Introduction
Prophylactic colectomy has provided a breakthrough in the management of familial adenomatous
polyposis (FAP) [1]
[2]
[3]. Adequate colorectal polyposis control has changed the natural history of the disease,
improving the prognosis and life expectancy of affected patients [1]. Within this context, periampullary carcinoma is the leading mortality etiology
among patients with FAP who have undergone prophylactic colectomy [4]
[5]
[6]
[7]. Therefore, a clear understanding of small-bowel adenomatosis in FAP seems mandatory.
Efforts have been made to identify the clinical factors associated with the development
of advanced duodenal disease and an increased risk for duodenal and ampullary adenocarcinoma.
However, results from different study groups have been inconsistent [8]
[9]
[10]. The only endoscopic feature that has been associated with the presence of foci
of high grade dysplasia and a subsequent higher risk for duodenal adenocarcinoma is
size of adenomas larger than 10 mm [8]
[10].
Thus, the aim of this study was to establish the clinical risk factors and endoscopic
features associated with the development of ampullary and advanced duodenal polyposis
in a Brazilian population with FAP. Additionally, we aimed to describe the prevalence
and clinical impact of jejunal adenomatosis in these patients.
Patients and methods
This is a prospective, single referral center study, undertaken between July 2013
and April 2016. The protocol was approved by University of Sao Paulo School of Medicine
Ethics Committee and registered at Clinical Trials (NCT02656134).
Patients
A cohort of 64 patients with clinical and/or endoscopic diagnosis of FAP met the inclusion
criteria for the study. Patients were routinely treated in the Colorectal Surgery
Division at the University of Sao Paulo Medical School according to standard international
surveillance intervals. Two patients refused to participate and so a total of 62 patients
in 46 different families were enrolled in the study. Endoscopic examinations were
performed at the Gastrointestinal Endoscopy Unit, Clinics Hospital, University of
Sao Paulo School of Medicine. All patients gave their informed consent before inclusion
in the study. Patients who had undergone previous duodenectomy/gastroduodenopancreatectomy,
pregnant women, and patients with severe comorbidities were excluded from the study.
Data collection
Clinical data were collected aided by electronic chart records and personal interviews
with patients. Age, gender, family history for FAP, colonic polyposis phenotype: classic
or attenuated based on the colonic count reported at colonoscopy and surgical report
(attenuated phenotype was classified, based on the number, distribution of polyps,
age of onset of the disease, and the presence of at least one first-degree relative
with the disease), presence of extraintestinal manifestations, type of colorectal
surgical reconstruction technique: total proctocolectomy with ileal pouch or total
colectomy with ileorectal anastomosis, and diagnosis of colorectal cancer data were
recorded.
Prospective endoscopic and histologic evaluation
Patients were prepared with a 6-hour fast and administration of 10 mL simeticone solution.
Esophagogastroduodenoscopies (EGD) were performed under conscious sedation with fentanyl,
midazolam, and propofol administered by a second physician. All patients were evaluated
with lateral (Olympus, TJF-Q180V) and forward view (Olympus, GIF-H180) EGD. Endoscopic
features, number, size, anatomic location, and Paris classification were reported
for every case. Duodenal polyposis was classified according to the Spigelman staging
system and ampullary adenomas were also identified. A minimum of four biopsies were
taken from larger duodenal polyps and two biopsies from suspicious ampullary lesions.
All histopathologic specimens were reviewed by an experienced pathologist with expertise
in gastrointestinal tract evaluation. Additionally, when endoscopic mucosectomies
were performed, the resected specimens were used to complement the Spigelman staging
of duodenal adenomatosis. Patients with advanced duodenal polyposis (Spigelman III
or IV) underwent antegrade balloon assisted endoscopy (BAE) (Fuji, EN-450T5 or Fuji,
EN-580 T) for jejunal examination approximately 1 month after initial EGD. All gastroduodenoscopies
and BAEs were performed by two experienced endoscopists (M. S. and A. S. R).
Data analysis
Non-ampullary duodenal adenomatosis was stratified into two groups according to Spigelman
stages: group 1 included Spigelman stages 0, I, and II; group 2 was represented by
patients classified as Spigelman stages III and IV.
According to the presence or absence of ampullary adenomas, patients were also stratified
into two groups.
Clinical variables: age, gender, family history for FAP, colonic polyposis type, presence
of extraintestinal manifestations, and type of colorectal surgical reconstruction
technique were related to stratified groups for non-ampullary duodenal adenomatosis
and ampullary polyposis.
Continuous data were analyzed using the Student’s t test and categorical variables by Fisher-exact test or Chi-squared test, aided by
the Statistical Package for the Social Sciences software version 20.0, with level
of significance of 5 %. For statistically significant variables, multivariate analysis
using logistic regression was performed.
Results
A total of 62 patients from 46 different families were studied, with a mean age of
36.1 ± 14.2 years; 32 (51.6 %) were female ( [Table1]). Regarding the 16 cases with extraintestinal manifestations, there were five cases
of desmoid tumors, four sebaceous cysts, two mandibular osteomas, two adrenal tumors,
two thyroid tumors, and one case of hypophysis tumor, solid pseudopapillary neoplasm
of the pancreas, and congenital hypertrophy of the retinal pigment epithelium (CHRPE).
Three patients presented chronic abdominal pain related to compression of related
organs by desmoid tumors and 59 patients were asymptomatic. Among the 62 patients,
52 (84 %) had already undergone colorectal surgical treatment. Of those, 44 (84.6 %)
underwent prophylactic colectomy, and 8 (15.4 %) patients had undergone surgical treatment
for colorectal cancer. Of those 8 patients, 6 curative and 2 palliative surgeries
were performed.
Table 1
Clinical variables related to FAP patient groups classified according to Spigelman.
|
Spigelman stage
|
|
|
|
Variable
|
0, I, II
n (%)
n = 49 (79 %)
|
III and IV
n (%)
n = 13 (21 %)
|
Total
n (%)
|
P value
|
|
Age, mean ± SD, years
|
35.75 ± 14.4
|
37.61 ± 13.9
|
36.14 ± 14.2
|
0.999[1]
|
|
Sex
|
|
|
|
0.083[2]
|
|
|
21
|
(42.9)
|
9
|
(69.2)
|
30 (48.4)
|
|
|
|
28
|
(57.1)
|
4
|
(30.8)
|
32 (51.6)
|
|
|
Family history
|
|
|
|
|
|
0.030
[2]
|
|
|
46
|
(93.9)
|
9
|
(69.2)
|
55 (88.7)
|
|
|
|
3
|
(6.1)
|
4
|
(30.8)
|
7 (11.3)
|
|
|
Colonic polyposis
|
|
|
|
|
|
0.183[2]
|
|
|
40
|
(81.6)
|
13
|
(100)
|
53 (85.5)
|
|
|
|
9
|
(18.4)
|
0
|
(0)
|
9 (14.5)
|
|
|
Extraintestinal manifestations
|
|
|
|
|
|
0.445[2]
|
|
|
12
|
(24.5)
|
4
|
(30.8)
|
16 (25.8)
|
|
|
|
37
|
(75.5)
|
9
|
(69.2)
|
46 (74.2)
|
|
|
Colorectal surgery
|
|
|
|
|
|
0.638[2]
|
|
|
26
|
(63.4)
|
7
|
(63.6)
|
33 (63.5)
|
|
|
|
15
|
(36.6)
|
4
|
(36.4)
|
19 (36.5)
|
|
|
Colorectal cancer
|
|
|
|
|
|
0.347[2]
|
|
|
5
|
(10.2)
|
3
|
(23.1)
|
8 (12.9)
|
|
|
|
44
|
(89.8)
|
10
|
(76.9)
|
54 (87.1)
|
|
|
Ampullary adenoma
|
|
|
|
|
|
0.153[2]
|
|
|
4
|
(8.2)
|
3
|
(23.1)
|
7 (11.3)
|
|
|
|
45
|
(91.8)
|
10
|
(76.9)
|
55 (88.7)
|
|
FAP, familial adenomatous polyposis; IRA, ileorectal anastomosis.
1 Student’s t test.
2 Fisher’s test.
Prevalence of duodenal adenomatosis and association with clinical variables
The prevalence of duodenal adenomatosis and advanced duodenal polyposis was 59.7 %
and 20.9 %, respectively and the distribution of patients according to Spigelman stages
can be seen in [Table 1]. When the association between Spigelman groups and clinical variables was evaluated,
the only variable with statistical significance was positive family history for FAP,
showing that 93.9 % of patients in Spigelman group 0 – II had a positive family history
for FAP, in contrast to 69.2 % of patients with a positive family history in the advanced
duodenal adenomatosis group (P = 0.030) ( [Table 1]). According to logistic regression modeling, patients with a positive FAP family
history had a 6.67 times lower risk of presenting advanced duodenal disease (P = 0.023) ( [Table 2]). There were no clinical variables associated with the development of Spigelman
III and IV advanced duodenal polyposis ( [Table 1]).
Table 2
Logistic regression of family history with groups according to Spigelman.
|
Parameter
|
OR
|
95 %CI
|
P value
|
|
No family history
|
1.00
|
|
|
|
Positive family history
|
0.15
|
0.03
|
0.77
|
0.023
|
Familial distribution of Spigelman stages
Familial distribution of Spigelman stages among the relatives from each family was
analyzed when at least two family members were included in the study. Within the total
group, 28 patients belonged to 12 different families. Four patients in two different
families presented advanced duodenal disease, Spigelman IV. A total of 20 relatives
from eight different families were consistently classified as Spigelman score 0 to
II, and four patients from two other families were staged as Spigelman II or III,
suggesting a familial segregation pattern for duodenal disease severity in first-degree
relatives ( [Table 3]).
Table 3
Familial distribution of Spigelman stages among different relatives from each family.
|
Family
|
No. of patients
|
Spigelman stage
|
Consanguinity degree
|
|
1
|
2
|
IV, IV
|
1°
|
|
2
|
2
|
IV, IV
|
1°
|
|
3
|
3
|
II, II, 0
|
1°
|
|
4
|
3
|
I, 0, 0
|
1°
|
|
5
|
2
|
0, 0
|
1°
|
|
6
|
2
|
II, 0
|
1°
|
|
7
|
2
|
II, II
|
2°
|
|
8
|
2
|
0, 0
|
1°
|
|
9
|
4
|
II, II, I, 0
|
1°
|
|
10
|
2
|
III, II
|
1°
|
|
11
|
2
|
III, II
|
1°
|
|
12
|
2
|
0, 0
|
1°
|
Endoscopic features of non-ampullary lesions
Systematic observation of non-ampullary duodenal lesions facilitated the identification
of different endoscopic types of lesion that presented specific histological association
patterns ([Table 4]).
Table 4
Endoscopic features of non-ampullary duodenal lesions.
|
Lesion type
|
Endoscopic features of lesions
|
Anatomic localization ordered by frequency in the duodenum
|
Paris endoscopic classification
|
No. of patients (%)
|
Spigelman stage
|
Histology
|
|
1a
|
Flat elevated whitish lesions, < 10 mm
|
2nd, 3rd portion and bulb
|
0 – IIa
|
37/62 (59.7 %)
|
I, II, III, IV
|
Tubular adenomas with low grade dysplasia
|
|
1b
|
Flat elevated whitish lesions, > 10 mm
|
2nd, 3rd portion and bulb
|
0 – IIa
|
7/13 (53.8 %)
|
III, IV
|
Tubular or tubulovillous adenomas with low grade dysplasia
|
|
2a
|
Flat elevated whitish lesions, with reddish central depression, 3 – 10 mm
|
2nd and 3rd portion
|
0 – IIa + IIc
|
4/13 (30.8 %)
|
III, IV
|
Tubular or tubulovillous adenomas with low grade dysplasia, tubular adenomas with
high grade dysplasia
|
|
2b
|
Flat elevated whitish lesions, with reddish central depression,
10 – 50 mm
|
2nd portion and bulb
|
0 – IIa + IIc
|
3/13 (23.1 %)
|
III, IV
|
Tubulovillous adenomas with low or high grade dysplasia
|
|
3
|
Sessile polypoid lesions, 10 – 40 mm
|
2nd portion and bulb
|
0 – Is
|
1/13 (7.7 %)
|
IV
|
Tubulovillous adenomas with high grade dysplasia
|
In total, 37 patients classified as Spigelman I, II, III, or IV presented small (< 10 mm)
flat elevated whitish lesions that corresponded to tubular adenomas with low grade
dysplasia (Lesion type 1a) ([Fig. 1]); 13 patients classified as Spigelman III or IV presented advanced adenomas (Lesion
types 1b, 2a, 2b, and 3) ([Figs. 2 – 5], [Video 1]). Different morphologic patterns with specific histologic associations for advanced
adenomas were identified, as shown in [Table 4].
Fig. 1 Lesion type 1a: Endoscopic image of flat elevated whitish lesions < 10 mm, located
in second duodenal portion of a 35-year-old male patient, Spigelman II.
Fig. 2 Lesion type 1b: Endoscopic image of flat elevated whitish lesion > 10 mm, located
in third duodenal portion of a 33-year-old male patient, Spigelman IV.
Fig. 3 Lesion type 2a. Endoscopic image of lesions with central depression < 10 mm in second
duodenal portion of a 23-year-old male patient, Spigelman III.
Fig. 4 Lesion type 2b: Endoscopic image of flat elevated adenoma with central depression
of approximately 20 mm size, located in duodenal bulb of a 55-year-old female patient,
Spigelman IV.
Fig. 5 Lesion type 3: Endoscopic image of a polypoid lesion, approximately 30 mm size, located
in second duodenal portion of a 27-year-old male patient, Spigelman IV.
Video 1 Endoscopic examination of a 27-year-old male patient, classified as Spigelman IV,
showing advanced adenomas (lesion type 3) and a scar from previous endoscopic mucosal
resection at the duodenal bulb. As the scope is advanced to the second duodenal portion,
the coexistence of different types of lesion (types 1a, 1b, 2a, 2b, and 3) can be
seen, with a major duodenal papilla with adequate bile drainage.
Ampullary adenomas
Seven cases (six male and one female) of ampullary adenoma were identified at a mean
age of 36.6 ± 16.7 years. Of these, 6 were classified as minor and 1 major adenoma
(> 10 mm) ([Fig. 6]). All patients with ampullary adenomas were from different families. Three patients
were Spigelman III, three were Spigelman II, and the patient with major ampullary
adenoma presented no polyps in the duodenum. All ampullary lesions corresponded to
tubular adenomas with low grade dysplasia.
Fig. 6 Endoscopic image of a major ampullary adenoma with low grade dysplasia in a 19-year-old
male patient, Spigelman 0.
When the group of patients with ampullary adenomas was related to clinical variables,
the presence of extraintestinal manifestations (P = 0.009) and colorectal cancer (P = 0.039) was statistically significant ([Table 5]). In multivariate analysis, the only variable that showed an independent association
with statistical significance was the presence of extraintestinal manifestations (P = 0.037) ([Table 6]). According to logistic regression analysis, patients with extraintestinal manifestations
have a 7.18 times higher risk of presenting ampullary adenoma ([Table 6]).
Table 5
Clinical variables related to presence or absence of ampullary adenomas in patients
with FAP.
|
Ampullary adenomas
|
|
|
|
Variable
|
Yes
n (%)
|
No
n (%)
|
Total
|
P value
|
|
Age, mean ± SD, years
|
36.6 ± 16.70
|
36.09 ± 14.05
|
36.14 ± 14.2
|
0.999[1]
|
|
Sex
|
|
|
|
0.066[2]
|
|
|
6
|
(85.7)
|
24
|
(43.6)
|
30 (48.4)
|
|
|
|
1
|
(14.3)
|
31
|
(56.4)
|
32 (51.6)
|
|
|
Family history
|
|
|
|
|
|
0.174[2]
|
|
|
5
|
(71.4)
|
50
|
(90.9)
|
55 (88.7)
|
|
|
|
2
|
(28.6)
|
5
|
(9.1)
|
7 (11.3)
|
|
|
Colonic polyposis
|
|
|
|
|
|
0.579[2]
|
|
|
7
|
(100)
|
47
|
(85.4)
|
54 (87.1)
|
|
|
|
0
|
(0)
|
8
|
(14.6)
|
8 (12.9)
|
|
|
Extraintestinal manifestations
|
|
|
|
|
|
0.009
[2]
|
|
|
5
|
(71.4)
|
11
|
(20)
|
16 (25.8)
|
|
|
|
2
|
(28.6)
|
44
|
(80)
|
46 (74.2)
|
|
|
Colorectal surgery
|
|
|
|
|
|
0.507[2]
|
|
|
4
|
(57.1)
|
29
|
(64.4)
|
33 (63.5)
|
|
|
|
3
|
(42.9)
|
16
|
(35.6)
|
19 (36.5)
|
|
|
Colectomy
|
|
|
|
|
|
0.039
[2]
|
|
|
3
|
(42.9)
|
5
|
(9.1)
|
8 (12.9)
|
|
|
|
4
|
(57.1)
|
50
|
(90.9)
|
54 (87.1)
|
|
|
Spigelman groups
|
|
|
|
|
|
0.153[2]
|
|
|
4
|
(57.1)
|
45
|
(81.8)
|
49 (79.0)
|
|
|
|
3
|
(42.9)
|
10
|
(18.2)
|
13 (21.0)
|
|
FAP, familial adenomatous polyposis; IRA, ileorectal anastomosis.
1 Student’s t test.
2 Fisher’s test.
Table 6
Logistic regression of extraintestinal manifestations and colorectal cancer related
to presence of ampullary adenomas.
|
Parameter
|
OR
|
95 %CI
|
P value
|
|
No extraintestinal manifestations
|
1.00
|
|
|
|
Presence of extraintestinal manifestations
|
7.18
|
1.1
|
45.9
|
0.037
|
|
No colorectal cancer
|
1.00
|
|
|
|
|
Presence of colorectal cancer
|
3.91
|
0.6
|
27.0
|
0.166
|
Jejunal polyposis
In total, 12 patients with Spigelman III/IV underwent BAE with a minimum insertion
length of 100 cm distal to the Treitz ligament. Of these 10 (83.3 %) patients presented
small (< 10 mm) flat elevated, whitish lesions located in the proximal jejunum, which
corresponded to tubular adenomas with low grade dysplasia. Two patients had no jejunal
lesions.
Discussion
The data presented in this study represent a large prospective series of patients
with FAP and with an important proportion of individuals already submitted to colectomy
in a single university tertiary hospital in Latin America. Our results indicate that
a positive family history of FAP was a protective factor against advanced duodenal
disease. The interpretation of this result may have several explanations. Relatives
from index cases may have incorporated sooner in the intestinal polyposis registry.
Consequently, this group of patients may have received a closer follow-up since an
earlier stage of the disease, which may have resulted in a more favorable duodenal
polyposis prognosis. On the other hand, advanced cases of duodenal polyposis showing
a negative family history may be the result of a different genetic background. De
novo germline mutations are present in 25 % of cases of FAP [11]
[12]. These mutations have been shown to correlate with a delay in diagnosis and a more
severe colorectal phenotype [13]. Perhaps spontaneous mutations could be responsible for a more severe duodenal phenotype
as well. Our study is based on phenotype characterization of duodenojejunal disease.
This approach may also have its own strengths and pitfalls. Although we can suggest
that it is possible that the presence of spontaneous mutations in patients with a
negative family history for the disease may have a role for conditioning a more aggressive
duodenal phenotype, we can only confirm this with further characterization of the
genetic background of this population. These results are not comparable to other studies
that intended to identify risk factors for advanced duodenal disease, mainly because
a positive family history for the disease was not one of the factors analyzed by those
authors [9]
[10]
[14]. On the other hand, the actual limitation of a wide genetic analysis at the present
time encouraged a more profound clinical analysis of the factors that could be implicated
in the development of advanced duodenal disease.
Familial distribution of Spigelman score among relatives from each family suggested
a familial segregation pattern of duodenal disease. Although the small number of patients
with at least one more relative included in the study may limit further statistical
analysis of this observation, familial clustering of duodenal/ampullary cancer has
previously been reported [14]
[15]. A larger study that included 144 patients in 74 families was able to demonstrate
that the occurrence and severity of periampullary neoplasia in FAP patients segregates
in families [15]. The next step that should be taken in this analysis would be characterization of
the molecular background of these patients, in order to determine whether this pattern
is the result of a genetic etiology or an environmental effect. Of note, a familial
clustering for ampullary adenomas was not observed in the patients enrolled in this
study. However, the hypothesis of familial clustering for this entity cannot be rejected
because patients who presented with ampullary adenomas in the present study did not
have sufficient relatives included in order to make a further analysis on this subject.
A previous study that retrospectively analyzed 41 consecutive patients with FAP concluded
that advanced age and mutations in the central part of the APC gene (codons 279 – 1309)
were risk factors for advanced duodenojejunal disease [9]. Two years later, in a prospective study with 48-month follow-up in 58 patients
with FAP who had a high initial Spigelman score (> 7 points), the same group demonstrated
that neither age nor mutation site were risk factors for the development of high grade
dysplasia [10]. Taking into consideration that the old classification of dysplasia gave a lowering
of the Spigelman score and stage by −1.33 points and −0.70 stages [16], whereas the modified Spigelman score according to Vienna classification updates
[17] gives 3 points for the presence of foci of high grade dysplasia and 1 point for
low grade dysplasia [10], it is likely and logical to believe that an initial Spigelman score of > 7 points
could be a risk factor for high grade dysplasia development.
The only endoscopic feature that has been associated with the presence of high grade
dysplasia, even using high-resolution endoscopy or narrow band imaging (NBI), is adenoma
size larger than 10 mm [8]
[10]. Additionally, studies that have incorporated the use of chromoendoscopy for duodenal
evaluation in patients with FAP have shown a higher number of identified polyps. Nevertheless,
the higher number of lesions identified has not been demonstrated to correlate with
a significant clinical impact [18]
[19]. Based on these facts, chromoendoscopy was not used routinely in the present study,
instead it was applied in selected cases to improve the detailed examination of specific
lesions. In the present study, we were able to recognize five different endoscopic
patterns of duodenal lesions present in patients with FAP. Four of these correspond
to lesions commonly described as advanced adenomas (Lesion types 1b, 2a, 2b, and 3).
We believe that this characterization is important in order to produce a risk stratification
for the development of high grade dysplasia among these lesions, as each endoscopic
pattern showed a specific histological association. Interestingly, lesions with a
central depression presented foci of high grade dysplasia, even when their size was
less than 10 mm, suggesting that this endoscopic feature could be predictive of higher
risk for advanced duodenal disease. Moreover, when we compare each lesion pattern
of size less than 10 mm with one with similar morphologic features but size larger
than 10 mm, we observe more aggressive histologic characteristics. This observation
suggests that we might be looking at a specific endoscopic pattern at different stages
of evolution. Although it would be interesting to validate this observation prospectively
in a larger population, the risk of leaving advanced adenomas in place would probably
outweigh the benefits of confirming this observation.
Additionally, the role of emerging technologies such as dual focus NBI and probe-based
confocal laser endomicroscopy (pCLE) for characterization of duodenal lesions should
be analyzed. Although these diagnostic modalities have demonstrated a high (90 %)
negative predictive value (NPV) with respect to standard histology, further characterization
of different histologic architecture has not been validated [20]. Taking into consideration that one of the major current limitations of actual duodenal
surveillance in FAP would be to overlook dysplastic lesions that may evolve to cancer
during the recommended surveillance interval [21], it does not seem useful to introduce a high cost technology such as pCLE in order
to overcome this limitation. In contrast, the routine use of high-resolution endoscopy
in specialized centers could contribute to a better standard endoscopic examination
that facilitates an accurate characterization of duodenal polyps and Spigelman score.
Regarding localization of duodenal adenomas, it has been classically described that
most dysplastic adenomas in FAP are located in the second and third duodenal portion
[22]. In the present study, the duodenal bulb was also a frequent location for advanced
adenomas. Although the ideal endoscopic screening protocol has not been prospectively
validated [21], this fact reinforces the observation that both axial and lateral view EGD should
be performed in order to have a clear view of all segments of the duodenum to optimize
its endoscopic evaluation and yield a more precise Spigelman score for each patient
[19]
[21].
Duodenal adenomatosis evaluation in FAP at the present time has its own limitations.
Although the worldwide adopted staging system, the Spigelman classification, has never
been studied prospectively, it has been shown to correlate with the risk of duodenal
malignancy. Stages II, III, and IV disease are associated with a 2.3 %, 2.4 %, and
36 % risk of duodenal cancer, respectively [23]. Some considerations should be made when interpreting this association. Understaging
of duodenal polyposis based on endoscopic biopsies can occur and has previously been
reported [1]
[24]. In our study, we report a case initially staged as Spigelman III based on endoscopic
biopsies. After analyzing the mucosectomy specimen of advanced adenoma, we reclassified
that patient as Spigelman IV. Taking into consideration the wide gap in estimated
duodenal cancer risk between a Spigelman III and IV, we can say that every time a
patient is substaged as Spigelman III, that patient’s risk for duodenal cancer is
being 15 times underestimated. Whenever a high index of suspicion of substaging occurs,
a very close follow-up should be taken to further establish the best therapeutic approach
for these patients.
When analyzing the clinical factors associated with ampullary adenomas, we have shown
that the only factor independently related to the presence of ampullary adenomas was
extraintestinal manifestations. Based on the fact that the presence of ampullary adenomas
itself is an extracolonic manifestation of the disease, it might be logical to presuppose
this association. Nevertheless, the same association was not found for non-ampullary
duodenal adenomas. The fact that ampullary adenomas were found in patients with different
Spigelman stages confirms that ampullary and non-ampullary duodenal disease should
be treated as different biological entities [14]. Moreover, the presence of extraintestinal manifestations should raise the clinical
suspicion for ampullary adenomas as these factors presented an independent association.
Regarding the possibility of random ampullary biopsies as protocol, we chose not to
perform biopsies in endoscopically normal ampulla. The presence of altered histology
of the ampulla in random biopsies has been described [25]. However, biopsies of the ampulla carry a small associated risk of pancreatitis.
Additionally, ampullary adenomas in FAP have a slow progression, with evidence that
development of ampullary cancer is higher in polyps larger than 1 cm [14], which were not found in the present study. We believe that the risks of collecting
biopsies in endoscopically normal ampulla outweigh the benefits of diagnosing an adenoma
that will take years to progress into clinically significant disease with criteria
for resection.
It has been demonstrated that the severity of duodenal polyposis is a clear predictor
for detecting adenomas distal to the Treitz ligament [26]
[27]
[28]. Taking this concept into consideration, BAE was performed in patients with Spigelman
score III or IV. The prevalence of jejunal polyposis was high (83.3 %) in these patients.
However, it was represented by lesions that were not clinically significant, similar
to what has already been described in previous studies [26]. In this context, we suggest that indications for BAE should be individualized in
patients with Spigelman score III or IV who may need further study of the extent of
jejunal involvement as potential surgery candidates. Regarding the method for enteroscopic
evaluation, BAE was chosen because of the possibility of histological confirmation
and therapeutic interventions if necessary [29]. Although capsule endoscopy has been demonstrated to be useful and safe for the
surveillance of jejunal-ileal polyps in patients with FAP [27], it may underestimate the number of polyps and miss the detection of large lesions
[30].
We acknowledge several limitations of the study. A genetic analysis should take place
in order to further understand and characterize the molecular background that could
predispose patients to a more severe duodenal phenotype. FAP is a rare genetic disease
and this limited the number of patients included in this study. Moreover, the distribution
of advanced duodenal disease led to a small number of patients with Spigelman score
III and IV for analysis. This limited the statistical analysis of important clinical
observations such as the association between specific endoscopic patterns and histopathology.
It would be useful to set up multicenter studies that could overcome this drawback.
In summary, the severity of duodenal adenomatosis may be predicted from the severity
of the duodenal phenotype in a first-degree relative. Adenomas larger than 10 mm or
with central depression may contain foci of high grade dysplasia with an increased
risk for developing advanced duodenal neoplasia. Extraintestinal manifestations should
raise the clinical suspicion for ampullary adenomas as these factors present an independent
association.
