Prognosis of Symptomatic Duodenal Adenomas in Familial Adenomatous Polyposis P. Sue

Beckwith, MD; Jon A.

van

frequent association between familial adenomatous polyposis and duodenal tumors is increasingly recognized, yet many patients do not benefit from adequate diagnosis and follow-up of upper gastrointestinal polyps. A retrospective review of 14 patients with duodenal tumors associated with familial adenomatous polyposis was undertaken to assess the impact of early diagnosis by screening asymptomatic patients. Six of eight patients presenting with symptoms suggesting duodenal disease had invasive cancer. Four of these six patients died after surviving a mean of 13 months after diagnosis. In contrast, none of the six patients diagnosed after screening with upper gastrointestinal endoscopy has had invasive carcinoma. Early diagnosis and long-term surveillance of asymptomatic patients with familial adenomatous polyposis affords the opportunity to diagnose and treat duodenal tumors at an early stage, thereby, avoiding the dismal prognosis once invasive cancer has developed. (Arch Surg. 1991;126:825-828) \s=b\ The

Heerden, MD; Roger R. Dozois,

MD

screening or for symptoms), age at diagnosis of duodenal tumors, pathologic diagnosis, and treatment of duodenal lesions. The

eventual clinical outcome as well as the cause of death were de¬ termined. The population studied included nine men and five women. Ten of the 14 patients had other extraintestinal manifestations (eight epidermoid cysts, five benign fibrous tissue tumors, four osteomata, one supernumerary teeth, one thyroid cancer, and one congenital hypertrophie retinal pigmentary epithelium). In four patients, the duodenum was the only apparent extracolonic site of involvement.

RESULTS The average age at the time of diagnosis of FAP was 27 years (range, 6 to 39 years), while that of patients with duodenal involvement was 4.6 years (range, 26 to 72 years). Thus, the average interval between the diagnosis in the two locations was 19 years (range, 0 to 39 years). The initial treatment of colonie polyposis included colectomy with either ileorectostomy (n 8) or ileosigmoidostomy (n 2), abdominal perineal resection for a sigmoid cancer prior to colectomy 27 years later (n 1), and coloproctectomy with ileoanal anastomosis (n 3). Two of the 10 patients whose rectum was retained eventually required proctectomy. =

I

he association between familial adenomatous polypo¬ sis (FAP) and duodenal adenomas is being increas¬ ingly recognized. However, despite this increased aware¬ ness, few patients are diagnosed at an early stage of their duodenal disease. In addition, once the diagnosis of duo¬ denal adenomas has been made, an appropriate follow-up and treatment regimen has yet to be determined. We undertook this retrospective review of 14 patients with duodenal tumors associated with FAP to help clarify the natural history of these duodenal adenomas. It is our belief that this knowledge may aid in determining the ap¬ propriate follow-up of such patients, as well as serve as a basis for comparison to assess the impact of early di¬ agnosis and treatment on eventual outcome. PATIENTS AND METHODS Between 1976 and 1989,14 patients with a diagnosis of FAP and neoplasms of the duodenum were examined at the Mayo Clinic, Rochester, Minn. Data obtained from a review of their files in¬ cluded age at diagnosis of colon polyps, method of therapy, rea¬ sons for evaluating the upper gastrointestinal tract (whether for

Accepted for publication March 9,1991. From the Department of Surgery, Mayo Clinic, Rochester, Minn. Read before the 98th Annual Meeting of the Western Surgical Association, Phoenix, Ariz, November 13, 1990. Reprint requests to Department of Surgery, Mayo Clinic, 200 First St

SW, Rochester,

MN 55905 (Dr

van

Heerden).

=

=

=

Duodenal

Abnormality

patients presented with symptoms of duodenal disease, and in another, the diagnosis was made at au¬ topsy. The average age of these seven patients was 55 years (range, 25 to 77 years). Presenting complaints in¬ cluded epigastric pain and burning, fatigue, weight loss, melena, pancreatitis, and anemia. Six of these eight pa¬ Seven

tients had invasive cancer,

one had carcinoma in situ, and another had focal cellular atypia in an adenoma. Another patient, believed to have posttraumatic pancreatitis, un¬ derwent an esophagogastroduodenoscopy (EGD) that demonstrated benign adenomas not considered to be the origin of his pancreatitis. An additional five patients stud¬ ied for evidence of duodenal tumors were asymptomatic. Their average age was 32 years (range, 26 to 41 years). This was done at an average interval of 11 years (range, 0 to 26 years) after diagnosis of FAP. Although none of these pa¬ tients had invasive cancer, three had atypia and one had carcinoma in situ. Among the eight patients without invasive carcinoma, five had villous adenomas, one had a tubular adenoma, and two had unspecified types of adenomas.

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Table 2.—Follow-up of Patients With Treated Duodenal Tumors

Table 1.—Treatment of Duodenal Tumors No. of Patients

Procedure

No. of Patients

Symptomatic Asymptomatic

Status at Last

Follow-up

Endoscopie treatment

0

4

Local excision Radical

2

1

Alive,

4

1

Postoperative death

1

0

Death due to duodenal

pancreaticoduodenectomy bypass

Palliative

no

Symptomatic Asymptomatic

evidence of invasive 1

cancer

Death due to rectal

The diagnosis of duodenal tumors was most commonly made with EGD. In two patients, results of barium duodenography were normal, but EGD demonstrated polyps with atypia or frank carcinoma. Treatment Treatment of duodenal tumors in the symptomatic pa¬ tients included radical pancreaticoduodenectomy in three patients and palliative bypass in one (Table 1). Average survival after diagnosis in these four patients was 13 months (Table 2). Atypia with no residual cancer was found in another patient who remained alive and well 8 years after pancreaticoduodenectomy. Two patients un¬ derwent transduodenal wedge excision of duodenal le¬ sions. One of these patients died in the immediate post¬ operative period of pancreatic abscess and another died 8.5 years later of metastatic rectal cancer. In all of these patients, the mean interval from diagnosis of FAP to death was 26 years (range, 10 to 40 years). As noted, one patient is still alive 37 years after diagnosis, having undergone pancreaticoduodenectomy 8 years previously. None of the six patients diagnosed after screening EGD has had invasive cancer, although one underwent pan¬ creaticoduodenectomy for carcinoma in situ. This patient is alive and well 48 months after operation. Another pa¬ tient had a transduodenal excision of a villoglandular ad¬ enoma at the time of colectomy. Four additional patients are being followed up after biopsies revealed atypia or dysplasia. The five patients available for follow-up are alive and without evidence of carcinoma 20 years (range, 3 to 31 years) after diagnosis of FAP.

COMMENT Duodenal adenomas associated with FAP were once thought to occur only in that subset of patients with FAP with the constellation of extracolonic manifestations lenown as Gardner's syndrome. More thorough investi¬ gation with EGD, however, has confirmed the presence of adenomatous changes in the duodenum in 48% to 100% of patients with FAP. In fact, FAP is now recognized as a genetic defect that predisposes the entire gastrointestinal tract to the development of polyps,2,5"7 the duodenum be¬ ing the most common site of extracolonic involvement by either benign adenomas or invasive cancer.1,8"10 The most accurate means of identifying duodenal ad¬ enomas is screening EGD. Several studies have docu¬ mented that duodenography fails to recognize 14% to 30% In addition, biopsy of even of duodenal adenomas. normal-appearing periampullary mucosa may reveal ad¬ enomatous changes.2,3,9 Although the second portion of the duodenum is the most common site of involvement, hypotonie duodenography may serve as a valuable com¬ plementary study to evaluate the distal duodenum.1,11,13

2 cancer

cancer

4 1

The importance of identifying duodenal adenomas lies in their premalignant behavior. Several studies have con¬ cluded that villous tumors of the duodenum have approx¬ imately the same malignant potential as similar adenomas at other sites.14 Repeated EGD has demonstrated that pol¬ ,15 yps increase in both size and in number over time.1,6, Further support for the polyp-cancer sequence lies in the

knowledge that benign adenomas tend to occur at an ear¬ lier age than carcinoma.9 The average age of our patients without evidence of invasive malignancy was 37 years, compared with 60 years in those with carcinoma. More¬ over, the incidence

of adenomas and

cancer

of the duo¬

higher in patients with FAP than in the general population.3,12,16 Although in the past, only 2% to 3% of patients with FAP may have developed duodenal cancer, the incidence may be expected to increase since earlier treatment of colonie polyps has led to an increased denum is much

life expectancy in these patients.2,5,7 Routine screening of patients with FAP not only affords the opportunity for early diagnosis of benign adenomas, but periodic surveillance should also allow cancer to be diagnosed at an earlier stage, thus improving therapeutic results. Kerremans et al1 witnessed a survival time of 57 months after resection of node-negative duodenal can¬ cer. This dropped to 6 months in those with lymph node involvement with metastatic disease. Also, destruction of benign adenomas diminishes the risk of cancer. Our results confirm that screening of asymptomatic pa¬ tients often leads to a diagnosis of benign adenoma or early malignant change but that the onset of symptoms is an ominous sign. Indeed, despite aggressive therapy, once symptoms had developed, the average survival time was a paltry 13 months. The small number of patients and the lack of prolonged follow-up in the screened population make it impossible to exclude the contribution of lead-time bias, accounting for some of the difference in survival times between our two groups, and further prospective studies will be required. We cannot establish the exact in¬ cidence of duodenal lesions in our patient population be¬ cause the upper gut of patients with FAP was not eval¬ uated prospectively and routinely. However, literature clearly shows that 50% to 90% of patients with FAP in whom this was done were found to have lesions. We there¬ fore recommend a routine initial EGD when the diagnosis of FAP is secured. Family members should be screened for colonie disease and those found to have it should also have their upper gut evaluated with EGD. Once duodenal adenomas have been identified, the ap¬ propriate follow-up and treatment has yet to be estab¬ lished. The 27% to 34% malignancy rate in villous tumors

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of the duodenum is significant.17,18 However, the prev¬ alence of specific types of adenomas identified in the duo¬ denum is difficult to ascertain from the literature.10 This further complicates the prediction of expected rates of can¬ cer in FAP. Villous tumors were reported in five of our eight patients without invasive cancer. Unlike prophylac¬ tic colectomy for benign polyps, subjecting all patients with duodenal adenomas to radical pancreaticoduodenec¬ tomy would obviously lead to unacceptable rates of mor¬ bidity and mortality. Most experts currently recommend screening EGD at the time of diagnosis of FAP. The importance of this sug¬ gested screening is emphasized in the studies by Kurtz et al,19 Sarre et al, and Jarvinen et al,21 who found gas¬ troduodenal polyps in 44%, 46%, and 90% of their respec¬ tive patients with FAP screened with routine EGD. If sur¬ gical treatment of duodenal polyps is indicated, it can be accomplished at the time of colectomy. If no polyps are found, EGD is repeated at 3- to 5-year intervals. The rec¬ ommendation to perform EGD every 3 to 5 years is some¬ what arbitrary but was arrived at when several world au¬ thorities on this subject met in England some years ago.22 If results of an initial EGD are negative when the colorectal disease is established, a repeated EGD at 3 to 5 years seems reasonable, at least in asymptomatic patients. Prolonged follow-up is required. The average interval between di¬ agnosis of FAP and finding of duodenal cancer in our pa¬ tients was 29 years, somewhat longer than that reported

by others.6,7,16,15 Endoscopie treatment with

snare excision, laser abla¬ tion, or cauterization has been recommended for small be¬

nign polyps. Due to the high rate of sampling error, Galandiuk et al10 emphasized the need to examine the entire polyp for evidence of malignancy. Larger polyps, espe¬ cially those with carcinoma in situ, may be treated with local excision. Once invasive cancer has developed, how¬ ever, radical pancreaticoduodenectomy remains the pro¬

cedure of choice.17,23 The duodenum is now recognized as the most frequent site of extracolonic involvement in patients with FAP. A high percentage of patients presenting with symptoms of duodenal disease will die of invasive cancer. Screening of asymptomatic relatives of patients with FAP has reduced the incidence of colon cancer from 60% to 10%.22,23 It is hoped that a similar reduction in the incidence of duodenal cancer can be realized by early diagnosis, prolonged sur¬ veillance, and appropriate treatment. 1.

tinaltpcolainfrdeoainmlyctiaptoas.il 339.

Jarvinson H, Nuberg

References M, Pectolazzio P. Upper gastrointesGut. 1983;24:333\x=req-\

2. Burt RW, Berenson MM, Lee RG, Tolman KG, Freston JW, Gardner EJ. Upper gastrointestinal polyp in Gardner's syndrome. Gastroenterology. 1984;86:255-301. 3. Bulow S, Lauritson KB, Johanssen A, Svendson LB, Sondergaard JO. Gastroduodenal polyps in familial polyposis coli. Dis Colon Rectum. 1985;28:90-93. 4. Yao T, lida M, Ohsato K, Watanabe H, Omae T. Duodenal lesions in familial polyposis of the colon. Gastroenterology.

1977;73:1086-1092. 5. Ohsato K, Yao T, Watanabe H, lida M, Itoh H. Small in-

testinal involvement in familial polyposis diagnosed by operative intestinal fibroscopy: report of four cases. Dis Colon Rectum.

1977;40:414-420.

6. Lees CD, Hermann RE. Familial polyposis coli associated with bile duct cancer. Am J Surg. 1981;141:378-380.

7. Schuchardt WA, Ponsky JL. Familial polyposis and Gardner's syndrome. Surg Gynecol Obstet. 1979;148:97-103. 8. Ushio K, Sasagawa M, Doi H, et al. Lesion associated with familial polyposis coli: studies of lesions of the stomach, duodenum, bones and teeth. Gastrointest Radiol. 1976;1:67-80. 9. lida M, Yao T, Itoh H, Ohsato K, Watanabe H. Endoscopicfeatures of adenoma of the duodenal papilla in familial polyposis of the colon. Gastrointest Endosc. 1981;27:6-8. 10. Galandiuk S, Hermann RE, Jagelman DG, Fazio FW, Sivak MV. Villous tumors of the duodenum. Ann Surg. 1988;207:234\x=req-\ 239. 11. Alwmark A, Andersson A, Lasson A. Primary carcinoma of the duodenum. Ann Surg. 1980;191:13-18. 12. Kerremans RP, Lerut J, Penninckx FM. Primary malignant duodenal tumors. Ann Surg. 1979;190:179-182. 13. Castagnone TR, Velio P, Bianchi P, Polli EE. Gastric and duodenal polyps in familial polyposis coli. Gut. 1981;22:363\x=req-\ 367. 14. Dupas JL, Marti R, Capron JP, Delamarre J. Villous adenoma of the duodenum: endoscopic diagnosis and resection.

Endoscopy. 1977;9:245-247. 15. Sugihara K, Muto T, Kamiya J, Konishi F, Sawada T, Morioka Y. Gardner's syndrome association with periampullary carcinoma, duodenal and gastric adenomatosis: report of a Dis Colon Rectum. 1982;25:766-771. S, Ware CC. Carcinoma of the duodenum: comparison of surgery, radiotherapy and chemotherapy. Br J Surg.

case.

16. Sakker

1973;60:867-872. 17. Kutin ND, Ranson JHC, Gouge TH, Localio A. Villous tumors of the duodenum. Ann Surg. 1975;181:164-168. 18. Mir-Madjlessi S, Farmer RG, Hawk WA. Villous tumors of the duodenum and jejunum: report of four cases and review of the literature. Am J Dig Dis. 1973;18:467-476. 19. Kurtz RC, Sternberg SS, Miller HH, DeCosse JJ. Upper

gastrointestinal neoplasia

in familial

polyposis. Dig

Dis Sci.

1987;32:459-465. 20. Sarre RG, Frost AG, Jagelman DG, Petras RE, Sivak MV,

polyps in familial adenompolyposis: a prospective study of the nature and prevalence of upper gastrointestinal polyps. Gut. 1987;28:306-314. 21. Jarvinen H. Time and type of prophylactic surgery for familial adenomatous coli. Ann Surg. 1985;202:93-97. 22. Dozois RR, Berk T, Bulow S, et al. Symposium on surgical aspects of familial adenomatous polyposis. Int J Colorectal Dis. McGannon E. Gastric and duodenal

atous

1988;3:1-16.

23. Cortese AF, Cornell GN. Carcinoma of the duodenum. Cancer. 1972;29:1010-1015. 24. Case records of the Massachusetts General Hospital. N Engl J Med. 1935;212:263. 25. Halstead JA, Harris EJ, Bartlett MK. Involvement of the stomach in familial adenomatous polyposis of the gastrointestinal tract: report of a family. Gastroenterology. 1950;31:763. 26. Sarre RG, Frost AG, Jagelman DG, et al. Gastric and duodenal polyps in familial adenomatous polyposis: a prospective study of the nature and prevalence of upper gastrointestinal polyps. Gut. 1987;28:206-214.

Discussion Stanley M. Goldberg, MD, Minneapolis, Minn: Once again, we must thank the group from the Mayo Clinic for bringing to our attention the association between malig¬ nant duodenal polyps and FAP. The association between malignant duodenal polyps and FAP was first described in 1935 by Cabot.24 As early as 1950, surgeons were rec¬ ommending endoscopy in patients with FAP because of the increased frequency of upper gastrointestinal pol¬ yps.25 What these and other studies have shown is that adenomatous changes occur in the upper gastrointestinal tract mucosa with FAP, especially in the duodenum, and that these ddtiiomds can degenerate into a malignancy.

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Sarre et al26 even note that in a retrospective analysis from the Cleveland (Ohio) Clinic, more patients with FAP died of periampullary cancer than of rectal cancer after under¬ going subtotal resection and ileorectostomy. This article by Beckwith et al shows the poor prognosis of symptomatic duodenal adenomatous lesions and con¬ cludes that asymptomatic FAP patients should be screened via the endoscope and treated while the polyps are still small and benign. The question, as with all screen¬ ing regimens, is whether all the effort will translate into a survival benefit. With this disease, the answer is prob¬ ably yes. Upper gastrointestinal endoscopy with either the standard endoscope or the side-viewing scope is safe to perform, well tolerated by the patient, and accurate in its assessment. The potential patient population, especially the inherited form, is small, easily identified, and could be readily followed up. Also, treatment of early lesions via the endoscope or with local excision carries little morbidity and mortality. This article also raises several questions. Should blind biopsy be performed on all patients with familial adenom¬ atous polyposis, and, if dysplasia is found without gross evidence of polyps, what course of action should be car¬ ried out? Ileal and jejunal polyps are also seen in familial adenomatous polyposis. Did any of your patients manifest polyps distal to the duodenum? Claude H. Organ, Jr, MD, Oakland, Calif: I would like to ask Dr Beckwith if any of these cases were associated with Gardner's syndrome? Is it your basic premise that these patients should be followed up with both upper and lower gastrointestinal endoscopy? In future studies, do you intend to look into the presence or absence of chro¬ mosomes 10 and 24? Lawrence H. Wilkinson, MD, Albuquerque, NM: In deal¬ ing with benign duodenal tumors that do not involve the wall of the duodenum adjacent to the pancreas, simple resection should be performed, even though it creates an opening several centimeters long. Reconstruction of the duodenum may be achieved by side-to-side duodenojejunostomy. The lumen of the jejunum need not be opened unless most of the circumference of the duodenum has been removed. In treating resectable malignancies that have grown into the wall of the second or third portion of the duodenum, utilization of the above technique has been effective (eg, cancer of the right colon). Charles E. Lucas, MD, Detroit, Mich: The sequential de¬ velopment of colon, then duodenal, and possibly smallbowel polyps suggests an etnologie factor which is extralu¬ minal. Have there been any biliary studies to try and identify the factor that is causing all of this? William R. Waddell, MD, Silver City, NM: I do not have anything particularly to say about duodenal polyps except that they present a problem that does not exist in the colon. As I am sure all of y ou know, there are chemical treatments available for residual polyps in the colon, both with the intact colon and after subtotal colectomy and ileoproctostomy. The treatment received by patients with arthritis

includes a commonly used drug called sulindac (Clinoril). As a result of interal hepatic circulation, about half of that drug is excreted through the biliary tract and goes on down into the colon where a high concentration of the active component is achieved in the lumen. A lot of people have had trouble believing that this will happen, but basically, thousands of polyps in colons will disappear in the course of about 6 to 12 months. As long as the drug is maintained that's the way it remains. The problem in the duodenum, and also to some extent, the stomach, is different because there is no opportunity for prolonged contact or high concentrations, such as exist in the colon. I believe that work is going on at a fairly rapid rate to achieve similar inhibition of this gross process in the entire gastrointestinal tract; to some extent that has been achieved already. For instance, one of the drugs used to eliminate desmoid tumors in these patients has either an antiestrogen agent (tomoxifin), or one that inhibits the synthesis of estrogen (testolactone [Teslac]). In Europe, there is now a new one that is even more powerful than tomoxifin. I wanted to bring to your attention that in the reports of the use of that drug for breast carcinoma and also in treating desmoid tumors, some of the patients had a rather dramatic resolution of polyps in their intestinal tract

throughout.

Dr Van Heerden: We appreciate the insightful comments of Dr Waddell, who has a long-standing interest in this fascinating disease. Dr Lucas, I am unaware of any biliary factors or any studies in that area. Dr Wilkinson is correct in that local excision of duodenal tumors can indeed be done. None was done in this series, but it is something to keep in our surgical armamentarium. Dr Organ, Gardner's syndrome is a variant of FAP. Since the colon has been removed or should have been removed in all of these pa¬ tients, one cannot advocate routine lower colonoscopy. I think the future will open the doors for us as we do chromosomal studies in patients such as these. I think the next decade is going to be most exciting as we look at this

group of diseases. Dr Goldberg, thank you, too, for your excellent discus¬ sion. The Japanese, in particular, have advocated that one should routinely perform biopsies on the duodenum in these patients even if the duodenum looks normal. They have demonstrated atypia and even carcinoma in situ in normal-looking periampullary mucosa. You are correct that one should look for jejunal polyps. We found none in this study, but one should be on the alert for them. In closing, I would like to say that I became interested in this entity almost 20 years ago when I was a young first assistant with Bill ReMine, MD, a former president of this organization. We had done a Whipple procedure on a pa¬ tient with a periampullary carcinoma and FAP. One of the relatives visiting this gentleman was his son, who was 28 years old. He said, "I wonder if I might not have this dis¬ ease." He was totally asymptomatic. We did an EGD on him and found a large periampullary carcinoma. Three days later, Bill did a curative Whipple procedure on him.

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Prognosis of symptomatic duodenal adenomas in familial adenomatous polyposis.

The frequent association between familial adenomatous polyposis and duodenal tumors is increasingly recognized, yet many patients do not benefit from ...
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