Introduction
Colonic adenomatous polyposis of unknown etiology (CPUE), also referred to as multiple
colorectal adenomas or colon polyposis of unknown etiology in previous literature,
has generally been defined as 10 or more cumulative adenomatous colorectal polyps
with negative germline genetic testing for familial adenomatous polyposis (APC) and MUTYH-associated polyposis (MUTYH) [1]
[2]. The National Comprehensive Cancer Network (NCCN) recommends colonoscopy every 1
to 2 years for individuals with 20 or more colorectal adenomas and consideration of
these intervals for those with 10 to 19 adenomas [3]. A recommendation to consider upper endoscopic screening for those individuals with
20 or more adenomas was more recently added to their guidelines. International guidelines
have similar recommendations for colonoscopy interval but do not recommend upper endoscopic
screening [4].
The risk of gastroduodenal neoplasia is well known in polyposis patients with APC and biallelic MUTYH pathogenic variants [5]. Only a few studies have reported the prevalence in those with CPUE. In an initial
small study of 19 patients from a single center in the United States, upper endoscopy
revealed duodenal neoplasia in 31.6 % of patients [1]. A more recent study of 83 participants from the United Kingdom and the Netherlands
reported duodenal adenomas in 9.6 % [2]. The generalizability of these case series with limited genetic testing is unclear
in the era of multi-gene panel testing (MGPT). Recent discoveries have shown that
pathogenic/likely pathogenic variants in multiple other genes, including AXIN2, GREM1, NTHL1, POLE, POLD1, and MSH3, result in a colonic adenomatous polyposis phenotype [6]. MGPT that includes simultaneous analysis of genes associated with polyposis and
non-polyposis colorectal cancer phenotypes has been shown to have a higher diagnostic
yield [7]. Given this, MGPT is now the standard of care for genetic evaluation of patients
with a colonic adenomatous polyposis phenotype [3]
[8].
At this time, there is minimal available information on the risk for gastric and duodenal
neoplasia in CPUE patients after MGPT. There is a clear need to clarify this risk
to help guide screening recommendations. The aim of our study was to assess the results
of upper endoscopic screening in a multicenter cohort of CPUE patients after uninformative
MGPT.
Patients and methods
This was a retrospective study assessing patients with CPUE that completed genetic
testing and were followed at specialized hereditary and high-risk gastroenterology
clinics at the participating centers. Institutional Review Board approval was obtained
at Ohio State University on April 29, 2020 and a reliance agreement was reached with
the other centers. A waiver of informed consent was approved, given the minimal risk
nature of the study.
Participants were considered for inclusion in the study if they had 10 or more cumulative
colorectal adenomas, uninformative MGPT, and received a screening upper endoscopy
after being diagnosed with colonic adenomatous polyposis from August 2014 through
January 2020. Patients were excluded if they were under age 18, did not have APC and MUTYH included in their genetic panel testing, had a known pathogenic/likely pathogenic
genetic variant in any hereditary cancer gene (including those not traditionally associated
with colorectal cancer), had a history of gastric or duodenal neoplasia (such as adenomatous
polyps or adenocarcinoma), had a diagnosis of serrated polyposis syndrome or had a
history of abdominal radiation or chemotherapy for a childhood cancer (given reports
of therapy-associated polyposis) [9]
[10].
If the participants met study criteria, demographic and clinical details were obtained
from medical records including endoscopy and pathology reports. This included data
on age, race, sex, past medical history, social history, family history (including
pedigrees obtained during genetic counseling sessions), genetic testing results, cumulative
colorectal adenoma counts, and findings on upper endoscopy after polyposis diagnosis
including whether the ampulla was visualized (utilizing either a side-viewing duodenoscope
or with a clear cap distal attachment). Standard clinical practice at all participating
centers during the study period was to resect or at least biopsy any lesions concerning
for neoplasia. As such, pathology results were assessed to confirm the presence of
gastric adenoma, gastric adenoma with high-grade dysplasia, gastric cancer, duodenal
adenoma, duodenal adenoma with high-grade dysplasia, duodenal cancer, ampullary adenoma,
ampullary adenoma with high-grade dysplasia, and ampullary cancer. The comprehensive
category of “any gastroduodenal neoplasia” was considered positive if any of these
were present.
The deidentified data were then collected and managed using Research Electronic Data
Capture (REDCap) tools hosted at the Ohio State University. REDCap is a secure, web-based
software platform designed to support data capture for research studies, providing:
1) an intuitive interface for validated data capture; 2) audit trails for tracking
data manipulation and export procedures; 3) automated export procedures for seamless
data downloads to common statistical packages; and 4) procedures for data integration
and interoperability with external sources [11]
[12].
Data are presented as mean and standard deviation or frequency and percentage. Comparisons
were done with t-tests for continuous variables and Fisher exact tests for categorical variables.
P < .05 was considered statistically significant. SAS software (version 9.4; SAS Institute,
Cary, North Carolina, United States) was used to perform all analyses.
Results
Across the five participating centers, 128 patients with CPUE met study criteria and
were further analyzed. The median number of participants per center was 19 (range
3–68). The colorectal phenotypes of the patients were 46 (35.9 %) with 10 to 19 colorectal
adenomas, 73 (57.0 %) with 20 to 99 colorectal adenomas and nine (7.0 %) with 100
or more colorectal adenomas. Twenty-six patients (20.3 %) had a personal history of
cancer, including colorectal cancer in 13 (10.2 %) and thyroid cancer in four (3.1 %).
Family history of colorectal cancer in a first-degree relative was present for 33
(25.8 %) subjects and 11 (8.6 %) reported a first-degree relative with colon polyposis.
Further demographic and clinical details are available in [Table 1]. Genetic counseling and MGPT was completed in all patients and [Table 2] includes the list of genes of interest that were assessed and for which no pathogenic/likely
pathogenic variants were identified.
Table 1
Demographics and clinical history.
|
n = 128
|
Age at index endoscopy (mean, SD)
|
58.1
|
13.0
|
Women
|
51
|
39.8 %
|
Body mass index (mean, SD)
|
29.3
|
6.4
|
Race
|
|
115
|
89.8 %
|
|
12
|
9.4 %
|
|
1
|
0.8 %
|
Alcohol use
|
|
47
|
36.7 %
|
|
8
|
6.3 %
|
|
73
|
57 %
|
Tobacco history
|
|
32
|
25 %
|
|
33
|
25.8 %
|
|
63
|
49.2 %
|
Aspirin use (daily)
|
41
|
32.0 %
|
History of Helicobacter pylori
|
14
|
10.9 %
|
Cumulative number of colorectal adenomas
|
|
46
|
35.9 %
|
|
73
|
57.0 %
|
|
9
|
7.0 %
|
History of colectomy
|
19
|
14.8 %
|
History of cancer[1]
|
26
|
20.3 %
|
History of colorectal cancer
|
13
|
10.2 %
|
History of thyroid cancer
|
4
|
3.1 %
|
Family history of colon cancer in first degree relative
|
33
|
25.8 %
|
Family history of polyposis in first degree relative
|
11
|
8.6 %
|
Variant of uncertain significance in a gene of interest
|
24
|
18.8 %
|
Single variant in a biallelic condition[2]
|
4
|
3.1 %
|
1 Excluding non-melanoma skin cancers
2
MSH3, MUTYH, NTLH1
Table 2
Genes of interest included in multi-gene panel testing
|
n = 128
|
APC
|
128
|
100 %
|
MUTYH
|
128
|
100 %
|
MLH1
|
121
|
94.5 %
|
MSH2
|
121
|
94.5 %
|
MSH6
|
121
|
94.5 %
|
PMS2
|
121
|
94.5 %
|
EPCAM
|
120
|
93.8 %
|
POLD1
|
119
|
93.0 %
|
POLE
|
119
|
93.0 %
|
GREM1
|
115
|
89.8 %
|
TP53
|
115
|
89.8 %
|
CHEK2
|
113
|
88.3 %
|
AXIN2
|
98
|
76.6 %
|
NTLH1
|
53
|
41.4 %
|
MSH3
|
52
|
40.6 %
|
GALNT12
|
10
|
7.8 %
|
RPS20
|
6
|
4.7 %
|
There were nine patients (7.0 %) with gastroduodenal neoplasia identified on the index
upper endoscopy. The cohort with 100 or more colorectal adenomas had a significantly
higher rate of any gastroduodenal neoplasia than those with 20 to 99 colorectal adenomas
or 10 to 19 colorectal adenomas (44.4 % vs 4.1 % vs 4.4 %, P = 0.002) ([Fig. 1]). Similar results were seen when the analysis was restricted to only duodenal adenomas
(33 % vs 2.7 % vs 4.4 %, P = 0.007) ([Fig. 1]). Interestingly, none of the 17 patients with 50 to 99 colorectal adenomas were
found to have gastroduodenal neoplasia. The only malignancy found on screening upper
endoscopy was gastric cancer in the setting of a concomitant Helicobacter pylori infection in a patient with 20 to 99 colorectal adenomas. For those with duodenal
adenomas, one subject had four duodenal adenomas, one subject had two duodenal adenomas,
and otherwise, a single adenomatous polyp was found per subject. The polyps ranged
in size from 2 mm to 2.5 cm and were all able to be resected endoscopically by snare
polypectomy or endoscopic mucosal resection.
Fig. 1 Results of index screening upper endoscopy in colonic adenomatous polyposis of unknown
etiology cohorts grouped by cumulative number of colorectal adenomas.
Documentation of ampullary visualization was present for 91 patients (71.1 %) with
similar rates across the three cohorts (P = 0.3). For those with an assessment performed, ampullary adenomas were only identified
in the cohort with 100 or more adenomas (33.3 % vs 0 % vs 0 %, P = 0.003) ([Fig. 1]).
The cumulative number of colorectal adenomas was the only significantly different
demographic or clinical feature between the cohort with gastroduodenal neoplasia on
index upper endoscopy and those without ([Table 3]). There was no difference across the participating medical centers (P = 0.604).
Table 3
Comparison of participants grouped by gastroduodenal neoplasia
|
With gastroduodenal neoplasia
|
Without gastroduodenal neoplasia
|
P value
|
|
n = 9
|
n = 119
|
|
Age at index endoscopy (mean, SD)
|
52.3
|
13.9
|
58.5
|
12.8
|
0.168
|
Women (sex)
|
5
|
55.6 %
|
46
|
38.6 %
|
0.482
|
Body mass index (mean, SD)
|
28.7
|
10.3
|
29.3
|
6.1
|
0.794
|
Race
|
1.000
|
|
8
|
88.9 %
|
107
|
89.9 %
|
|
|
1
|
11.1 %
|
11
|
9.2 %
|
|
|
0
|
0 %
|
1
|
0.8 %
|
|
Alcohol use
|
1.000
|
|
3
|
33.3 %
|
44
|
37.0 %
|
|
|
0
|
0 %
|
8
|
6.7 %
|
|
|
6
|
66.7 %
|
67
|
56.3 %
|
|
Tobacco history
|
0.437
|
|
2
|
22.2 %
|
30
|
25.2 %
|
|
|
4
|
44.4 %
|
29
|
24.4 %
|
|
|
3
|
33.3 %
|
60
|
50.4 %
|
|
Aspirin use (daily)
|
3
|
33.3 %
|
38
|
31.9 %
|
1.000
|
History of Helicobacter pylori
|
1
|
11.1 %
|
13
|
10.9 %
|
1.000
|
Cumulative number of colorectal adenomas
|
0.002
|
|
2
|
22.2 %
|
44
|
37.0 %
|
|
|
3
|
33.3 %
|
70
|
58.8 %
|
|
|
4
|
44.4 %
|
5
|
4.2 %
|
|
History of colectomy
|
3
|
33.3 %
|
16
|
13.5 %
|
0.130
|
History of cancer[1]
|
1
|
11.1 %
|
25
|
21.0 %
|
0.685
|
History of colon cancer
|
0
|
0 %
|
13
|
10.9 %
|
0.597
|
Family history of colorectal cancer in first degree relative
|
3
|
33.3 %
|
30
|
25.2 %
|
0.694
|
Family history of polyposis in first degree relative
|
1
|
11.1 %
|
10
|
8.4 %
|
0.567
|
Variant of uncertain significance in a gene of interest
|
1
|
12.5 %
|
23
|
22.3 %
|
1.000
|
Single variant in a biallelic condition[2]
|
1
|
12.5 %
|
3
|
3.0 %
|
0.266
|
1 Excluding non-melanoma skin cancers.
2
MSH3, MUTYH, NTLH1
Additional upper endoscopies were performed on 28 patients without baseline neoplasia.
From this group, gastroduodenal neoplasia was noted in two patients (7.1 %), including
one with gastric adenoma 7 years after index upper endoscopy and one with duodenal
adenoma 2 years after index procedure.
Discussion
In this multicenter analysis of CPUE patients after negative MGPT, we found a 7.0 %
rate of gastroduodenal neoplasia at initial screening upper endoscopy. This was primarily
duodenal adenomas, although two ampullary adenomas and a gastric cancer were also
identified. These results are noteworthy as this is the largest cohort of CPUE patients
receiving upper endoscopic screening to be reported to date and is the first to have
inclusion criteria requiring broad multi-gene genetic testing.
The prevalence of gastroduodenal neoplasia in our cohort is lower than in previous
reports focused on upper gastrointestinal findings in CPUE patients. One potential
cause for this is the different genetic testing criterion between the studies. Tieu
et al. reported on upper endoscopic findings on 19 patients with CPUE after genetic
testing for only APC and MUTYH
[1]. They reported six patients (31.6 %) with duodenal adenomas and did not find any
malignancies. Kallenberg et al. included 83 patients that were also primarily patients
with CPUE after genetic testing for only APC and MUTYH, although their cohort did include two with MGPT and 23 with small genetic testing
panels [2]. They found eight patients (9.6 %) with duodenal adenomas and did not report any
malignancies. Although pathogenic/likely pathogenic variants in the additional genes
tested are rare individually, recent evaluation of colonic adenomatous polyposis patients
has found an increased yield when MGPT is performed, especially in patients with less
than 100 colorectal adenomas [7]. As such, it seems likely that some patients included in previous series would be
found to have identifiable hereditary cancer syndromes with currently available MGPT,
and thus, not be eligible for our study and, more importantly, not be managed as CPUE
clinically.
Given its nature as a diagnosis of exclusion based on a fairly common clinical phenotype,
CPUE represents a heterogeneous mixture of patients. We need to ensure the use of
optimal available testing to identify those that may no longer have an unknown etiology.
As such, the current definition of CPUE, both clinically and in research efforts,
needs to be updated to include unremarkable MGPT that includes available polyposis
and non-polyposis colorectal cancer genes rather than only the classic polyposis genes
APC and MUTYH.
In our cohort, the cumulative number of colorectal adenomas was significantly different
between subjects with gastroduodenal neoplasia and those without. Those with over
100 colorectal adenomas had a significantly higher risk of having gastroduodenal neoplasia
when compared to the other cohorts and seem to be a clearly different phenotype. This
lends credence to recommendations to manage those with over 100 colorectal adenomas
according to familial adenomatous polyposis guidelines independently of an identified
genetic pathogenic variant [3].
Although the risk of duodenal neoplasia was lower in those with 10 to 19 and 20 to
99 colorectal adenomas, these cohorts still had a rate of gastroduodenal neoplasia
over 4 %. For comparison, the prevalence of sporadic duodenal adenomas in the general
population is estimated at 0.1 % to 0.3 % while MUTYH-associated polyposis and familial adenomatous polyposis have prevalence rates of
21.1 % and 65 %, respectively [13]
[14]
[15]. We were unable to otherwise identify any demographic or clinical features to help
guide decision-making regarding upper endoscopic screening. This is similar to previous
studies, as Kallenberg et al. also reported a lack of significant differences in their
neoplasia and non-neoplasia cohorts while Tieu et al. only found that their neoplasia
patients were younger at diagnosis [1]
[2]. With these factors taken into account, we feel the current evidence supports the
recommendation to perform at least a baseline screening upper endoscopy for all CPUE
patients. To limit risk of multiple sedation events, we favor performing this at the
time of a surveillance colonoscopy. Future work should continue to attempt to identify
the most appropriate age to initiate screening and if there are clinical features
that can be used to optimize screening guidelines.
Similarly, optimal screening and surveillance intervals are unknown. For those with
identified neoplasia, we would favor following the guidelines in place for familial
adenomatous polyposis-related neoplasia. The necessity and appropriate interval for
repeat screening after a negative initial screening event remains to be elucidated,
although our experience suggests this should at least be considered, given the rate
of neoplasia identified in those undergoing more than one upper endoscopy in our cohort.
To clarify this, the effectiveness of ongoing screening programs should also be a
focus of future research.
There are limitations to this study that need to be considered. This includes that
this is a retrospective analysis relying on review of medical records for documentation
of clinical and endoscopic findings and the inherent potential of inaccuracy. Similarly,
the endoscopies were performed according to standard practice at each institution
rather than a strict study protocol. In addition, this cohort may not be truly representative
of all oligopolyposis patients given the use of genetic testing as an inclusion criterion
and the lack of racial diversity. However, we feel that the size and multicenter nature
of the reported cohort outweigh these concerns.
Conclusions
In summary, we found a 7 % rate of gastroduodenal neoplasia in patients with CPUE
after MGPT. Although patients with over 100 colorectal adenomas had a significantly
higher risk, 4 % of those with 10 to 99 adenomas had gastroduodenal neoplasia. Given
this, we favor performing screening upper endoscopy at the time of a colonoscopy after
CPUE diagnosis.