Introduction
Recent studies have demonstrated a gradual increase in the incidence of duodenal adenocarcinoma
[1]
[2]. Superficial nonampullary duodenal epithelial tumors (NADETs) including duodenal
adenoma and carcinoma with no submucosal invasion are candidates for endoscopic resection
(ER) [3]
[4]
[5]. Recent studies have reported the efficacy of ER for superficial NADETs [3]
[4]
[5]. However, due to the anatomical characteristics of the duodenum such as its narrow
lumen, thin wall, and long distance from the mouth, which sometimes makes it difficult
to manipulate an endoscope, duodenal ER harbors a higher risk of complication than
does ER in the stomach or colon [4]
[5]
[6]
[7]. Therefore, the diagnosis of superficial NADETs is important when considering resection
or follow-up and when choosing which method of ER to undertake in the case of resection
[3].
Obtaining a biopsy from the lesion is considered to be the gold standard of diagnosis
[8]. However, a biopsy may cause inadvertent submucosal fibrosis and further complicate
ER [4]. In addition, diagnoses based on biopsy and resected specimens can pose considerable
discrepancies [4]
[5]
[9]. Therefore, an endoscopy-based diagnosis is preferable for superficial NADETs that
are likely to undergo ER.
Previous studies have analyzed the macroscopic characteristics of superficial NADETs
and reported that a reddish color [5]
[9] and depressions within the lesion [9]
[10] are suggestive of carcinoma rather than adenoma. Moreover, a lesion with a biopsy-based
diagnosis of high grade adenoma (Vienna classification category 4.1, VCL4.1) often
yields a final diagnosis of adenocarcinoma [5]
[9]
[10]. However, no comprehensive diagnostic criteria have yet been proposed for the endoscopic
diagnosis of duodenal carcinoma. This study aimed to clarify the endoscopic characteristics
of superficial NADETs and establish simple endoscopic diagnostic criteria to differentiate
between duodenal low grade adenoma (VCL3) and VCL4 or higher.
Materials and methods
Patients
This retrospective study included 150 lesions in 134 consecutive patients with superficial
NADETs who underwent tumor resection by ER or surgery between June 2004 and November
2016 at Shizuoka Cancer Center Hospital. The hospital’s institutional review board
approved this retrospective medical record review study (25-J155-25-1-3).
Derivation dataset
Two endoscopists (N. K., M. Y.) reviewed endoscopic images of 72 lesions of superficial
NADETs among 62 patients who were resected between June 2004 and December 2013. Both
were board-certified endoscopists with more than 7 years of endoscopy experience.
Two patients diagnosed as having familial adenomatous polyps (FAP) with 5 lesions
and 1 lesion, respectively, were included. Fifty-two lesions among 72 lesions had
been biopsied (median number of biopsies, 1) before examination in our hospital. All
images were taken by high-resolution forward-view endoscopes (H260-GIF or H260Z-GIF,
Olympus, Tokyo) without magnification. White-light images and chromoendoscopy with
indigo carmine images were analyzed. If there was any inconsistency in the assessment
of the endoscopic findings, a final diagnosis was decided upon by a joint review of
these images. Preoperative assessment variables such as patient’s age, sex, and lesion
location, and endoscopic characteristics such as lesion diameter, color, presence
of depression and nodularity, and macroscopic type were recorded. The macroscopic
types of superficial NADETs were classified using the Paris endoscopic classification
[11]. According to endoscopic features, the macroscopic types included protruded pedunculated
(Ip), protruded sessile (Is), superficial elevated (IIa), and superficial shallow
or depressed types (IIc). Mixed patterns, including IIa + Is or IIa + IIc, were diagnosed
when more than one component was observed. Colors of the lesion were described as
white, isochromatic or red. Nodularity of the lesion was described as “uniform” or
“heterogenous” when the surface was covered with even or uneven nodules ([Fig. 1]). If the lesion was depressed (IIc), the finding of nodularity was described as
“none”. Histological features were evaluated according to the revised Vienna classification
of gastrointestinal epithelial neoplasia [12]. Lesions were diagnosed as VCL3, VCL4 or higher depending on the degree of cytological
and architectural atypia, and invasion into the lamina propria.
Fig. 1 a A 10-mm white Isp lesion with uniform nodularity. b A 12-mm Is lesion with heterogenous nodularity with a reddish large component and
isochromatic small component. c A 18-mm IIa lesion with no nodularity. A reddish depression is observed on the surface.
Univariate analysis was performed to assess significant factors indicative of VCL4
or higher. A scoring system was established based on endoscopic characteristics to
differentiate between VCL3 and VCL4 or higher. This system only included predictor
variables that remained statistically significant (P < 0.05).
Validation dataset
The established scoring system was applied to diagnose 78 lesions of superficial NADETs
among 72 patients who were treated between January 2014 and November 2016. Two patients
diagnosed as having FAP with one lesion each were included. In total, 54 lesions among
78 lesions had been biopsied (median number of biopsies, 1) before examination in
our hospital. The diagnosis based on the scoring system was compared to the final
histology. Endoscopic characteristics of the lesions were recorded immediately after
endoscopy performed by six endoscopists (N. K., M. Y., T. I., K. T., M. T., N. K.)
who were blinded to the final histology. The score was calculated based on the recorded
endoscopic characteristics. Endoscopic experience among the six endoscopists varied
from 6 to 17 years.
Statistical analysis
Descriptive statistics for all patients were generated for all measures, including
medians and ranges for continuous measures, and frequencies and proportions for categorical
measures. Univariate analyses were performed to examine the relationships among each
of the individual patient and lesion measures and VCL3 or VCL4 or higher. Chi-squared
and Fisher’s exact tests were used to calculate statistical significance for categorical
predictors, and the Mann-Whitney U test was used for continuous predictors. All analyses were performed using Excel
statistics 2012 (Social Survey Research Information, Tokyo, Japan).
Results
Factors indicative of Vienna classification category 4 or higher
Preoperative assessment variables of 72 lesions according to the final histology of
VCL3 or VCL4
or higher are shown in [Table 1]. Of these 72 lesions, 10 were VCL3, 5 were VCL4.1, 51 were intramucosal carcinoma
(VCL4.4), and 6 were submucosal invasive carcinoma (VCL5). The median diameters of
lesions preoperatively assessed by endoscopy were 10 and 15 mm for VCL3 and VCL4 or
higher, respectively. Lesion diameter, color, macroscopic type, presence of depression,
and heterogeneous or no nodularity were predictive factors for VCL4 or higher (P < 0.05).
Table 1
Preoperative assessment variables of 72 superficial nonampullary duodenal epithelial
tumors.
|
Variable
|
VCL3
|
VCL4 or higher
|
P value
|
|
Sex
|
|
|
9
|
49
|
0.7
|
|
|
1
|
13
|
|
|
Age, median (range)
|
67 (34 – 81)
|
61 (27 – 84)
|
0.21
|
|
Location (portion of the duodenum)
|
|
|
3
|
7
|
0.11
|
|
|
7
|
49
|
|
|
|
0
|
6
|
|
|
Lesion diameter, median (range), mm
|
10 (6 – 25)
|
15 (4 – 50)
|
0.013
|
|
Color
|
|
|
7
|
11
|
0.0003
|
|
|
3
|
10
|
|
|
|
0
|
41
|
|
|
Macroscopic type
|
|
|
9
|
27
|
0.006
|
|
|
1
|
35
|
|
|
Depression
|
|
|
9
|
30
|
0.014
|
|
|
1
|
32
|
|
|
Nodularity
|
|
|
7
|
12
|
0.0007
|
|
|
3
|
50
|
|
VCL3, Vienna classification category 3; VCL4, Vienna classification category 4.
Scoring system to predict VCL4 or higher
A predictive scoring system was created by allocating points from 0 to 2 to each endoscopic
finding, as shown in [Table 2]. When a lesion had mixed color, the color with the highest point was selected. A
box plot of scores allocated for each endoscopic finding and final diagnoses as VCL3
or VCL4 or higher is shown in [Fig. 2]. The median scores for VCL3 and VCL4 or higher were 1 and 4, respectively. Lesions
diagnosed as VCL4 or higher had significantly higher scores than those diagnosed as
VCL3 (Mann-Whitney U test, P = 0.0001). To investigate the relationship between the scoring system and the final
diagnosis of VCL3 or VCL4 or higher, a receiver operating characteristic (ROC) curve
was derived. On the basis of the ROC curve, a score of 3 points was defined as an
appropriate cutoff for predicting VCL4 or higher with a sensitivity rate of 0.84,
specificity rate of 0.90, and a false positive rate of 0.1 ([Fig.3]).
Table 2
Scoring system for VCL3 and VCL4 or higher.
|
Endoscopic finding
|
Score
|
|
0
|
1
|
2
|
|
Lesion diameter
|
< 10 mm
|
≥ 10 mm
|
|
|
Color
|
White
|
Isochromatic
|
Red
|
|
Macroscopic type
|
Is, Ip, IIa without depression
|
Any type with depression or mixed type
|
|
|
Nodularity
|
Uniform
|
Heterogeneous or none
|
|
Fig. 2 A box plot of the scores of lesions with a final histology of Vienna classification
category 3 (VCL3) or VCL4 or higher. The difference in the scores between the two
groups was significant (Mann-Whitney U test, P = 0.0001).
Fig. 3 A receiver operating characteristic curve was derived and a score of 3 points was
defined as an appropriate cutoff for predicting Vienna classification category 4 or
higher.
Validation analysis
To test the validity of our predictive model, we examined 78 additional lesions in
72 patients treated between January 2014 and November 2016. The data for these patients
were not used in the process of building our scoring system. Of these 78 lesions,
14 were VCL3, 4 were VCL4.1, 56 were VCL4.4, and 4 were VCL5. When the lesion had
a total score of 3 points or more, the sensitivity, specificity, and accuracy of diagnosing
VCL4 or higher were 88 %, 79 %, and 86 %, respectively. A box plot of scores and final
diagnoses as VCL3 or VCL4 or higher is shown in [Fig. 4]. The difference in scores among the groups was statistically significant at P = 0.0001 (Mann-Whitney U test).
Fig. 4 A box plot of the scoring system in the validation analysis. The difference in the
scores between the two groups was significant (Mann-Whitney U test, P = 0.0001).
Lesions inconsistent with the scoring system
In the validation analysis, three lesions in three patients who had a score of 3 points
or more had a final histology of VCL3. The first lesion was a 6-mm red IIa lesion
with no nodularity. The scoring system allocated 3 points, but the subjective impression
of the endoscopist was that the lesion was adenoma. This lesion was followed previously
for 2 years before resection and the color changed from white to red. The second lesion
was a 5-mm red IIc lesion with no nodularity. The scoring system allocated 4 points
and the subjective impression of the endoscopist was carcinoma. The final lesion was
a 12-mm partially red IIa + IIc lesion with no nodularity. The scoring system allocated
5 points and the subjective impression of the endoscopist was carcinoma. All three
patients underwent ER.
Eight lesions in eight patients who had a score of < 3 points had a final histology
of VCL4 or higher. The color was isochromatic in 2 lesions and white in 6 lesions.
The macroscopic types were IIc for 1 lesion, Is for 1 lesion, and the remainder were
IIa lesions. Nodularity was heterogeneous or not found in 6 lesions. The subjective
impression of the endoscopist was adenoma in 5 lesions. The other 3 lesions were diagnosed
as carcinoma regardless of the score because of the heterogeneous appearance of the
lesion. According to the final pathology, 1 lesion had a focal high grade component
in a VCL3, 6 lesions were VCL4.4, and 1 lesion showed carcinoma with minute submucosal
invasion (VCL5). The submucosal carcinoma was a 7-mm white IIa lesion with a score
of 1 point. This patient underwent partial duodenectomy because he had 2 lesions in
the 2nd and 3 rd portions of the duodenum, which were considered difficult for ER.
Of the remaining 7 patients, 6 underwent ER, and 1 underwent a partial duodenectomy.
Discussion
From previous studies, it is considered that most primary nonampullary duodenal carcinomas
(NADCs) follow the adenoma – carcinoma sequence [13]
[14]
[15]. Focal carcinoma has been recognized in adenomatous polyps [13], and residual adenomatous tissue has been recognized in surgically resected duodenal
carcinoma [13]
[14]
[15]. A follow-up study including patients with superficial NADETs demonstrated that
the majority of VCL3 showed no progression during follow-up, but 21 % showed progression
to VCL4 or higher [10]. Therefore, diagnosing VCL3 from VCL4 or higher among NADETs is essential to decide
clinical management.
In this study, we created a simple scoring system using endoscopic findings to distinguish
between VCL3 and VCL4 or higher. The endoscopic findings could be assessed using only
white-light imaging (WLI) with or without chromoendoscopy. A score of 3 points or
more correlated strongly with the final pathology of VCL4 or higher. The endoscopic
findings of reddish color, the presence of depression, loss of nodularity, and mixed
macroscopic types are also important in diagnosing carcinoma in the stomach or colorectum
[16]
[17]
[18]
[19]
[20]. Therefore, it is acceptable for endoscopists who are familiar with diagnosing carcinoma
of the stomach or the colorectum to retrieve these WLI findings among superficial
NADETs.
The accuracy of diagnosing VCL4 or higher using our scoring system was 86 % in the
validation study. A similar result has been reported in a retrospective multicenter
study with 75 % accuracy when using endoscopic features such as reddish color, nodular/rough
surface, and depressed portion [5]. Considering that the reported accuracy of biopsy-based diagnosis is 68 % – 74 %
[5]
[9], it is important to make an endoscopic diagnosis before taking a biopsy. The merit
of endoscopic diagnosis is that we can judge the lesion from the whole image, whereas
biopsies have issues of false negatives when they are performed in an area with a
lower grade of histology, or the retrieved specimen may not be sufficient for evaluation.
Total biopsy for small lesions may be quick, but it is sometimes difficult for large
lesions and for patients with multiple lesions. As heterogeneity of histologic grade
within a single lesion is not rare [3]
[4]
[5]
[9]
[18], endoscopic diagnosis may facilitate biopsies from areas with higher grades of histology.
The use of narrow-band imaging (NBI) with or without magnified endoscopy for the diagnosis
of superficial NADETs has been reported in a few small studies [21]
[22]
[23]. Yoshimura et al. reported that NBI with magnified endoscopy following WLI might
be a useful method to predict histological grade of NADETs [21]. Kikuchi et al. assessed surface and vascular patterns of NADETs and proposed a
diagnostic algorithm to differentiate histological grade of NADETs [22]. On the other hand, Tsuji et al. reported that there was no significant difference
in microvascular patterns between VCL3 and VCL4 lesions, but an irregular surface
pattern was more often observed among VCL4 lesions [23]. Although the diagnosis using NBI for NADETs seems promising, it is still not standardized
and its superiority compared to WLI diagnosis still requires further evaluation.
In the validation study, one lesion with submucosal invasion had a score of 1 point.
Duodenal carcinoma with invasion limited to the submucosa is extremely rare, and it
has been reported that reddish color is a common factor, but the prediction of submucosal
invasion is difficult [5]. In our case, the invasion depth was minute, the lesion was white without depression,
and we could not find any endoscopic features suggestive of submucosal invasion even
after re-evaluation of the endoscopic image.
Our study included four patients with FAP having a total of nine lesions. We used
the same diagnostic system for both sporadic and FAP associated NADETs. Patients with
FAP are known to have a high prevalence of NADETs [24]
[25]. Both sporadic and FAP associated duodenal carcinoma may occur because of the adenoma
carcinoma sequence, and thus macroscopic types of NADET are assumed to be similar.
However, this should be confirmed in further studies.
The first limitation of our study is that the number of VCL3 lesions included was
relatively small. As we only included lesions that were resected, some lesions with
an endoscopic or biopsy diagnosis of VCL3 may have been followed without resection.
Thus, the possibility of selection bias cannot be ignored. Another limitation is that
endoscopic findings of color or macroscopic type may be influenced by biopsy. There
is a possibility that the color may change to red, and a depression may appear after
taking a biopsy. However, biopsy-induced changes are often focal or limited and sometimes
are accompanied by regenerative mucosa or slight fold convergence. Therefore, we should
be careful to observe the whole lesion to extract appropriate endoscopic findings
with consideration for artificial changes caused by previous biopsies. Finally, this
is a retrospective study performed in a single institution. We showed good reproducibility
of the scoring system in our own validation study; however, this should be confirmed
in a prospective, multicenter study.
In conclusion, a simple and useful endoscopic scoring system was developed to differentiate
preoperatively between VCL3 and VCL4 or higher among superficial NADETs.
