin,

X 25).

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that combat reflux (such as cisapride) might be useful. Once again, we do not remove these polyps unless biopsies taken at surveillance endoscopy indicate that intervention is necessary. The duodenum Duodenal cancer kills approximately 5% of these patients. Most of these tumours occur in the periampullary region (Jagelman et al, 1988). Virtually all FAP patients have duodenal adenomas (Figure 5), although only 10% have severe or stage IV duodenal polyposis (Spigelman et al, 1989).

Figure 5. Periampullary duodenal (Olympus JFVlO, Keymed).

polyp seen through

a side-viewing

video-endoscope

Surveillance using a side-viewing endoscope (to visualize the periampullary area where many adenomas reside-Figure 6) is recommended to document the natural history of these lesions and to facilitate assessment of intervention. Multiple biopsies are taken, and screening intervals vary from every 6 months for presumed high-risk individuals to 3 years for those with early (stage I) duodenal disease. Intervention is individualized; our own policy is one of non-intervention unless polyp induration, rapid polyp growth or severe dysplasia is found. Some patients have, however, been randomized to a long-term study of chemoprevention with sulindac. Endoscopic options for treatment include electrocoagulation (which may scar and narrow the ampulla of Vater), snaring (which is difficult as many polyps are sessile) and conventional Nd-YAG laser therapy (which carries a risk of perforation-van Stolk et al, 1987). Photodynamic laser therapy, on the other hand, may be a safer mode of treatment of superficial duodenal

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Figure 6. Distribution of foregut polyps in 102 FAP patients: 0 = one patient with fundic gland polyp(s); l = one patient with adenoma(s). From Spigelman et al (1989) with permission.

tumours. In this technique a sensitizing agent which concentrates in tumour tissue is administered to the patient. Upon exposure to light the agent produces a phototoxic reaction which destroys turnour cells (Ash and Brown, 1989; Daniel1 and Hill, 1991). Surgical options are limited. Excision of large polyps via a duodenotomy is of temporary benefit only, as the polyps regrow. Pancreaticoduodenectomy is only recommended where there is a strong likelihood of duodenal cancer. The jejunum

and ileum

Although adenomatous polyps and cancers occur in the small bowel, they have been reported with much less frequency than duodenal polyps and cancers (Bulow, 1987; Jagelman et al, 1988; Jagelman, 1990). This distribution of tumours (more frequent in the second part of the duodenum, which represents only 4% of the surface area of the small bowel, than in the jejunum and ileum) also occurs in patients without FAP (Ross et al, 1991) and suggests that bile plays an important role in tumour development. Routine small bowel surveillance is not recommended, but examination either by enteroscopy (Lewis et al, 1991) or by small bowel X-ray is indicated if the patient complains of gastrointestinal symptoms (Jagelman, 1990). The gallbladder,

bile ducts, liver and pancreas

Anecdotal reports of adenomatous polyps and cancers in FAP patients occurring in the gallbladder (Bombi et al, 1984), bile ducts (Jarvinen et al

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Fig;ure 7. Gallbladder,

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bile duct, liver and pancreatic cancers in a single patient with E AP.

Figure 8. Cancer of the gallbladder (haematoxylin

and eosin, x 25).

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1983) and liver (Laferla et al, 1988), and in all of these sites and in the pancreas (Spigelman et al, 1991b; Figures 7 and 8) further suggest that mucosa exposed to bile is at risk. Screening of these areas is not currently practised in the asymptomatic patient in most centres. However, regular ultrasound examinations might allow some of these lesions to be detected while they are still able to be removed. The risk for hepatoblastoma, a rare childhood cancer, is excessive in families with FAP. This association has led to the establishment of a Hepatoblastoma-Adenomatous Polyposis Registry to assist further study of this association (Garber et al, 1988). The thyroid gland

The risk for thyroid cancer (papillary) is estimated to be 100-160 times that of the non-FAP population (Plail et al, 1987; Bulow et al, 1988). Women under the age of 35 years appear to bear the highest risk. The brain

There are over 60 reported cases of brain tumours in patients with FAP. Medulloblastomas were the most frequently encountered tumours in the Cleveland Clinic series (Kropilak et al, 1989), but glioblastomas and astrocytomas are also seen. They occur most commonly at an early age (less than 20 years). Screening of at-risk FAP children is not common practice.

Figure

9. Osteomas

of the forehead.

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Skin abnormalities

Epidermoid cysts occur at a younger age and with increased frequency in patients with FAP than in the normal population. In FAP patients they are located on the limbs, face and scalp rather than on the back (Leppard, 1974, 1975). Treatment is as for the non-FAP population. Bone and dental abnormalities

Osteomas occur mainly in the skull (Figure 9). Dental abnormalities include supernumerary teeth and odontomas (Carl and Herrera, 1987; Parks, 1990). Desmoid tumours

Desmoid tumours may be intra- or extra-abdominal in location (Figure 10). They consist mainly of fibrous tissue, and contain multiple dilated blood vessels which are prone to bleed excessively when cut (Figure 11). Desmoids are locally infiltrating tumours; they are benign in that they do not metastasize, but intra-abdominal desmoids may nonetheless cause great morbidity and even death by virtue of their local effects (Figures 12 and 13). The true incidence of desmoid tumours in FAP patients remains unknown, although most would agree with an estimate of 10% (Jones et al, 1986; Klemmer et al, 1987). Extra-abdominal desmoids may be successfully treated by wide excision (Shpitz et al, 1985). Intra-abdominal desmoids, on the other hand, frequently involve the mesenteric vessels by the time they become clinically apparent.

Figure

10. Intra-abdominal

desmoid

tumour.

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This may necessitate removal of sufficient small bowel to render the patient totally dependent on parenteral nutrition. As a consequence of the operative difficulties encountered and of the potential for considerable postoperative morbidity, non-surgical measures have been employed to treat desmoid tumours. Success has been mixed. Agents that have been used include

Figure

11.

Desmoid tumour showing fibrous stroma and dilated vessels.

Figure 12. Computed tomography appearance of a massive intra-abdominal

desmoid tumour.

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Figure 13. Intravenous urogram showing bilateral ureteric obstruction caused by an intraabdominal desmoid tumour.

indomethacin and ascorbate (Waddell and Gerner, 1980), tamoxifen (Waddell et al, 1983; Baba et al, 1991), toremifene (Brooks et al, 1990), sulindac, testolactone, warfarin and vitamin K (Waddell and Kirsch, 1991), and cytotoxic chemotherapy (Church et al, 1991). Radiotherapy achieved marked success in a study of 21 patients with desmoid tumours, but this paper did not record whether the patients treated had FAP (Keus and Bartehnk, 1986). The Cleveland Clinic have reported the failure of radiotherapy in three patients with FAP (Church et al, 1991). At the present time, it would seem that toremifene should be tried first in treating inoperable desmoid tumours. If this fails to elicit a significant response, then sulindac may be added or substituted. SUMMARY

The management of FAP involves treatment of affected individuals and their families. Such an approach is best coordinated by registrars working in

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dedicated registries, in close collaboration with nurses, physicians, surgeons, clinical geneticists and others who become involved in the care of these patients. The large bowel of patients with FAP should be removed (totally or subtotally) by the third decade of life. Screening of other areas at risk is recommended to document the natural history of extracolonic manifestations and to allow study of the effects of intervention. Despite these other, sometimes life-threatening manifestations, a near to normal life span is possible in the majority of patients with FAP. The aims of management of the individual and of the family are to ensure that their quality of life is optimal, that support is provided in times of emotional need, that anxiety is minimized and that relatives are adequately screened and treated. REFERENCES Ash D & Brown SB (1989) Photodynamic therapy-achievements and prospects. British Journal of Cancer 60: 151-152. Baba S, Kurahashi T & Nakamura S (1991) Treatment of desmoid disease. Proceedings of the 4th Biennial Meeting of the Leeds Castle Polyposis Group, Fort Lauderdale, Florida, May 9-11, p 24. Beart RW Jr & Welling DR (1990) Surgical alternatives in the treatment of familial adenomatous polyposis. In Herrera L (ed.) Familial Adenomatous Polyposis, pp 199-208. New York: Alan R Liss. BerkT,CohenZ,McLeodRS&ParkerJA(1988) Congenitalhypertrophyoftheretinalpigment epithelium as a marker for familial adenomatous polyposis. Diseases of the Colon and Rectum

31: 253-257.

Bess MA, Adson MA, Elveback LR & Moertel CG (1980) Rectal cancer following colectomy for polyposis. Archives of Surgery 115: 460-466. Blair NP & Trempe CL (1980) Hypertrophy of the retinal pigment epithelium associated with Gardner’s syndrome. American Journal of Ophthalmology 90: 661-667. Bombi JA, Rives A, Astudillo E, Pera C & Cardesa A (1984) Polyposis coli associated with adenocarcinoma of the gallbladder. Cancer 53: 2561-2563. Brooks MD, Colletta AA & Baum M (1990) The use of triphenylethylene drugs with desmoid tumours. International Journal of Colorectal Disease 5: 53-54. Bulow S (1987) Incidence of associated diseases in familial polyposis coli. Seminars in Surgical Oncology

3: 84-87.

Bulow S (1990) Extracolonic manifestations of familial adenomatous polyposis. In Herrera L (ed.) Familial Adenomatous Polyposis, pp 109-114. New York: Alan R Liss. Bulow S, Holm NV & Mellemgaard A (1988) Papillary thyroid cancer in Danish patients with familial adenomatous polyposis. International Journal of Colorectal Disease 3: 29-31. Burn J, Chapman PD, Delhanty J et al (1991) The UK Northern Region Genetic Register for familial adenomatous polyposis: use of age of onset, CHRPE and DNA markers in risk calculations. Journal of Medical Genetics 28: 289-296. Carl W & Herrera L (1987) Dental and bone abnormalities in patients with familial polyposis coli. Seminars in Surgical Oncology 3: 77-83. Chapman PD, Church W, Burn J & Gunn A (1989) Congenital hypertrophy of retinal pigment e$t,helium: a sign of familial adenomatous polyposis. British Medical Journal 298: 353Chapman PD, Burn J & Gunn A (1991) Patient compliance in screening for colorectal polyps in FAP families, within the Northern Region Polyposis Registry. Proceedings of the 4th Biennial Meeting of the Leeds Castle Polyposis Group, Fort Lauderdale, Florida, May 9-11, p 22. Church JM, Tsukada K, Jagelman DG, Fazio VW & McGannon EA (1991) The treatment of desmoid tumours in patients with familial adenomatous polyposis. Proceedings of the 4th Biennial Meeting of the Leeds Castle Polyposis Group, Fort Lauderdale, Florida, May 9-11, p 25.

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Daniel1 MD & Hill JS (1991) A history of photodynamic therapy. Australian Journal

of Surgery

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ET AL

and New Zealand

61: 340-348.

Domizio P, Talbot IC, Spigelman AD, Williams CB & Phillips RKS (1990) Upper gastrointestinal pathology in familial adenomatous polyposis: results from a prospective study of 102 patients. Journal of Clinical Pathology 43: 738-743. Dunlop MG, Wyllie AH, Stell CM, Piris J & Evans HJ (1991) Linked DNA markers for presymptomatic diagnosis of familial adenomatous polyposis. Lancet 337: 313-316. Everett WG & Forty J (1989) The functional result of pelvic ileal reservoir in 10 patients with familial adenomatous polyposis. Annals of the Royal College of Surgeons of England 71: 28-30. Farmer KCR & Phillips RKS (1991) Reduced mucosal proliferation after ileorectal anastomosis (IRA) in familial adenomatous polyposis (FAP) may explain rectal polyp regression. Gut 32: A1203. Feinberg SM, Jagelman DG & Sarre RG (1988) Spontaneous resolution of rectal polyps in patients with familial adenomatous polyposis following abdominal colectomy and ileorectal anastomosis. Diseases of the Colon and Rectum 31: 169-175. Friedman E, Lipkin M, Winawer S, Buset M & Newmark H (1989) Heterogeneity in the response of familial polyposis epithelial cells and adenomas to increasing levels of calcium in vitro. Cancer 63: 2486-2491. Gadacz TR, McFadden DW, Gabrielson EW, Ullah A & Berman JJ (1990) Adenocarcinoma of the ileostomy: The latent risk of cancer after colectomy for ulcerative colitis and familial polyposis. Surgery 107: 698-703. Garber JE, Li FP, Kingston JE et al (1988) Hepatoblastoma and familial adenomatous polyposis. Journal of the National Cancer ksti&te 80: 1626-1628. Groden J. Thliveris A. Samowitz W et al (1991) Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66: 589-600. Herrera L, Petrelli NJ & Farah G (1990) Nd-YAG laser treatment of gastrointestinal polyps in patients with familial adenomatous polyposis. In Herrera L (ed.) Familial Adenomatous Polyposis, pp 109-114. New York: Alan R Liss. Houlston R, Slack J & Murday V (1990) Risk estimates for screening adenomatous polyposis coli. Lancet i: 484. Itoh H, Ohsato K & Iida M (1991) Intrarectal chemotherapy for rectal polyposis in familial adenomatous polyposis. Proceedings of the 4th Biennial Meeting of the Leeds Castle Polyposis Group, Fort Lauderdale, Florida, May 9-11, p 45. Jagelman DG (1990) Evaluation of the gastrointestinal tract in patients with familial adenomatous polyposis. In Herrera L (ed.) Familial Adenomatous Polyposis, pp 97-100. New York: Alan R Liss. Jagelman DG (1991) Choice of operation in familial adenomatous polyposis. World Journal of Surgery

15: 47-49.

Jagelman DG, DeCosse JJ & Bussey HJR (1988) Upper gastrointestinal cancer in familial adenomatous polyposis. Lancet i: 1149-1151. Jarvinen HJ & Luukkonen P (1991) Comparison of restorative proctocolectomy with and without covering ileostomy in ulcerative colitis. British Journal of Surgery 78: 199-201. Jarvinen HJ, Nyberg M & Peltokallio P (1983) Biliary involvement in familial adenomatosis coli. Diseases of the Colon and Rectum 26: 525-528. Jones IT, Fazio VW, Weakley FL et al (1986) Desmoid tumours in familial polyposis coli. Annals

of Surgery

204: 94-97.

Joslyn G, Carlson M & Thliveris A (1991) Identification of deletion mutations and three new genes at the familial polyposis locus. Cell 66: 601-613. Keus R & Bartelink H (1986) The role of radiotherapy in the treatment of desmoid tumours. Radiotherapy and Oncology 7: l-5. Kinzler KW, Nilbert MC, Vogelstein B et al (1991a) Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science 251: 1366-1370. Kinzler KW, Nilbert MC, Su LK et al (1991b) Identification of FAP locus genes from chromosome 5q21. Science 253: 661-665. Klemmer S, Pascoe L & DeCosse J (1987) Occurrence of desmoids in patients with familial adenomatous polyposis of the colon. American Journal of Medical Genetics 28: 385-392. Kropilak M, Jagelman DG, Fazio VW, Lavery IL & McGannon E (1989) Brain tumours in familial adenomatous polyposis. Diseases of the Colon and Rectum 32: 778782.

MANAGEMENT

OF FAMILIAL

ADENOMATOUS

POLYPOSIS

93

Laferla G, Kaye SB & Crean GP (1988) Hepatocellular and gastric carcinoma associated with familial polyposis coli. Journal of Surgical Oncology 38: 19-21. LCPG (1991) Proceedings of the 4th Biennial Meeting of the Leeds Castle Polyposis Group, Ford Lauderdale, Florida, May 9-11. Leppard BJ (1974) Epidermoid cysts and polyposis coli. Proceedings of the Royal Society of Medicine 67: 10361037. Leppard BJ (1975) -Epidermoid cysts, polyposis coli and Gardner’s syndrome. British Journal of Surgery

62: 387-393.

Lewis BS, Kornbluth A & Waye JD (1991) Small bowel tumours: yield of enteroscopy. Gut 32: 763-765. Lipkin M & Newmark H (1985) Effect of added dietary calcium on colonic epithelial-cell proliferation in subjects at high risk for familial colonic cancer. New England Journal of Medicine 313: 1381-1384. Lipkin M, Newmark H, Boone CW & Kellof GJ (1991) Calcium, vitamin D, and colon cancer. Cancer

Research

51: 3069-3070.

Llopis MD & Menezo JL (1987) Congenital hypertrophy of the retinal pigment epithelium and familial polyposis of the colon. American Journal of Ophthalmology 103: 235-236. Madden MV, Neale KF, Nicholls RJ et al (1991) Comparison of morbidity and function after colectomy and ileorectal anastomosis or restorative proctocolectomy for familial adenomatous polyposis. British Journal of Surgery 78: 789-792. Murday V & Slack J (1989) Inherited disorders associated with colorectal cancer. Cancer Surveys

8: 139-157.

Nicholls RJ, Springall RG & Gallagher P (1988) Regression of rectal adenomas after colectomy and ileorectal anastomosis for familial adenomatous polyposis. British Medical Journal 296: 1707-1708. Nishisho I, Nakamura Y, Miyoshi Y et al (1991) Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253: 665-669. Northover JM & Murday V (1989) Familial colorectal cancer and familial adenomatous polyposis. Baillidre’s Clinical Gastroenterology 3: 593-613. O’Connell PR. Pemberton JH. Weiland LH et al (1987) Does rectal mucosa regenerate after ileoanal anastomosis? Diseases of the Colon and Rectum 30: 1-5. Parks TG (1990) Extracolonic manifestations associated with familial adenomatous polyposis. Annals of the Royal College of Surgeons of England 72: 181-184. Plail RO, Bussey HJR, Glazer G & Thomson JPS (1987) Adenomatous polyposis: an association with carcinoma of the thyroid. British Journal of Surgery 74: 377-380. Polkinghorne PJ, Ritchie S, Neale K, Schoeppner G, Thomson JPS &Jay B (1990) Pigmented lesions of the retinal pigment epithelium and familial adenomatous polyposis. Eye 4: 216-221. Rhodes M, Chapman PD, Burn J & Gunn A (1991) Role of a regional register for familial adenomatous polyposis. British Journal of Surgery 78: 451-452. Romania A, Zakov ZN, McGannon E, Schroeder T, Heyen F & Jagelman DG (1989) Congenital hypertrophy of the retinal pigment epithelium in familial adenomatous polyposis. Ophthalmology 96: 879-884. Ross RK, Hartnett NM, Bernstein L & Henderson BE (1991) Epidemiology of adenocarcinomas of the small intestine: is bile a small bowel carcinogen? British Journal of Cancer 63: 143-145. Shepherd NA (1990) The pelvic reservoir: apocalypse later? British Medical Journal 301: 886-887. Shpitz B, Siegal A, Witz M, Kaufman Z & Dinbar A (1985) Desmoid tumour-review and follow upof ten cases. Journal of Surgical Oncology 28:‘67-71. Skarsaard ED. Atkinson KG. Bell GA et al (1989) Function and aualitv of life results after ileal p&ch surgery for chronic ulcerative colitis and familial pojypo&. American Journal of Surgery

157: 467-471.

Spigelman AD, Williams CB, Talbot IC, Domizio P & Phillips RKS (1989) Upper gastrointestinal cancer in patients with familial adenomatous polyposis. Lancet ii: 783-785. Spigelman AD, Granowska M & Phillips RKS (1991a) Duodeno-gastric reflux and gastric adenomas: a scintigraphic study in patients with familial adenomatous polyposis. Journal of the Royal

Society

of Medicine

84: 476478.

Spigelman AD, Farmer KCR, James M, Richman PI & Phillips RKS (1991b) Tumours of the

94

A.

D.

SPIGELMAN

ET AL

liver, bile ducts, pancreas and duodenum in a single patient with familial adenomatous polyposis. British Journal of Surgery 78: 979980. Stern H. Gregoire RC, Kashtan H, Stadler J & Bruce RW (1990a) Long-term effects of dietary calcium on risk markers for colon cancer in patients with familial polyposis. Surgery 108: 528-533. Stern H, Walfisch S, Mullen B, McLeod R & Cohen Z (1990b) Cancer in an ileoanal reservoir: a new late complication? Gut 31: 473-475. Thomson JPS (1990) Familial adenomatous polyposis: the large bowel. Annals of the Royal College of Surgeons of England 72: 177-180. Tonelli F, Bianchini F, Lodovici M et al (1991) Mucosal cell proliferation of the rectal stump in ulcerative colitis patients after ileorectal anastomosis. Diseases of the Colon and Rectum 34: 385-390. Traboulsi EI, Krush AJ, Gardner EJ et al (1987) Prevalence and importance of pigmented ocular lesions in Gardner’s syndrome. New England Journal of Medicine 316: 661-667. Tsunoda A, Talbot IC & Nicholls RJ (1990) Incidence of dysplasia in the anorectal mucosa in patients having restorative colectomy. British Journal of Surgery 77: 506308. van Stolk R, Sivak MV, Petrini JL et al (1987) Endoscopic management of upper gastrointestinal polyps and periampullary lesions in familial adenomatous polyposis and Gardner’s syndrome. Endoscopy 19: 19-22. Vasen HFA, Griffioen G, Offerhaus JA et al (1990) The value of screening and central registration of families with familial adenomatous polyposis. Diseases of the Colon and Rectum

33: 227-230.

Waddell WR & Gerner RE (1980) Indomethacin Journal

of Surgical

Oncology

and ascorbate inhibit desmoid tumours.

15: 85.

Waddell WR & Kirsch WM (1991) Testolactone, sulindac, warfarin, and vitamin Ki for unresectable desmoid tumours. American Journal of Surgery 161: 416-421. Waddell WR, Gerner RE & Reich MP (1983) Nonsteroid inflammatory drugs and tamoxifen for desmoid tumours and carcinoma of the stomach. Journal of Surgical Oncology 22: 197-211. Waddell WR, Ganser GF, Cerise EJ & Loughry RW (1989) Sulindac for polyposis of the colon. American

Journal

of Surgery

157: 175-179.

Wolfstein IH, Bat L & Neumann G (1982) Regeneration of rectal mucosa and recurrent polyposis coli after total colectomy and ileoanal anastomosis. Archives of Surgery 117: 1241-1242.