Keywords
Familial adenomatous polyposis - duodenal surgery - endoscopic surveillance - gastric
neoplasia - jejunal neoplasia
Introduction
By performing colectomy and lifelong endoscopic surveillance, lower gastrointestinal
polyposis can be safely managed in the majority of patients with familial adenomatous
polyposis (FAP), whereas upper gastrointestinal disease is becoming an increasingly
important cause of morbidity and mortality [1]
[2]
[3]. For patients with FAP, upper gastrointestinal endoscopic surveillance is recommended,
beginning at age 25 years. Nearly all FAP patients develop duodenal adenomas, predominantly
around the ampulla of Vater, and historic data report a lifetime risk of duodenal
cancer of 5% to 10% [4]
[5]
[6]. Guidelines advise endoscopic resection of duodenal and ampullary adenomas > 10
mm in the hope that this will prevent cancer and either defer or obviate the need
for major resection surgery [7]. A more aggressive technique was recently introduced, referred to as intensive downstaging
polypectomy (IDP), with removal of high numbers of small duodenal adenomas [8]; however, long-term data about effectiveness of this approach are lacking. Patients
with extensive duodenal polyposis not amenable to endoscopic management or those who
have duodenal or ampullary cancer require total duodenectomy, either by pancreatoduodenectomy
(PD) or pancreas-preserving total duodenectomy (PPTD).
PD and PPTD are both associated with substantial morbidity, primarily due to high
rates of pancreatic fistulae. Data underscore the need for ongoing postoperative surveillance.
In particular, there are reports that in 59% to 81% of patients, adenomas are detected
in the remaining jejunal loops, requiring an additional jejunal resection in 3% to
15% [9]
[10]. In these two largest cohorts, no jejunal cancers were observed during endoscopic
surveillance. In addition, there is a continued need for gastric surveillance, with
the emergence of gastric adenomas and cancers becoming an increasingly described clinical
issue in FAP in the Western world [11]
[12].
To our knowledge, limited data have been published about risk of developing gastric
adenomas and cancer after total duodenectomy. In a recent study, after PPTD, two of
47 patients (4%) patients developed high-grade dysplasia in the stomach and two of
47 patients (4%) developed gastric cancer [13]. Bile reflux into the stomach may be an important contributor to development of
gastric dysplasia, and therefore, it may be predictable that the risk of gastric adenoma/cancer
would increase following resection of the pylorus at duodenectomy.
We aimed to evaluate long-term outcomes in patients with FAP after total duodenectomy
in a large cohort in two expert centers.
Patients and methods
We conducted a retrospective review of all patients with FAP who underwent total duodenectomy
either by PD or PPTD. We studied gastric and jejunal adenoma development and causes
of postoperative death. Data were extracted from two prospectively maintained databases,
at St Mark’s Hospital (London, UK) and Amsterdam UMC (Amsterdam, the Netherlands),
both tertiary referral centers for FAP. The study was approved by the Institutional
Review Board of both centers by September 17, 2020 and informed consent was only required
and obtained from patients at Amsterdam UMC.
Pancreatoduodenectomy was performed in case of cancer in a traditional fashion and
reconstruction was accomplished by constructing a long isolated afferent jejunal limb
(approximately 50 cm) with hepaticojejunostomy and pancreatojejunostomy; a subset
of patients underwent pancreatogastrostomy. PPTD, only performed in patients for whom
there was no suspicion of cancer, included dissection of the duodenum from the pancreas
and construction of a short isolated afferent jejunal limb (approximately 30 cm) with
a combined hepaticopancreatojejunostomy near the blind end of the limb; PPTD was only
performed for benign disease, because it does not provide an oncologic resection.
Computed tomography (CT) imaging was performed on patients with cancer for staging,
and in more recent years, magnetic resonance imaging also was performed to assess
for presence of a pancreas divisum.
Endoscopic surveillance was performed on dedicated endoscopy lists by endoscopists
experienced with FAP, using gastroscopes or pediatric colonoscopes. The presence of
jejunal polyps was not assessed systematically during preoperative endoscopy, given
the historical nature of this cohort. In a subset of patients in whom extensive jejunal
polyposis was identified, endoscopy during surgery was performed to choose the transection
plane. Postoperatively, both reconstructed jejunal limbs and the stomach were assessed
using high-definition white light endoscopy and dye-based or virtual chromoendoscopy
at the discretion of the endoscopist. Surveillance intervals were based on the so-called
neo-Spigelman stage (SS) and gastric appearance [14].
Collected data included baseline characteristics for demographics, APC mutation, preoperative SS, history of gastric adenomas, type of total duodenectomy
(PD or PPTD), pyloric preservation, and type of reconstruction. Data on postoperative
outcomes included number, size, location and grade of dysplasia of gastric and jejunal
adenomas, presence of gastric and jejunal cancer, number of fundic gland polyps, gastric
and jejunal surgeries performed, and causes of death.
Continuous variables are presented as the mean with standard deviation or median with
interquartile range, depending on whether the data were normally distributed or not,
and compared using a t-test or Mann-Whitney U test. Categorical variables are presented as numbers and percentages
and compared using Fisher’s exact test. Analyses were performed using SPSS 26 (IBM
Corp. Released 2019. IBM SPSS Statistics for Windows, Version 26.0. Armonk, New York,
United States: IBM Corp).
Results
A total of 119 patients (50% female) with FAP underwent total duodenectomy between
1981 and 2021; 86 underwent PD and 33 underwent PPTD. Baseline characteristics are
presented in [Table 1]. Nineteen patients underwent PD for ampullary cancer (n = 13) or duodenal cancer
(n = 6). Ninety-six patients underwent duodenectomy for extensive benign polyposis:
63 PD and 33 PPTD. Four patients underwent combined gastrectomy and duodenectomy (2
PD and 2 PPTD) for gastric cancer (n = 3) or severe gastric polyposis (n = 1) and
benign duodenal polyposis. Two patients (2%) underwent PD for what was thought to
be benign duodenal polyposis, which unexpectedly turned out to be cancer in the resection
specimen. Of the patients who underwent surgery for benign duodenal polyposis, four
(5%) had SS stage II, 18 (21%) SS stage III, and 62 (74%) SS stage IV. Within the
PPTD group, 18% had SS stage III and 82% SS stage IV. Within the PD group, 8% had
SS stage II, 24% had SS stage III, and 69% had SS stage IV. The pylorus was preserved
in 22 patients (19%). Eleven patients (9%) had been diagnosed with one or more gastric
adenomas before they underwent duodenectomy.
Table 1 Patient characteristics.
|
|
119 FAP patients
|
|
*For patients that underwent surgery for benign polyposis.
FAP, familial adenomatous polyposis; IQR, interquartile range.
|
|
Female sex, n (%)
|
59 (50%)
|
|
Proven pathogenic germline variant in APC
|
109 (92%)
|
|
History of (procto)colectomy
|
119 (100%)
|
|
Age at duodenectomy (median and IQR)
|
48 (40–59)
|
|
Type of duodenectomy
|
|
|
86 (72%)
|
|
|
33 (28%)
|
|
Combined duodenectomy and gastrectomy
|
4 (3%)
|
|
Pylorus preservation
|
22 (19%)
|
|
Indication for duodenectomy
|
|
|
100 (84%)
|
|
|
6 (5%)
|
|
|
13 (11%)
|
|
Preoperative Spigelman stage available*
|
84 (84%)
|
|
|
4 (5%)
|
|
|
18 (21%)
|
|
|
62 (74%)
|
|
Gastric adenoma previous to duodenectomy
|
9 (8%)
|
In 88 of 119 patients, one or more postoperative surveillance endoscopies were performed
at our centers. Median duration of endoscopic follow-up was 106 months (interquartile
range [IQR] 33–167). [Fig. 1] shows the endoscopic appearance of adenomas detected after duodenectomy.
Fig. 1 Endoscopic images of a jejunal and b gastric adenomas after duodenectomy.
Jejunal outcomes
[Table 2] summarizes findings from postoperative endoscopic follow-up. Thirty-six patients
(41%) were diagnosed with a total of 501 jejunal adenomas after duodenectomy, of which
261 (52%) were located in the isolated afferent loop and 237 (48%) in the efferent
loop. Median size of the largest adenoma detected was 16 mm (IQR 4–40). High-grade
dysplasia in jejunal polyps was found in three patients (2.5%). [Fig. 2] shows the proportion of patients who developed jejunal adenomas over time. There
was a significant difference in detection of jejunal adenomas between patients who
underwent PD and patients who underwent PPTD. At 5 and 10 years after duodenectomy,
58% vs 5% and 90% vs 15% had one or more jejunal adenomas after PPTD and PD, respectively
(log rank, P < 0.01) ([Fig. 3]).
Table 2 Findings during postoperative endoscopic follow-up.
|
|
119 FAP patients
|
|
FAP, familial adenomatous polyposis; IQR, interquartile range.
|
|
Duration of endoscopic follow-up (months) (median and IQR)
|
106 (33–167)
|
|
Number of endoscopies (median and IQR)
|
6 (2–11)
|
|
Follow-up details available for the jejunum
|
88 (74%)
|
|
Jejunal adenoma
|
36 (41%)
|
|
Total number of jejunal adenomas in cohort
|
501
|
|
|
261 (52%)
|
|
|
237 (48%)
|
|
Number of jejunal adenomas, median (IQR, range)
|
10 (3–20)
|
|
Jejunal adenoma with high-grade dysplasia
|
3 (3%)
|
|
Jejunal cancer
|
2 (2%)
|
|
Follow-up details available for the stomach
|
87 (73%)
|
|
Gastric adenoma
|
26 (30%)
|
|
Number of gastric adenomas (median and range)
|
1 (1–17)
|
|
Total number of gastric adenomas in cohort
|
66
|
|
|
40 (61%)
|
|
|
26 (39%)
|
|
Gastric adenoma with high-grade dysplasia
|
4 (5%)
|
|
Gastric cancer
|
5 (6%)
|
|
|
5
|
|
|
0
|
|
Fundic gland polyps
|
77 (88%)
|
|
|
7 (10%)
|
|
|
12 (17%)
|
|
|
5 (7%)
|
|
|
3 (4%)
|
|
|
45 (63%)
|
Fig. 2 Proportion of patients diagnosed with a gastric and b jejunal adenomas.
Fig. 3 Proportion of patients diagnosed with jejunal adenomas after PPTD versus PD.
Two patients developed jejunal cancer (2%) 2.6 and 12.8 years after PD. One patient
had extensive polyposis and jejunal cancer in the efferent jejunal limb diagnosed
at endoscopy, which was found to be inoperable at laparotomy. The other patient had
a postoperative bile leak after PD, underwent three laparotomies, presented later
with an abdominal wall fistula, and was found to have jejunal cancer.
Four patients (5%) underwent an additional jejunal resection due to extensive jejunal
polyposis.
Gastric outcomes
Twenty-six patients (30%) were diagnosed with a total of 66 gastric adenomas, of which
61% were located in the fundus/body and 39% in the antrum ([Table 2]). Nineteen of these patients (73%) had carpeting fundic gland polyposis and two
had a gastric adenoma before duodenectomy (8%). The proportions of patients developing
gastric adenomas at 5, 10, and 15 years after duodenectomy were 12%, 25%, and 34%,
respectively ([Fig. 2]). No differences were observed when comparing procedures in which the pylorus was
preserved or resected (log rank, P = 0.11). Of 47 patients with features of biliary reflux/gastritis, 17 (36%) developed
one or more gastric adenomas (mean 2.8). Of the 40 patients without features of biliary
reflux/gastritis, nine (23%) developed one or more gastric adenomas (mean 2.1) (P = 0.24).
Four patients (5%) developed gastric adenomas with high-grade dysplasia (HGD), of
which three were located in the fundus or body and one in the antrum with a median
adenoma size of 30 mm.
Five patients (6%) developed gastric cancer after a median of 15 years (IQR 9.5–22.4)
after duodenectomy at a median age of 56. The cancers developed in the fundus (n =
1) and body (n = 4), and all except one in areas with carpeting fundic gland polyposis.
One patient did not undergo endoscopic surveillance between surgery and gastric cancer
diagnosis 5 years after duodenectomy. The other three patients were diagnosed with
gastric cancer 5 months, 16 months, 5 years, and 6 years after their last postoperative
endoscopic surveillance. Four of the five patients had been diagnosed with at least
one gastric adenoma (range 1–17 adenomas) before cancer diagnosis but after duodenectomy,
including two patients with a gastric adenoma with HGD. Four patients died from metastatic
gastric cancer and one patient, who underwent endoscopic submucosal dissection for
a T1 cancer, remained alive 16 months later and currently has no signs of metastases
on CT.
Postoperative deaths
Five- and 10-year postoperative survival estimates were 92% and 86% for patients who
underwent duodenectomy for benign disease and 48% and 39% for patients who underwent
duodenectomy for cancer, respectively (P = 0.006). Among the 10 patients who underwent duodenectomy for cancer and died, the
causes of death were as follows: metastatic duodenal/ampullary cancer (n = 7), pulmonary
embolism with gastric cancer (n = 1), and unknown causes (n = 2). Among the 25 patients
who underwent duodenectomy for benign disease and who died, the causes of death were
as follows: metastatic gastric cancer (n = 4), jejunal cancer (n = 2), ileal pouch
cancer (n = 2), Kock pouch cancer (n = 1), pancreatic cancer (n = 1), ovarian cancer
(n = 1), brain tumor (n = 2), metastatic disease from an unknown primary tumor (n
=2), pancreatitis (n = 1), biliary sepsis (n = 1), and other not FAP or surgery related
causes (n = 8).
Discussion
In this study, we evaluated follow-up outcomes after total duodenectomy in a relatively
large cohort of FAP patients. During postoperative endoscopic surveillance, 33% of
the patients were diagnosed with one or more gastric adenomas and 6% with gastric
cancer. In addition, 41% of the patients were diagnosed with one or more adenomas
in the remaining jejunal loops. These findings underscore that even after resection
of the duodenum, high-quality endoscopic surveillance remains essential and should
be improved for the stomach and jejunum.
In a smaller single-center series reporting on long-term outcomes after pancreas-sparing
duodenectomy, two of 47 patients (4%) developed HGD and two of 47 patients (4%) developed
gastric cancer [13]. In the same series, two of 47 patients (4%) developed HGD in the jejunum and one
of 47 patients (2%) developed jejunal cancer. These findings are comparable to the
findings from our study.
Because adenomas and cancer in FAP often arise around the ampulla, it has been suggested
that bile might be cytotoxic in these patients. Several studies in mice and humans
with FAP have shown that bile exposure may play a role in development of duodenal
polyps [15]. However, a randomized study showed no effect of ursodeoxycholic acid on duodenal
adenoma development [16]. Little is known about the influence of bile exposure on gastric adenoma/cancer
development. A longer duration of bile exposure in the stomach was observed in FAP
patients with gastric polyps compared with FAP patients without polyps [17]. A recent cross-sectional study in the sporadic setting found bile reflux to be
an independent risk factor for gastric adenoma and gastric cancer [18]. We did not observe a significant difference in terms of gastric adenoma development
between patients with/without pylorus and patients with/without features of biliary
reflux/gastritis, which might be partly because of the sample size and potentially
due to absence of documentation about bile reflux/gastritis in some cases. However,
71% of gastric adenomas developed in patients with documented biliary reflux/gastritis.
There was a striking difference in jejunal adenoma detection between patients who
underwent PD compared with patients who underwent PPTD. The main difference between
the two techniques lies in the reconstruction, with a separate hepaticojejunostomy
and pancreatojejunostomy (or pancreatogastrostomy) after PD compared with a single
hepatopancreatojejunostomy after PPTD, and a longer isolated jejunal limb after PD
compared with a shorter (approximately 30 cm) jejunal limb after PPTD. A short isolated
limb facilitates complete endoscopic surveillance in most patients [9], which may be less feasible when the jejunal limb is longer. Therefore, lesions
may be missed, which could explain the lower rate of detection for jejunal adenomas
after PD.
It is important to note that FAP patients who do not undergo duodenal surgery also
may develop jejunal adenomas and even jejunal cancer [19]
[20]
[21]. Based on the data from the present study, we cannot categorically state that jejunal
adenoma development is caused by duodenal surgery itself, because systematic screening
of the jejunum was performed before surgery was performed only in a subset of patients.
In addition, development of jejunal adenomas may just represent the natural history
of polyposis, although clinically significant jejunal lesions and cancer in the absence
of duodenal surgery are very uncommon. Nevertheless, the difference in detection of
jejunal adenomas according to type of surgery remains striking.
One of the limitations of the present study was the retrospective design. Retrospective
collection of data from endoscopy reports is prone to inaccuracy. Completeness of
endoscopy, defined as reaching the end of the isolated jejunal limb, was not documented
in all reports. Moreover, it is likely that information about signs of bile reflux
were not well documented. Where possible, endoscopic images were assessed to collect
additional data. Prospective data collection with standardized endoscopy reports would
remove this limitation. Moreover, quality of endoscopic surveillance and endoscopes
has improved in recent decades, and today, endoscopists treating FAP patients are
more aware of the occurrence of gastric adenoma and cancer.
Considering the challenges of diagnosing gastric adenomas in FAP, especially once
located within carpeting fundic gland polyposis and against the background of biliary
gastritis, it seems logical that historically, they may have been missed and may even
still be missed in current practice. Therefore, in this study, the incidence may have
been underestimated. Also, detection of jejunal adenomas may have improved over the
study period, which might have led to a higher rate of detection of jejunal adenomas
during more recently performed endoscopies. Finally, selection bias was introduced
in this study, whereas patients with cancer underwent PD and patients with extensive
benign polyposis PD or PPTD, which might have influenced the results.
Currently, endoscopic upper gastrointestinal surveillance protocols exist only for
patients who have not undergone duodenectomy [22]
[23]. Centers use a “neo-Spigelman stage” for jejunum assessment after surgery, which
does not take into account gastric findings. Two patients in the present study had
no jejunal adenomas during follow-up, which resulted in an endoscopic surveillance
interval of 5 years. At their next surveillance endoscopies, they were diagnosed with
gastric cancer. This underscores the importance of gastric findings when choosing
the next surveillance interval. Based on data from the present study reporting on
risks of developing adenomas and cancer in the jejunum and stomach after duodenectomy,
the authors propose development of a different endoscopic surveillance protocol for
this specific group of patients, which should be evaluated in a prospective study.
There may be an opportunity to optimize endoscopic surveillance of the stomach. In
the present series, gastric cancers were observed in patients who were under active
surveillance in an expert center. However, we acknowledge that some of these cases
may be historical and may have been detected before the increased risk of gastric
dysplasia in patients with FAP was recognized. In keeping with this, Leone et al.
found that of 10 gastric cancers in FAP patients treated at a single expert center,
only two were identified on endoscopy [24]. Future studies should focus on what the precursor(s) of gastric cancer in FAP is/are
and how to detect them during endoscopic surveillance before they progress to cancer.
Conclusions
Although duodenectomy can treat or prevent duodenal cancer in FAP, these patients
still have a considerable risk of developing jejunal and gastric adenomas and even
cancer, which should be discussed with them before they undergo surgery. There is
a clear need for a better understanding of the endoscopic appearance and pathophysiology
of these lesions to guide surgical decision making and to improve post-duodenectomy
endoscopic surveillance.
