Abstract
Background
Sporadic nonampullary duodenal adenocarcinoma is a rare malignant neoplasm in which poor prognosis is often associated with delayed diagnosis.
Objective
A case-control study was designed to evaluate the clinical and endoscopic characteristics of patients with nonampullary duodenal epithelial tumours (NADETs).
Methods
Patients with NADETs were chronologically divided into a discovery and a validation sets. Two age- and sex-matched control individuals for each case in the discovery set were randomly selected from individuals without NADET. A prediction model for the presence of NADET, constructed in the discovery set, was evaluated in the validation set.
Results
In total, 368 adenomas, 81 adenocarcinomas, and 314 controls were analysed. Current smoking, Barrett oesophagus, fundic gland polyps, history of malignant disease, and absence of dyslipidaemia were independently associated with the presence of NADET. The combination of these five factors enabled significant discrimination for NADET in the bulb with a sensitivity of 0.81 in the validation set. We also showed that duodenal adenocarcinomas in the bulb had greater invasive potential than adenocarcinomas in the second portion.
Conclusion
The presence of a duodenal tumour in the bulb could be predicted by clinical and endoscopic findings, which helps improve the prognosis and quality of life of patients.
Keywords: Atherosclerosis, chronic mesenteric ischemia, computed tomography angiography, endovascular therapy, median arcuate ligament syndrome
Key summary
- Summarise the established knowledge on this subject:
- Nonhereditary, sporadic, nonampullary duodenal adenomas and adenocarcinomas are rare and their tumourigenesis is unclear.
- Improving strategies for their early detection of duodenal adenocarcinoma helps improve the prognosis and quality of life of patients.
- What are the significant and/or new findings of this study?
- Duodenal adenoma/carcinoma was associated with current smoking, Barrett oesophagus, fundic gland polyps, history of malignant disease, and absence of dyslipidaemia.
- A five-point Risk Assessment of Duodenal Adenoma/carcinoma consisting of these five factors was developed and successfully detected duodenal adenoma/carcinoma especially in the bulb.
- Bulb tumours were more invasive and differed from those in second portion of the duodenum.
Introduction
Cancers of the small intestine are rare malignant neoplasms that account for less than 5% of all gastrointestinal malignancies.1 Among these, adenocarcinomas are more frequently identified in the duodenum (50%–60%), whereas carcinoid tumours occur more frequently in the ileum (40%–50%) in the United States.2 A previous retrospective cohort study3 showed that < 40% of patients were eligible for resection, with a median survival of 23 months and an estimated five-year survival of 27%. In Japan, more than 40% of duodenal adenocarcinomas are asymptomatic, and most cases are detected by surveillance esophagogastroduodenoscopy (EGD).4 Duodenal adenomas, which are precursor lesions of duodenal adenocarcinomas, are rare tumours accounting for <0.4% of cases among individuals referred for diagnostic EGD.5 Approximately 40% of duodenal adenomas are sporadic, and the remaining 60% present in patients with familial adenomatous polyposis (FAP).6 Recent advances in endoscopic treatment, such as endoscopic submucosal dissection, have allowed increased numbers of patients to avoid open surgery for the treatment of duodenal adenoma and intramucosal carcinoma.7 Therefore, early diagnosis and appropriate treatment or follow-up can greatly improve the prognosis and quality of life of patients with duodenal adenocarcinoma. However, strategies for the early detection of nonhereditary, sporadic, nonampullary duodenal epithelial tumours (NADETs) remain to be designed.8 As NADET is a rare tumour, misdiagnosis during endoscopy can frequently occur. A previous study reported that detection of 37% of NADETs in the proximal and 83% in the distal duodenum failed during the first endoscopic investigation.9 Therefore, proper knowledge of clinical and endoscopic characteristics associated with the presence of NADET could help us reduce misdiagnosis.
The objective of the present study was to define the clinical and endoscopic characteristics of patients with NADET in Japan. As our hospital specialises in endoscopic resection of the duodenum,10 we were able to perform one of the largest case-control studies to date for NADET in a single centre with respect to sample size. Because previous studies showed a positive association between the presence of NADET and colorectal adenoma/carcinoma,11 a history of colorectal carcinoma and other malignant diseases was included among the factors investigated in the present study. In addition, lifestyle-related factors were carefully explored because of the association between the development of colorectal cancer and obesity and metabolic syndrome.12 A novel scoring system to assess the risk of NADETs was constructed based on the study results. In addition, the characteristics of tumours in the bulb (D1) and the second portion (D2) of the duodenum were compared.
Materials and methods
(See supplementary text for more information.).
Ethics statement
The protocol for the study was performed in accordance with the Declaration of Helsinki, and approved by the ethics committee of Keio University School of Medicine (no. 20130502, 24 March 2014). Because of the nonintrusive retrospective study design, the enrolment of participants without written informed consent was permitted in the present study protocol. Instead, we posted a notice on the website for opt-out to decline to participate. The analysed data of the participants were retrospectively collected using electronic medical records and anonymised prior to analysis.
Study population and settings
All consecutive patients who underwent EGD and received a histological diagnosis of NADET at Keio University Hospital between January 2010 and January 2018 were included in the study. Patients were divided into a discovery set and a validation set. Two age- and sex-matched control individuals for each case in the discovery set were randomly selected from among individuals who were not found to have NADET on EGD performed during the same period as part of a comprehensive medical examination at the Center for Preventive Medicine, Keio University Hospital, based on computer-generated random numbers. Individuals who underwent surgical resection in the oesophagus, stomach, or duodenum were excluded from the study. Those with FAP, Peutz-Jeghers syndrome, or hereditary nonpolyposis colon cancer (Lynch syndrome) were also excluded. Data obtained included age, sex, body mass index (BMI, kg/m 2), cigarette smoking status, alcohol consumption, comorbidities, medical history, and EGD findings.
To identify factors associated with the presence of NADET, clinical characteristics and endoscopic findings were compared between cases in the discovery set and controls. Based on the cumulative number of associated factors, a risk assessment model for NADET was constructed. The predictive performance of the risk assessment model was evaluated using receiver operating characteristic (ROC) curve analysis. Furthermore, the predictive sensitivity of the risk assessment model was also evaluated in the validation set.
Results
Participant characteristics
A total of 72,117 EGD examinations were conducted between January 2010 and January 2018, and 449 patients were histologically diagnosed with NADET (Figure 1(a)). These patients were chronologically divided into a discovery set (124 adenomas and 33 adenocarcinomas) and a validation set (244 adenomas and 48 adenocarcinomas). Depending on the age and sex distribution of the 157 patients with NADET in the discovery set, 314 age- and sex-matched individuals without NADET were assigned to the control group. Representative endoscopic images of duodenal adenoma and adenocarcinoma are shown in Figure 1(b).
Figure 1.
Study design. (a) Patient recruitment flowchart. (b) Representative endoscopic images of adenoma, adenocarcinoma in situ (Tis), and adenocarcinoma with submucosal invasion (T1≤) in the duodenal bulb (D1) and the second portion (D2).
The clinical characteristics of the discovery set are shown in Table 1. The percentage of current smokers was higher among patients with NADET than among the control individuals. The prevalence of Barrett oesophagus (BO) and FGP and history of other malignant diseases were higher in patients with NADET than in the controls. All identified BO cases were short-segment BO, as defined by the presence of a columnar-lined oesophagus extending < 3 cm into the oesophagus.13 The prevalence of dyslipidaemia and diabetes mellitus was marginally higher in patients with NADET than in the control participants (p < 0.1). Patients were categorised according to the histological features (adenoma or adenocarcinoma) or location (D1 or D2) of the tumour, and the characteristics of the patients in the respective groups were compared with those of individuals without NADET. Patients with duodenal adenocarcinoma were older than those with adenoma, which implied the slow development from duodenal adenoma to adenocarcinoma. In patients with a D2 tumour, the prevalence of open-type gastric mucosal atrophy was lower than that in the controls. In patients with adenoma or those with a D2 tumour, the prevalence of reflux esophagitis was marginally higher than that in the controls (p < 0.1). Based on these results, the following eight clinical factors were selected for further analysis: current smoking, presence of BO, reflux esophagitis, FGP, open-type gastric mucosal atrophy, dyslipidaemia, diabetes, and history of other malignant diseases. The details of other malignant diseases are shown in Supplementary Table 1. The two most prevalent malignant diseases in patients with NADET were colorectal cancer (5.7%) and gastric cancer (5.1%).
Table 1.
Differences between the characteristics of individuals with and without NADET in the discovery set.
| NADET (–) (n = 314) | NADET (+) (n = 157) | Histological feature |
Location |
|||
|---|---|---|---|---|---|---|
| Adenoma (n = 124) | Adenocarcinoma (n = 33) | D1 (n = 20) | D2 (n = 137) | |||
| Age (y) | 64.0 ± 12.2 | 64.1 ± 12.3 | 62.8 ± 12.2 | 69.1 ± 12.3 | 64.0 ± 12.3 | 64.1 ± 12.2 |
| Gender Men | 214 (68.2%) | 107 (68.2%) | 86 (69.4%) | 21 (63.6%) | 14 (70.0%) | 93 (67.9%) |
| Women | 100 (31.8%) | 50 (31.8%) | 38 (30.6%) | 12 (36.4%) | 6 (30.0%) | 44 (32.1%) |
| BMI (kg/m2) | 23.1 ± 3.2 | 23.4 ± 3.7 | 23.6 ± 3.7 | 22.4 ± 3.4 | 23.0 ± 4.1 | 23.4 ± 3.6 |
| Alcohol consumption | ||||||
| Drinking every day | 79 (25.2%) | 33 (21.0%) | 29 (23.4%) | 4 (12.1%) | 4 (20.0%) | 29 (21.2%) |
| >40 g of ethanol/drinking day | 64 (20.4%) | 23 (14.6%) | 20 (16.1%) | 3 (9.1%) | 5 (25.0%) | 18 (13.1%) |
| Smoking habit | ||||||
| Current smoker | 32 (10.2%) | 28 (17.8%) | 28 (22.6%) | 1 (3%) | 7 (35.0%) | 22 (16.0%)▴ |
| Ex-smoker | 126 (40.1%) | 52 (33.1%) | 40 (32.3%) | 12 (36.4%) | 5 (25.0%) | 47 (34.3%) |
| SSBO | 21 (6.7%) | 33 (21.0%) | 27 (21.8%) | 6 (18.2%) | 5 (25.0%) | 28 (20.4%) |
| Reflux esophagitis | 24 (7.6%) | 19 (12.1%) | 16 (12.9%)▴ | 3 (9.1%) | 1 (5.0%) | 18 (13.1%)▴ |
| Fundic gland polyp | 45 (14.3%) | 42 (26.8%) | 33 (26.6%) | 9 (27.3%)▴ | 3 (15.0%) | 39 (28.5%) |
| Gastric mucosal atrophy | ||||||
| C-II or C-III | 53 (16.9%) | 29 (18.5%) | 22 (17.7%) | 7 (21.2%) | 2 (10.0%) | 27 (19.7%) |
| Open-type | 80 (25.5%) | 29 (18.5%) | 21 (16.9%)▴ | 8 (24.2%) | 8 (40.0%) | 21 (15.3%) |
| Hypertension | 97 (30.9%) | 56 (35.7%) | 46 (37.1%) | 10 (30.3%) | 6 (30.0%) | 50 (36.5%) |
| Dyslipidaemia | 76 (24.3%) | 26 (16.6%)▴ | 20 (16.1%)▴ | 6 (18.2%) | 3 (15.0%) | 23 (16.8%)▴ |
| Diabetes | 60 (19.1%) | 20 (12.7%)▴ | 17 (13.7%) | 3 (9.1%) | 3 (15.0%) | 17 (12.4%) |
| Other malignant diseases | 38 (12.1%) | 40 (25.5%) | 31 (25.0%) | 9 (27.3%) | 8 (40.0%) | 32 (23.4%) |
Bold values, p < 0.05; ▴p < 0.1 (compared with individuals without NADET using Fisher exact test for categorical variables or Student t test for continuous variables).
BMI: body mass index; D1: duodenal bulb; D2: second part of the duodenum; NADET: nonampullary duodenal epithelial tumours; SSBO: short-segment Barrett oesophagus; y: years.
Factors associated with presence of NADET
Univariable logistic regression analysis revealed that seven of the eight identified clinical factors were significantly or marginally associated with the presence of NADET (Table 2). Reflux esophagitis showed no association. Multivariable analysis showed that current smoking, BO, FGP, and history of other malignant diseases were positively associated with the presence of NADET, whereas dyslipidaemia was negatively associated with the presence of NADET. Separate analysis of duodenal adenoma and adenocarcinoma showed that duodenal adenoma was independently associated with current smoking, BO, FGP and history of other malignant diseases. Duodenal adenocarcinoma was also independently associated with BO and FGP. Separate analysis of D1 and D2 tumours showed that a D1 tumour was independently associated with BO and history of other malignant diseases, while a D2 tumour was independently associated with current smoking, BO, FGP and history of other malignant diseases (see Supplementary Table 2).
Table 3.
Chronological validation for the sensitivity of RADA-5.
| Total | Histological feature |
Location |
|||
|---|---|---|---|---|---|
| Adenoma (n = 244) | Adenocarcinoma (n = 48) | D1 (n = 36) | D2 (n = 256) | ||
| Age (y) | 63.3 ± 10.7 | 62.9 ± 10.7 | 65.3 ± 11.0 | 67.7 ± 9.5 | 62.7 ± 10.8 |
| Gender | |||||
| Men | 200 (68.5%) | 169 (69.3%) | 31 (64.6%) | 24 (66.7%) | 176 (68.8%) |
| Women | 92 (31.5%) | 75 (30.7%) | 17 (35.4%) | 12 (33.3%) | 80 (31.3%) |
| BMI (kg/m2) | 23.4 ± 4.0 | 23.3 ± 3.9 | 23.9 ± 4.5 | 23.2 ± 4.5 | 23.5 ± 3.9 |
| Risk factors | |||||
| Current smoker | 70 (24.0%) | 59 (24.2%) | 11 (22.9%) | 10 (27.8%) | 60 (23.4%) |
| SSBO | 80 (27.4%) | 67 (27.5%) | 13 (27.1%) | 9 (25.0%) | 71 (27.7%) |
| Fundic gland polyp | 110 (37.7%) | 93 (38.1%) | 17 (35.4%) | 16 (44.4%) | 94 (36.7%) |
| Dyslipidaemia | 43 (14.7%) | 38 (15.6%) | 5 (10.4%) | 4 (11.1%) | 39 (15.2%) |
| Other malignant diseases | 72 (24.7%) | 59 (24.2%) | 13 (27.1%) | 12 (33.3%) | 60 (23.4%) |
| RADA-5 | |||||
| 0 | 7 (2.4%) | 5 (2.0%) | 2 (4.2%) | 0 (0%) | 7 (2.7%) |
| 1 | 79 (27.1%) | 68 (27.9%) | 11 (22.9%) | 7 (19.4%) | 72 (28.1%) |
| 2 | 134 (45.9%) | 110 (45.1%) | 24 (50.0%) | 19 (52.8%) | 115 (44.9%) |
| 3 | 56 (19.2%) | 50 (20.5%) | 6 (12.5%) | 7 (19.4%) | 49 (19.1%) |
| 4 | 14 (4.8%) | 9 (3.7%) | 5 (10.4%) | 2 (5.6%) | 12 (4.7%) |
| 5 | 2 (0.7%) | 2 (0.8%) | 0 (0%) | 1 (2.8%) | 1 (0.4%) |
| Sensitivity of RADA-5 ≥ 2 | 0.71 (0.65–0.76) | 0.70 (0.64–0.76) | 0.73 (0.60–0.86) | 0.81 (0.67–0.94) | 0.69 (0.63–0.75) |
Bold values, p < 0.05.
BMI: body mass index; D1: duodenal bulb; D2: second part of the duodenum; SSBE, short-segment Barrett oesophagus; y: years.
Table 2.
Factors associated with the presence of NADET.
| Univariable analysis |
Multivariable analysisa |
|||||||
|---|---|---|---|---|---|---|---|---|
| Adenoma + adenocarcinoma |
Adenoma + adenocarcinoma |
Adenoma |
Adenocarcinoma |
|||||
| OR | (95% CI) | OR | (95% CI) | OR | (95% CI) | OR | (95% CI) | |
| Current smoker | 2.01 | (1.16–3.48) | 2.61 | (1.45–4.68) | 3.35 | (1.79–6.30) | ||
| SSBO | 3.71 | (2.07–6.67) | 4.73 | (2.55–8.80) | 4.23 | (2.17–8.25) | 9.05 | (1.65–49.5) |
| Reflux esophagitis | 1.66 | (0.88–3.14) | ||||||
| Fundic gland polyp | 2.18 | (1.35–3.49) | 2.73 | (1.62–4.59) | 2.29 | (1.29–4.06) | 4.68 | (1.44–15.2) |
| Open-type gastric mucosal atrophy | 0.66▴ | (0.41–1.07) | ||||||
| Dyslipidaemia | 0.62▴ | (0.38–1.01) | 0.53 | (0.31–0.92) | ||||
| Diabetes | 0.62▴ | (0.36–1.07) | ||||||
| Other malignant diseases | 2.49 | (1.51–4.08) | 2.93 | (1.72–5.00) | 2.84 | (1.57–5.15) | ||
| Gastric cancer | 5.57 | (1.46–21.3) | ||||||
| Colorectal cancer | 2.76▴ | (0.94–8.09) | ||||||
Bold values, p < 0.05; ▴p < 0.1.
CI: confidence interval; NADET: nonampullary duodenal epithelial tumours; OR: odds ratio; SSBO, short-segment Barrett oesophagus.
Logistic regression analysis adjusted for factors selected by stepwise method from marginally associated factors in univariable analyses (p < 0.1).
Based on the results of the multivariable analysis, we constructed a novel five-point Risk Assessment model for Duodenal Adenoma/carcinoma (RADA-5) that included the cumulative number of the following risk factors: current smoking (+1), presence of BO (+1), presence of FGP (+), absence of dyslipidaemia (+1) and history of malignant disease (+1). As shown in Figure 2(a), increased RADA-5 scores were significantly associated with the presence of NADET. The predictive accuracies are shown in Figure 2(b). The areas under the ROC curves (AUCs) for duodenal adenoma and adenocarcinoma were 0.68 (95% confidence interval (CI), 0.62–0.74) and 0.65 (95% CI, 0.54–0.77), respectively. The RADA-5 achieved good accuracy for a D1 tumour with an AUC of 0.81 (95% CI, 0.70–0.92). At a cut-off RADA-5 score of 2, the sensitivity and specificity for a D1 tumour were 0.85 (95% CI, 0.68–1.00) and 0.73 (95% CI, 0.58–0.87), respectively.
Figure 2.
Five-point Risk Assessment model for Duodenal Adenoma/carcinoma (RADA-5). (a) The association between duodenal adenoma/adenocarcinoma and RADA-5. Numbers (%) in the bottom show the sensitivities for each score of the RADA-5. Odds ratios were calculated by logistic regression analysis. Error bars: 95% confidence interval. (b) Receiver operating characteristic curves according to RADA-5 for predicting the presence of duodenal adenoma/adenocarcinoma, or each location of the duodenum (D1/D2). Arrows show cut-off points, defined as RADA-5 ≥ 2. AUC: area under the ROC curve.
Chronological validation of the prevalence of risk factors for NADET
Subsequently, the prevalence of the associated factors identified in the discovery set was examined in the validation set. As shown in Table 1, the age, sex, and BMI of individuals with NADET in the validation set were almost same as those in the discovery set, suggesting that these demographic factors would be representative of Japanese patients with NADET. The increased prevalence of BO and FGP in the validation set might be caused by the lower prevalence of Helicobacter pylori infection in Japan.14 In the validation set, the sensitivity of the RADA-5 for the presence of NADET was 0.71 (95% CI, 0.65–0.76). The highest sensitivity for a D1 tumour (0.81 (95% CI, 0.67–0.94)) was validated.
Association between location and clinicohistological features of NADET
Finally, we evaluated the clinical and histological characteristics of a D1 tumour in the sample set. The presence of a D1 tumour was independently associated with BO and history of other malignant diseases, whereas the presence of a D2 tumour was independently associated with current smoking, BO, FGP and history of other malignant diseases (see Supplementary Table 3). The invasion depth of duodenal adenocarcinoma was significantly different between the two locations (Figure 3(a)). In the discovery set, all cases of adenocarcinoma in D1 showed submucosal or deeper invasion (>T1), whereas most cases of adenocarcinoma in D2 were intramucosal carcinomas (Tis). In the validation set, the percentage of adenocarcinoma was greater in D1 than in D2. Regarding the histological subtypes of adenocarcinoma (Figure 3(b)), the gastric type was significantly more frequent in adenocarcinomas in D1 than in D2 in the discovery set (Figure 3(c)). Among gastric-type adenocarcinomas, positive immunostaining for MUC5AC was observed in all epithelial cells of adenocarcinoma tissue in D1, whereas it was observed in 50% of epithelial cells of adenocarcinoma tissue in D2 (Figure 3(b), Supplementary Table 3). Based on these findings, a D1 tumour showed a greater potential for progression than a D2 tumour, although a D1 tumour was a rare finding in comparison to a D2 tumour.
Figure 3.
Pathological characteristics. (a) Difference of the invasion depth of nonampullary duodenal epithelial tumours between D1 and D2. Invasive duodenal adenocarcinoma was more prevalent in D1 in both discovery and validation sets. (b) Representative histological images of gastric-type and intestinal-type duodenal adenocarcinoma. The right panels show the expanded images of the left panels. Scale bar, 200 μm. (c) Difference of the histological type of duodenal adenocarcinoma between D1 and D2 in the discovery set. Gastric-type adenocarcinoma was more prevalent in D1. (d) Representative immunohistological images of gastric-type and intestinal-type duodenal adenocarcinoma. The presence/absence of immunostaining for gastric markers proved the morphological diagnosis of gastric-type or intestinal-type tumours. Scale bar, 200 μm.
Discussion
The present study revealed that current smoking, presence of BO and FGP, and history of other malignant diseases were independently associated with both duodenal adenoma and adenocarcinoma. The presence of dyslipidaemia was negatively associated with the presence of NADET. A predictive approach incorporating these five factors could significantly assist in discriminating between individuals with and without duodenal adenoma/carcinoma. Considering that the predictive accuracy for oesophageal squamous cell carcinoma (AUC, 0.673) was similar to that achieved using a health risk appraisal model based on drinking, smoking, dietary habits, and alcohol flushing (i.e. a surrogate marker for inactive ALDH2),15 the present model could be a useful assessment tool to prevent misdiagnosis of duodenal adenoma/carcinoma during endoscopy.
Among lifestyle-related factors, current smoking and absence of dyslipidaemia were associated with the presence of NADET. The positive association of smoking with NADET or small intestinal adenocarcinoma was demonstrated previously.16 In addition, Hung et al. reported that smoking was associated with overall survival in duodenal adenocarcinoma.17 The results of the present study confirmed that the presence of NADET was not positively associated with obesity-related factors, such as BMI, diabetes and dyslipidaemia. Sharaiha and colleagues also reported that BMI was not associated with the presence of a sporadic duodenal adenoma.18 In addition, recent evidence suggests that statins may have chemopreventive potential against various cancers, including colorectal and oesophageal adenocarcinomas.19,20 In the present study, as the presence of dyslipidaemia was largely determined by current use of a lipid-lowering agent, the negative association between dyslipidaemia and NADET might be due to the chemopreventive effect of statins.
According to the histological evaluation, all cases of D1 tumour showed submucosal or deeper invasion (>T1), and gastric type was significantly more frequent in D1 than in D2 in the discovery set. A study in Japan reported that all gastric-type adenomas were located in D1.21 As gastric-type duodenal adenocarcinoma has a poorer prognosis than intestinal type,22 early detection is essential, particularly for D1 tumours. Recently, Toya et al. also reported that gastric-type NADET was more frequently located in D1.23 In addition, 37.5% of gastric-type NADET were diagnosed as carcinoma, whereas 2.9% of intestinal-type NADET were diagnosed as carcinoma (p < 0.001). Lee et al. reported that 8 of 12 cancers (67%) found in D1 and 14 of 60 cancers (23%) in D2 were unresectable upon diagnosis.24 In our validation set, as well, the ratio of duodenal adenocarcinoma/adenoma was higher in D1 than in D2. Thus, NADET in D1 is highly progressive, and the fact that the presence of a D1 tumour could be accurately predicted using the RADA-5 is meaningful.
Our study demonstrated that 25% of patients with NADET had a history of malignant disease. Maruoka and colleagues also reported the frequent overlap of malignant diseases in other organs.25 These results indicate that certain systemic risk factors, such as heterozygous oncogenic germline mutations, might play an important role in the development of NADET. Consistent with the findings of previous reports,11,18 colorectal cancer was the most frequent malignant disease reported in the cancer history of patients with NADET. Importantly, the second most frequent malignant disease in patients with NADET was gastric cancer, in both the discovery and validation sets (see Supplementary Table 1). Considering the regional prevalence of gastric cancer, this frequency would be characteristic of Japan or East Asian countries. According to previous studies performed in Japan, H pylori infection is an independent risk factor for duodenal adenocarcinoma,16 and duodenal adenomas in patients with H pylori are more frequently located on the oral side of the ampulla of Vater than on its anal side.25 This finding is consistent with the present data showing that the prevalence of open-type gastric mucosal atrophy was 40.0% and 25.5% in patients with a D1 tumour and those without NADET, respectively, although the difference was not statistically significant owing to the limited sample size. In contrast, the presence of open-type gastric mucosal atrophy was negatively associated with the presence of a D2 tumour. This finding is similar to the positive association between FGP, a representative finding of H pylori-uninfected mucosa, and the presence of a D2 tumour but not of a D1 tumour. Taken together, these findings suggest that a D1 tumour, but not a D2 tumour, can develop from H pylori-related aetiologies.
There are no previous reports regarding the association between the presence of BO and FGP and the presence of NADET. These factors are strongly associated with the absence of H pylori infection, suggesting that H pylori-unrelated mechanisms could also contribute to the development of NADET. Notably, one patient had both oesophageal adenocarcinoma and NADET, although oesophageal adenocarcinoma is rare in Japan.26 This finding suggests that the mechanisms underlying the development of NADET and Barrett metaplasia/adenocarcinoma could be similar. Considering the aetiology of BO and oesophageal adenocarcinoma,27–29 aberrant acid and bile exposure might promote tumourigenesis in the duodenum. In D1 tumours, both H pylori-related and -unrelated aetiologies may play a role, similar to the circumstances of adenocarcinoma in the gastric cardia and the oesophagogastric junction.30,31
The present study had several limitations. Because age- and sex-matched analyses were performed, the causal association of NADET with age or sex could not be investigated. In addition, the retrospective study design did not permit accurate review of important clinical data, such as the presence or absence of H pylori infection, family history of malignant diseases and medication use. Despite data suggesting that the use of proton pump inhibitors affects the development of NADET, we could not obtain reliable information regarding this factor. Data of colonoscopy findings also was unavailable because most of the participants did not undergo the colonoscopy in our hospital. Finally, the study was conducted in a single institution in Japan. Larger studies including Western countries are warranted to confirm and further explore the associations identified in the present research.
In conclusion, we identified factors associated with the presence of duodenal adenoma/adenocarcinoma and constructed a predictive model (RADA-5). The model showed high accuracy particularly for a D1 tumour, which is rare but has a greater potential for invasion. The present results could be useful in the development of optimal strategies for the early detection of duodenal adenoma/carcinoma. In addition, considering the previous history or coexistence of other malignant diseases including colorectal and gastric cancer, systemic screening should be recommended for patients with NADET.
Supplemental Material
Supplemental Material for Clinical and endoscopic findings to assist the early detection of duodenal adenoma and adenocarcinoma by Juntaro Matsuzaki, Hidekazu Suzuki, Masayuki Shimoda, Hideki Mori, Seiichiro Fukuhara, Sawako Miyoshi, Tatsuhiro Masaoka, Yasushi Iwao, Yae Kanai and Takanori Kanai in United European Gastroenterology Journal
Acknowledgments
We thank Dr. Tsuyoshi Yamane and Dr. Masahiro Ueda for their support with data collection.
Declaration of conflicting interests
During the last two years, HS received scholarship funds from Daiichi-Sankyo, Co., Otsuka Pharmaceutical Co Ltd, Tsumura Co Ltd, and Tsumura Co to conduct the research. HS received service honoraria from Astellas Pharma Inc, AstraZeneca K.K., Daiichi-Sankyo, Co., Otsuka Pharmaceutical Co Ltd, Takeda Pharmaceutical Co Ltd, Tsumura Co., Mylan EPD Co, and Zeria Pharmaceutical Co Ltd. TK received scholarship funds from Astellas Pharma Inc, AstraZeneca K.K., Otsuka Pharmaceutical Co Ltd, Takeda Pharmaceutical Co Ltd, Eisai Pharmaceutical Co Ltd, Zeria Pharmaceutical Co Ltd, Tanabe Mitsubishi Pharmaceutical Co Ltd, JIMRO Co Ltd, and Kyorin Pharmaceutical Co Ltd to conduct the research. TK received service honoraria from Astellas Pharma Inc, Eisai Pharmaceutical Co Ltd, JIMRO Co Ltd, Tanabe Mitsubishi Pharmaceutical Co Ltd, Otsuka Pharmaceutical Co Ltd, Takeda Pharmaceutical Co Ltd, Miyarisan Pharmaceutical Co Ltd, and Zeria Pharmaceutical Co Ltd. The other authors have nothing to declare.
Ethics approval
The protocol for the study was performed in accordance with the Declaration of Helsinki, and approved by the ethics committee of Keio University School of Medicine (no. 20130502, 24 March 2014).
Funding
This work was supported by a Grant-in-Aid for Young Scientists B (26860527 to JM), a Grant-in-Aid for Scientific Research B (16H05291, to HS), a Grant-in-Aid for Scientific Research C (17K09471 to JM), and a Grant-in-Aid for Challenging Exploratory Research (26670065 to HS) from the Japan Society for the Promotion of Science, MEXT-Supported Program for the Strategic Research Foundation at Private Universities (S1411003 to HS), the Princess Takamatsu Cancer Research grants (to HS), a grant from Takeda Science Foundation (to JM), and Keio Gijuku Academic Development Funds (to JM and to HS). The sponsors had no roles in study design, data collection, data analysis, data interpretation, or writing of the report.
Informed consent
Because of the nonintrusive retrospective study design, the enrolment of participants without written informed consent was permitted in the present study protocol. Instead, we posted a notice on the website for opt-out to decline to participate.
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Supplementary Materials
Supplemental Material for Clinical and endoscopic findings to assist the early detection of duodenal adenoma and adenocarcinoma by Juntaro Matsuzaki, Hidekazu Suzuki, Masayuki Shimoda, Hideki Mori, Seiichiro Fukuhara, Sawako Miyoshi, Tatsuhiro Masaoka, Yasushi Iwao, Yae Kanai and Takanori Kanai in United European Gastroenterology Journal