Surveillance and treatment of duodenal adenomatosis in familial adenomatous polyposis

• Introduction
• Patients and methods
• Results
• Endoscopic findings and progression of adenomatosis
• Endoscopic treatment
• Open duodenotomy
• Pancreaticoduodenectomy
• Other cancers
• Discussion
• Acknowledgment
• References

Background and study aims: Patients with familial adenomatous polyposis (FAP) are at increased risk for duodenal cancer whereas colorectal cancer is largely prevented by prophylactic colectomy. We analyzed the results of endoscopic surveillance and different treatment modalities of duodenal adenomatosis in patients with FAP.

Patients and methods: Data on endoscopies, histopathological examinations, and surgical therapies were collected from the medical histories of 129 patients with FAP. The cumulative incidences of duodenal adenomatosis and severe dysplasia and cancer were calculated using Kaplan-Meier analysis.

Results: By the age of 60 years, the cumulative incidence was 80 % for any adenomatosis and 23 % for severe dysplasia or cancer. Duodenal cancer was observed in six patients (4.7 %). Fifteen endoscopic excisions in 14 patients, and 19 open duodenotomies in 17 patients were carried out. Later, pancreaticoduodenectomy was undertaken in six (35.3 %) of these 17 patients. Altogether, 12 patients (9.3 %) underwent pancreaticoduodenectomy. Except for one patient, the indication for surgery was based on follow-up endoscopies, and none of these patients died of duodenal cancer. No postoperative deaths occurred. Seven patients (58.3 %) had major complications, four (33.3 %) of which were surgical.

Conclusions: The high incidence of severe dysplasia and cancer in duodenal polyps suggests that endoscopic surveillance is essential. Endoscopic polypectomies under sedation anesthesia have partly replaced open duodenotomies. High-risk patients with Spigelman IV adenomatosis or adenomas with persisting severe dysplasia should undergo surgery with pylorus-preserving pancreaticoduodenectomy before invasive cancer develops.

Introduction

Duodenal polyps in patients with familial adenomatous polyposis (FAP) were first described in 1904 [1] and duodenal cancer in 1935 [2]. Today, the duodenum is the second most common site of polyps after the colon [3]. Indeed, the life-time risk of duodenal adenomas approaches 100 % in this patient population [4] [5]. The cumulative risk of duodenal cancer by the age of 60 years is from 4.0 % to 10 % [5] [6] [7] [8]. While colonoscopy surveillance and prophylactic proctocolectomy have decreased the proportion of colorectal cancer as a cause of death in FAP, duodenal and desmoid-related deaths have become potential life threats for these patients [9]. Endoscopic surveillance has been shown to be worthwhile in preventing duodenal cancer [10]. However, the choice of treatment and the optimal timing of interventions based on endoscopic view and histopathologic examination of biopsies remain a great clinical challenge in each patient. Although some tendency in mutations of the APC gene with severe duodenal adenomatosis has been observed [8], no clinically useful association has been found [11] [12].

We have been arranging endoscopic surveillance of duodenal adenomas for patients with FAP for 27 years and here now report the results of this surveillance and the different treatment modalities used. This is a retrospective analysis of an extended cohort of 129 patients with FAP, 98 of whom were previously reviewed about 10 years ago [4].

Patients and methods

Since 1980, upper intestinal endoscopy has been used for surveillance of patients with FAP at Helsinki University Central Hospital. A total of 129 patients (64 men and 65 women) from 66 families, were invited for upper intestinal endoscopy. The mean age at time of first upper endoscopy was 37 years (range 18 – 80 years) and at the time of last endoscopy it was 46 years (range 20 – 85 years). Median follow-up time after the first examination was 8.5 years (range 0.2 – 26 years). Surveillance was arranged at 2- to 3-year intervals. In the case of adenomas with a size of about 20 mm or larger and in those with severe dysplasia, more frequent examination was undertaken. Since 1990, routine random biopsies have been taken. Between 1 and 14 endoscopies (mean 5 endoscopies) were performed for each patient.

The patients were examined with the Olympus QIF-Q-series of fiberoptic or videogastroscopes (Olympus, Hamburg, Germany). The severity of duodenal adenomatosis was staged according to the Spigelman classification ([Table 1]) [13].

Endoscopic papillectomies and snare excisions for large adenomas were performed with a duodenoscope (Olympus TJF-160) under sedation anesthesia. Adenomas under 10 mm in diameter were electrocauterized. Of 129 patients, 16 (12.4 %) used sulindac therapy for desmoids or rectal stump adenomatosis for a mean of 9.2 years (range 0.1 – 23 years).

The surgical technique for open duodenotomy included midline laparotomy, Kocher maneuver, and oblique duodenotomy. Adenomas over 4 mm in diameter were excised submucosally and smaller ones were fulgurated. Adenomas or tumors of the ampulla of Vater were excised locally with sphincteroplasty to prevent scarring of biliary or pancreatic ducts. The previously described techniques of pancreaticoduodenectomy and pylorus-saving pancreaticoduodenectomy were used [14] [15].

The cumulative incidence of duodenal adenomatosis and severe dysplasia and cancer were calculated by the Kaplan-Meier method. The change in the mean Spigelman class after treatment was analyzed by the Wilcoxon test, and correlation between sulindac use and Spigelman class or dysplasia were analyzed by the Mann-Whitney U-test (SPSS 15.0 for PC +, SPSS Inc., Chicago, Illinois, USA).

Results

Endoscopic findings and progression of adenomatosis

At first endoscopy, duodenal adenomatosis was observed in 90 patients (69.8 %). Gastric fundic gland polyps were detected in 79 patients (61.2 %). Nine patients (7.0 %) had moderate or severe dysplasia in the endoscopic biopsies, and one patient (0.8 %) had an early duodenal carcinoma at the first endoscopy.

Progression of duodenal adenomatosis is shown in [Fig. 1].

The cumulative incidences of any adenomatosis and severe dysplasia or cancer are shown in [Fig. 2].

Risk for severe dysplasia or cancer was 5.7 % (SE 2.3 %) at 40 years, 15.2 % (SE 2.3 %) at 50 years, and 23.2 % (SE 5.9 %) at 60 years. Duodenal cancer was observed in six patients (4.7 %). Five of these patients underwent pancreaticoduodenectomy and one underwent open duodenotomy. The cumulative incidence of duodenal cancer was 3.2 % (SE 1.8 %) at 40 years, 7.6 % (SE 3.8 %) at 60 years, and 34.0 % (SE 16.0 %) at 75 years ([Fig. 2]). The site of duodenal cancer and of severe dysplasia was typically in the second part of the duodenum at the periampullary area or within 5-cm distance from the papilla. Pre-existing adenoma invariably occurred beneath the carcinoma.

The use of sulindac therapy did not correlate with the Spigelman class (P = 0.030) nor the occurrence of severe dysplasia (P = 0.09).

Endoscopic treatment

Seven papillectomies and eight snare excisions were performed on 14 patients with 1 – 3 adenomas of 10 – 20 mm in diameter. In seven of the specimens (47 %), severe dysplasia was observed during histopathological examination, and in one case severe dysplasia was noted in biopsies taken at follow-up endoscopy. The distribution of Spigelman stage before and after the endoscopic procedure is shown in [Table 2].

Any residual adenomatous tissue was treated at the first postoperative examination. At the first postoperative endoscopy, the Spigelman stage decreased in seven patients (50 %), increased in two (14.3 %), and remained unchanged in three (21.4 %) patients. Follow-up endoscopy had yet to be carried out in three patients. The change in the mean Spigelman class was statistically significant (P < 0.01, Wilcoxon test). At the latest endoscopy, the Spigelman distribution in these 14 patients was: stage I, three patients; stage II, five patients; stage III, one patient; and stage IV, two patients. One patient (7.1 %) with stage IV adenomatosis at the latest endoscopy had undergone pancreaticoduodenectomy. No severe complications were observed after the endoscopic procedures except for one postoperative hemorrhage, which was treated by red blood cell transfusion.

Open duodenotomy

Nineteen open duodenotomies were undertaken in 17 patients with 1 – 5 adenomas of 10 – 30 mm in diameter. Preoperative distribution of Spigelman stage was: stage I, one patient; stage II, three patients; stage III, seven patients; and stage IV, four patients. Preoperative stage was unknown in two patients. In histological examination of specimens, moderate-to-severe dysplasia was observed in five (29.4 %) and early invasive cancer (pT1N0M0) in two patients (11.8 %). The distribution of Spigelman stage before and after duodenotomy is shown in [Table 3].

At first postoperative endoscopy 6 months to 2 years after duodenotomy, the Spigelman stage had decreased in five patients (29.4 %), increased in two (11.8 %), and remained unchanged in six patients (35.3 %). The change in the mean Spigelman class was statistically significant (P < 0.02, Wilcoxon test). No follow-up endoscopy was performed in two patients. Two patients underwent another open duodenotomy, one for a cancerous adenoma in the first specimen and the other for redundant adenomatosis. The latter underwent pancreaticoduodenectomy 5 years later. Pancreaticoduodenectomy has been performed on six (35.3 %) of these 17 patients.

Pancreaticoduodenectomy

Twelve of the 129 patients (9.3 %; five men and seven women), underwent pancreaticoduodenectomy for duodenal adenomatosis or cancer ([Table 4]).

Their median age at the operation was 52 years (range 38 – 74 years). Except for one patient, the indication for the operation was based on clinical and histological findings at follow-up endoscopies. The indication was based on carcinoma at histopathological examination of biopsies in three patients (25.0 %), severe dysplasia in three (25.0 %), redundant adenomatosis in three (25.0 %), and on suspect view in endoscopy in one patient (8.3 %). One man (case 2) visited hospital because of obstructive jaundice and was diagnosed as having duodenal cancer at endoscopy. He died 2 years after the operation. He had had Spigelman stage I disease at his first endoscopy 5 years earlier but due to severe problems with intra-abdominal desmoid the second endoscopy was delayed. In one patient (case 1), the first endoscopy led to open duodenotomy because of redundant adenomatosis, and duodenal cancer (pT1) was observed in the excised polyp. No cancer was observed in pancreaticoduodenectomy specimens. She died of gastric cancer at the age of 54 years, 16 years after the pancreaticoduodenectomy. One patient (case 6) died of gastric cancer 2.5 years after pancreaticoduodenectomy, and one patient (case 7) died of anal adenocarcinoma 3.1 years after pancreaticoduodenectomy. None of the patients who had undergone pancreaticoduodenectomy based on findings in surveillance endoscopy died of duodenal cancer.

There were no postoperative deaths. Seven patients (58.3 %) had major complications, four (33.3 %) of which were surgical. Leakage and hemorrhage of pancreaticojejunal anastomoses required new laparotomy in two patients. In one patient, hepaticojejunal leakage was treated conservatively, and in another case hemorrhage of the bulbojejunal anastomosis was treated by endoscopy. One patient returned to hospital 1 month after the operation because of massive gastrointestinal bleeding from an ulcer in the bulbojejunal anastomosis. Five endoscopies, several angiographies combined with endoluminal stenting, and a laparotomy were needed. The hemorrhage was finally controlled with endoluminal stenting of the hepatic artery. One patient was treated with anticoagulant therapy for pulmonary embolism, and another was treated with antibiotics for pneumonia. One patient survived a Gram-positive sepsis after therapy at the intensive care unit.

At the postoperative follow-up endoscopy, three patients had adenomas in the jejunum, which were up to 2 cm in diameter in one patient. The Spigelman class of jejunal adenomatosis was III in two patients and II in one patient. A woman (case 6) who died of gastric cancer at only 2.5 years postpancreaticoduodenectomy had not received upper intestinal endoscopies after the operation.

Other cancers

Fifteen of the 129 patients (11.6 %) died of cancers other than duodenal adenocarcinoma: 10 died of colorectal cancer, three of gastric cancer, one of ovarian cancer, and one with unknown site of the primary cancer. One patient who contacted the hospital between regular follow-up endoscopies for jaundice and carcinoma of the main bile duct was diagnosed by endoscopic retrograde cholangiopancreatography (ERCP). She died of rectal stump cancer 3 years after the pancreaticoduodenectomy. Two of the gastric cancers occurred in the gastric stump after pancreaticoduodenectomy. In addition, two patients underwent surgery because of adenocarcinoma of the jejunum (pT1N1 and pT2N0) and are still alive 37 and 28 months after surgery.

Discussion

The cumulative incidence of any duodenal adenomatosis at the age of 50 years is about 70 %, and the severity of polyposis increases with age [5]. The cumulative incidence of 15.2 % for severe dysplasia or duodenal adenocarcinoma at the age of 50 in our study emphasizes the importance of endoscopic surveillance and early prophylactic therapy. In fact, the risk of duodenal cancer was 7.6 % at the age of 60 years and as high as 34 % at 75 years, although the latter figure is biased because of the small number of patients in follow-up. Earlier estimates of cumulative duodenal cancer risk varying from 3 % to 10 % at the age of 60 years are in line with our findings [5] [6] [8].

As nonsteroidal anti-inflammatory drugs (NSAIDs) regress colorectal adenomas in patients with FAP, much hope has been directed on the use of pharmacological treatment of early duodenal adenomatosis. Unfortunately, the results of NSAIDs, and other compounds on regression or prevention of duodenal adenomas in FAP appear disappointing, although regression of small adenomas may occur [12]. The use of cyclo-oxygenase-2 inhibiting agents, such as celecoxib, is limited by a potential risk of subsequent cardiovascular morbidity [16].

At the beginning of the surveillance period in the early 1980 s, open duodenotomy was a common choice of treatment for large adenomas when snare excision was not possible or the patient had redundant duodenal adenomatosis. Since then, endoscopic techniques have developed and papillary lesions in particular are often removed endoscopically under sedation anesthesia [17]. In our series, reduction of Spigelman stage was observed in half of the patients 1 – 3 months after endoscopic excision, and only 7.1 % of patients (i. e. one patient), underwent pancreaticoduodenectomy after the endoscopic procedure. A drawback of open duodenotomies has been the recurrence of adenomas and the possibility of a duodenal leak [17] [18]. In our series, a reduction in Spigelman stage was noted in about one-third of patients 6 months to 2 years after duodenotomy and 35.3 % later underwent pancreaticoduodenectomy. This suggests that open duodenotomy should be reserved for the minority of patients, those with 1 – 5 large adenomas that are not removable by endoscopy and in whom invasive cancer is not suspected.

Pancreaticoduodenectomy is a major operation, which is why it is considered only after duodenal cancer had been proven in endoscopic biopsy. In a prospective series of 114 patients, Groves and co-workers [11] observed duodenal cancer in six patients, all of whom died of their disease. As most of them had had Spigelman stage III or IV adenomatosis, the authors suggested that patients with stage IV disease should be offered pylorus-preserving pancreaticoduodenectomy [18]. High recurrence rates have also been reported by others in patients undergoing surgery for invasive duodenal cancer [18] [19] [20] [21] [22]. The outcome of our seven patients with duodenal carcinoma was more encouraging. All cases detected based on surveillance were of an early stage (five pT1N0, one pT2N0) and had no signs of recurrence. Only one patient with no systematic surveillance died of disseminated disease. Prophylactic pancreaticoduodenectomy was undertaken in eight patients with stage III or IV adenomatosis. There was no postoperative mortality but major complications occurred often, in seven (58.3 %) of 12 patients. In series from other highly specialized centers, operative mortality has varied between 0 % and 6.3 % and morbidity between 0 % and 100 % [18] [22] [23].

The relatively high postoperative morbidity of patients with FAP after pancreaticoduodenectomy is partly explained in some patients by demanding operative conditions related to adhesions caused by earlier proctocolectomy. In addition, the leakage of pancreaticojejunal anastomosis is more common when the parenchyme of the pancreas is normal, as in patients with FAP, compared with patients undergoing surgery due to pancreatic pathology. However, in a larger series of patients undergoing surgery for indications other than FAP, surgical mortality was 0 % – 2.2 % after standard resection and 5 % – 10 % after extended resection, and morbidity was 25 % – 50 % [24]. Thus, rather high morbidity rates apparently occur after pancreaticoduodenectomy even in the hands of highly specialized surgeons.

An important finding in the follow-up of patients after pancreaticoduodenectomy is that the patients often develop new adenomas in the upper jejunum [21] [23]. Therefore, upper intestinal endoscopy must continue even after excision of the duodenum. Of note is also the occurrence of gastric cancer, bile duct cancer, and jejunal cancer. The diagnosis of all these is a challenge as they may remain beyond the reach of usual endoscopy or are otherwise difficult to detect (e. g. due to fundic gland polyps).

In conclusion, a high incidence of severe dysplasia, and thus increased risk of cancer, in duodenal polyps confirms that endoscopic surveillance is essential, preferably starting at the time of prophylactic colectomy [7]. The surveillance interval depends on the findings at the baseline examination [5] [7] but cancer may develop even in cases with no or few lesions initially. Endoscopic polypectomies under sedation anesthesia have partly replaced open duodenotomies. Concerning timing of surgery, a particularly demanding group of patients are those with Spigelman grade IV adenomatosis because the endoscopic view of this group is heterogeneous. They are known to have a 36 % crude risk of developing cancer [11]. High-risk patients with Spigelman IV adenomatosis or adenomas with persisting severe dysplasia should undergo surgery with pylorus-preserving pancreaticoduodenectomy before invasive carcinoma develops.

Acknowledgment

The authors thank Mrs Tuula Lehtinen for assistance and Mrs Carol Ann Pelli for linguistic revision.

Competing interests: None

References

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  Search in Google Scholar

A. LepistöMD, PhD 

Department of Surgery
Helsinki University Central Hospital

P.O. Box 340
Helsinki
00029 HUS
Finland

Fax: +358-9-74609

Email: anna.lepisto@hus.fi

References

• 1 Funkenstein O. Über polyposis intestinalis.  Z Klin Med, Berlin. 1904;  55 236-248
  PubMedSearch in Google Scholar
• 2 Cabot R C. Case records of the Massachusetts General Hospital case 21 061.  N Engl J Med. 1935;  212 363-368
  PubMedSearch in Google Scholar
• 3 Järvinen H J, Nyberg M, Peltokallio P. Upper gastrointestinal tract polyps in familial adenomatosis coli.  Gut. 1983;  24 333-339
  CrossrefPubMedSearch in Google Scholar
• 4 Heiskanen I, Kellokumpu I, Järvinen H. Management of duodenal adenomas in 98 patients with familial adenomatous polyposis.  Endoscopy. 1999;  31 412-416
  Thieme ConnectPubMedSearch in Google Scholar
• 5 Bülow S, Björk J, Christensen I J. et al . Duodenal adenomatosis in familial adenomatous polyposis.  Gut. 2004;  53 381-386
  CrossrefPubMedSearch in Google Scholar
• 6 Vasen H FA, Myrhoj T, Mathus-Vliegen L. et al . Decision analysis in the management of duodenal adenomatosis in familial adenomatous polyposis.  Gut. 1997;  40 716-719
  CrossrefPubMedSearch in Google Scholar
• 7 Wallace M H, Phillips R KS. Upper gastrointestinal disease in patients with familial adenomatous polyposis.  Br J Surg. 1998;  85 742-750
  CrossrefPubMedSearch in Google Scholar
• 8 Björk J, Åkerbrandt H, Iselius L. et al . Periampullary adenomas and adenocarcinomas in familial adenomatous polyposis: Cumulative risks and APC gene mutations.  Gastroenterology. 2001;  121 1127-1135
  CrossrefPubMedSearch in Google Scholar
• 9 Jagelman D G, DeCosse J J, Bussey H J. Upper gastrointestinal cancer in familial adenomatous polyposis.  Lancet. 1988;  1 1149-1151
  PubMedSearch in Google Scholar
• 10 Bülow S. Results of national registration of familial adenomatous polyposis.  Gut. 2003;  52 742-746
  CrossrefPubMedSearch in Google Scholar
• 11 Groves C J, Saunders B P, Spigelman A D, Phillips R KS. Duodenal cancer in patients with familial adenomatous polyposis (FAP): results of a 10 year prospective study.  Gut. 2002;  50 636-641
  CrossrefPubMedSearch in Google Scholar
• 12 Brosens L AA, Keller J J, Offerhaus G JA. et al . Prevention and management of duodenal polyps in familial adenomatous polyposis.  Gut. 2005;  54 1034-1043
  CrossrefPubMedSearch in Google Scholar
• 13 Spigelman A D, Williams C B, Talbot I C. et al . Upper intestinal cancer in patients with familial adenomatous polyposis.  Lancet. 1989;  ii 783-785
  PubMedSearch in Google Scholar
• 14 Whipple A O, Parsons W B, Mullins C R. Treatment of carcinoma of the ampulla of Vater.  Ann Surg. 1935;  102 763
  CrossrefPubMedSearch in Google Scholar
• 15 Grace P A, Pitt H A, Longmire W P. Pancreaticoduodenectomy with pylorus preservation for adenocarcinoma of the head of the pancreas.  Br J Surg. 1986;  73 647
  PubMedSearch in Google Scholar
• 16 Bresalier R S, Sandler R S, Quan H. et al . Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.  N Engl J Med. 2005;  352 1092-1102
  CrossrefPubMedSearch in Google Scholar
• 17 Alarcon F J, Burke C A, Church J M, van Stolk R U. Familial adenomatous polyposis: efficacy of endoscopic and surgical treatment for advanced duodenal adenomas.  Dis Colon Rectum. 1999;  42 1533-1536
  CrossrefPubMedSearch in Google Scholar
• 18 Penna C, Bataille N, Balladur P. et al . Surgical treatment of severe duodenal polyposis in familial adenomatous polyposis.  Br J Surg. 1998;  85 665-668
  CrossrefPubMedSearch in Google Scholar
• 19 Balladur P, Penna C, Tiret E. et al . Pancreatco-duodenectomy for cancer and precancer in familial adenomatous polyposis.  Int J Colorectal Dis. 1993;  8 151-153
  CrossrefPubMedSearch in Google Scholar
• 20 Sarmiento J M, Thompson G B, Nagorney D M. et al . Pancreas-sparing duodenectomy for duodenal polyposis.  Arch Surg. 2002;  137 557-563
  CrossrefPubMedSearch in Google Scholar
• 21 de Vos tot Nederveen Cappel W H, Järvinen H J, Björk J. et al . Worldwide survey among polyposis registries of surgical management of severe duodenal adenomatosis in familial adenomatous polyposis.  Br J Surg. 2003;  90 705-710
  CrossrefPubMedSearch in Google Scholar
• 22 Gallagher M C, Shankar A, Groves C J. et al . Pylorus-preserving pancreaticoduodenectomy for advanced duodenal disease in familial adenomatous polyposis.  Br J Surg. 2004;  91 1157-1164
  CrossrefPubMedSearch in Google Scholar
• 23 Ruo L, Coit D G, Brennan M F. et al . Long-term follow-up of patients with familial adenomatous polyposis undergoing pancreaticoduodenal surgery.  J Gastrointest Surg. 2002;  6 671-675
  CrossrefPubMedSearch in Google Scholar
• 24 Lillemore K D, Cameron J L. Postoperative results following pancreaticoduodenectomy. In: Zinner MJ, Schwartz SI, Ellis H, eds Maingot’s Abdominal operations, 10th edn. USA; Appleton & Lange, A Simon & Schuster Company 1997: 1991-1992
  Search in Google Scholar

A. LepistöMD, PhD 

Department of Surgery
Helsinki University Central Hospital

P.O. Box 340
Helsinki
00029 HUS
Finland

Fax: +358-9-74609

Email: anna.lepisto@hus.fi